Genetics and Molecular Biology

Our goal is to illustrate that Darwinian and autopoietic views of the organism are not as squarely opposed to each other as is often assumed. Indeed, we will argue that there is much common ground between them and that they can usefully supplement each other.

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also targets the apical polarity (...) protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

During the 1960s and 1970s population geneticists pushed beyond models of single genes to grapple with the effect on evolution of multiple genes associated by linkage. The resulting models of multiple interacting loci suggested that blocks of genes, maybe even entire chromosomes or the genome itself, should be treated as a unit. In this context, Richard Lewontin wrote his famous 1974 book The Genetic Basis of Evolutionary Change, which concludes with an argument for considering the entire genome as the unit (...) of selection as a result of linkage. Why did Lewontin and others devote so much intellectual energy to the “complications of linkage” in the 1960s and 1970s? We argue that this attention to linkage should be understood in the context of research on chromosomal inversions and co-adapted gene complexes that occupied mid-century evolutionary genetics. For Lewontin, the complications of linkage were an extension of this chromosomal focus expressed in the new language of models for linkage disequilibrium. (shrink)

En los últimos años, algunos autores han venido sosteniendo que la validez de la representación arborescente del patrón filético generado por la evolución está siendo menoscabada por el reconocimiento del impacto evolutivo que tendrían la transferencia genética horizontal, la simbiogénesis, la especiación por hibridación y la introgresión. Esa concepción o representación cladogenética de la evolución sólo nos dejaría ver un aspecto parcial de las relaciones de filiación que conectan a los diferentes linajes de seres vivos; ocultando otro aspecto cuya representación (...) más adecuada sería un reticulado de relaciones entre taxones. Con todo, aún sin poner en tela de juicio la frecuencia y la relevancia explicativa de dichos fenómenos, en este trabajo se intentará mostrar que su admisión y reconocimiento no tiene por qué ir en detrimento de esa concepción cladogenética de la evolución cuya relativización se está pregonando. Por el contrario, la comprensión y la representación de tales fenómenos supone dicha concepción. Palabras clave: Filogénesis, Especiación por hibridación, Introgresión, Simbiogénesis, TGH. (shrink)

The notion of biological function is fraught with difficulties—intrinsically and irremediably so, we argue. The physiological practice of functional ascription originates from a time when organisms were thought to be designed and remained largely unchanged since. In a secularized worldview, this creates a paradox which accounts of functions as selected effect attempt to resolve. This attempt, we argue, misses its target in physiology and it brings problems of its own. Instead, we propose that a better solution to the conundrum of (...) biological functions is to abandon the notion altogether, a prospect not only less daunting than it appears, but arguably the natural continuation of the naturalisation of biology. (shrink)

This study takes off from the ethical problem that racism grounded in population genetics raises. It is an analysis of four standard scientific responses to the problem of genetically motivated racism, seen in connection with the Human Genome Diversity Project (HGDP): (1) Discriminatory uses of scientific facts and arguments are in principle ‘misuses’ of scientific data that the researcher cannot be further responsible for. (2) In a strict scientific sense, genomic facts ‘disclaim racism’, which means that an epistemically correct grasp (...) of genomics should be ethically justified. (3) Ethical difficulties are issues to be ‘resolved’ by an ethics institution or committee, which will guarantee the ethical quality of the research scrutinized. (4) Although population genetics occasionally may lead to racism, its overall ‘value’ for humankind justifies its cause as a desirable pursuit. I argue that these typical responses to genetically motivated racism supervene on a principle called the ‘ethic of knowledge’, which implies that an epistemically correct account has intrinsic ethical value. This principle, and its logically related ideas concerning the ethic of science, effectively avoids a deeper ethical question of responsibility in science from being raised. (shrink)

How we ought to diagnose, categorise and respond to spectrum disabilities such as autism and Attention Deficit/Hyperactivity Disorder (ADHD) is a topic of lively debate. The heterogeneity associated with ADHD and autism is described as falling on various continua of behavioural, neural, and genetic difference. These continua are varyingly described either as extending into the general population, or as being continua within a given disorder demarcation. Moreover, the interrelationships of these continua are likewise often vague and subject to diverse interpretations. (...) -/- In this paper, I explore geneticists' and self-advocates’ perspectives concerning autism and ADHD as continua. These diagnoses are overwhelmingly analysed as falling on a continuum or continua of underlying traits, which supports the notion of “the neurodiversity spectrum”, i.e., a broader swath of human neural and behavioural diversity on which some concentrations of different functioning are diagnosed. I offer a taxonomy of conceptions of the genetic, phenotypic, and endophenotypic dimensionality within and beyond these diagnostic categories, and suggest that the spectrum of neurodiversity is characteristically endophenotypic. (shrink)

In 1976, the Genetics Society of America published a document entitled “Resolution of Genetics, Race, and Intelligence.” This document laid out the Society’s position in the IQ controversy, particularly that on scientific and ethical questions involving the genetics of intellectual differences between human populations. Since the GSA was the largest scientific society of geneticists in the world, many expected the document to be of central importance in settling the controversy. Unfortunately, the Resolution had surprisingly little influence on the discussion. In (...) 1979, William Provine analyzed the possible factors that decreased the impact of the Resolution, among them scientists’ limited understanding of the relationship between science and ethics. Through the analysis of unpublished versions of the Resolution and exchanges between GSA members, I will suggest that the limited impact of the statement likely depended on a shift in the aims of the GSA due to the controversies that surrounded the preparation of the document. Indeed, the demands of the membership made it progressively more impartial in both scientific and political terms, decreasing its potential significance for a wider audience. Notably, the troubled history of the Resolution raises the question of what can make effective or ineffective the communication between scientists and the public—a question with resonance in past and present discussions on topics of social importance. (shrink)

In this paper, we aim at rethinking the concept of obesity in a way that better captures the connection between underlying medical aspects, on the one hand, and an individual’s developmental history, on the other. Our proposal rests on the idea that obesity is not to be understood as a phenotypic trait or character; rather, obesity represents one of the many possible states of a more complex phenotypic trait that we call ‘energy metabolism.’ We argue that this apparently simple conceptual (...) shift can help solve important theoretical misconceptions regarding the genetics, epigenetics, and development of obesity. In addition, we show that our proposal can be fruitfully paired with the concept of developmental channeling of a trait, which connects to the study of the plasticity and canalization of complex traits. Finally, we discuss the potential impact of our approach on the assessment, treatment, and social narratives of obesity. (shrink)

In the half century since the formulation of the prokaryote : eukaryote dichotomy, many authors have proposed that the former evolved from something resembling the latter, in defiance of common (and possibly common sense) views. In such ‘eukaryotes first’ (EF) scenarios, the last universal common ancestor is imagined to have possessed significantly many of the complex characteristics of contemporary eukaryotes, as relics of an earlier ‘progenotic’ period or RNAworld. Bacteria and Archaea thus must have lost these complex features secondarily, through (...) ‘streamlining’. If the canonical three-domain tree in which Archaea and Eukarya are sisters is accepted, EF entails that Bacteria and Archaea are convergently prokaryotic.We ask what this means and how it might be tested. (shrink)

It is widely accepted that the way information transfers across networks depends importantly on the structure of the network. Here, we show that the mechanism of information transfer is crucial: in many respects the effect of the specific transfer mechanism swamps network effects. Results are demonstrated in terms of three different types of transfer mechanism: germs, genes, and memes. With an emphasis on the specific case of transfer between sub-networks, we explore both the dynamics of each of these across networks (...) and a measure of their comparative fitness. Germ and meme transfer exhibit very different dynamics across linked networks. For germs, measured in terms of time to total infection, network type rather than degree of linkage between sub-networks is the primary factor. For memes or belief transfer, measured in terms of time to consensus, it is the opposite: degree of linkage trumps network type in importance. The dynamics of genetic information transfer is unlike either germs or memes. Transfer of genetic information is robust across network differences to which both germs and memes prove sensitive. We also consider function: how well germ, gene, and meme transfer mechanisms can meet their respective objectives of infecting the population, mixing and transferring genetic information, and spreading a message. A shared formal measure of fitness is introduced for purposes of comparison, again with an emphasis on linked sub-networks. Meme transfer proves superior to transfer by genetic reproduction on that measure, with both memes and genes superior to infection dynamics across all networks types. What kinds of network structure optimize fitness also differ among the three. Both germs and genes show fairly stable fitness with added links between sub-networks, but genes show greater sensitivity to the structure of sub-networks at issue. Belief transfer, in contrast to the other two, shows a clear decline in fitness with increasingly connected networks. When it comes to understanding how information moves on networks, our results indicate that questions of information dynamics on networks cannot be answered in terms of networks alone. A primary role is played by the specific mechanism of information transfer at issue. We must first ask about how a particular type of information moves. (shrink)

This short paper comments on the connections between epigenetics, responsiveness and embodiment. Epigenetics has solidified a new conception of DNA as “responsive,” and rightfully so. Yet, the discussion too easily falls back to metaphors of agency and can show a tendency to see responsiveness and embodiment as based on epigenetics, which is shown to be wrong.

In their 1987 Nature publication, “Mitochondrial DNA and Human Evolution,” Rebecca Cann, Mark Stoneking, and Allan C. Wilson gave a new reconstruction of human evolution on the basis of differences in mitochondrial DNA among contemporary human populations. This phylogeny included an African common ancestor for all human mitochondrial DNA (mtDNA) lineages, and Cann et al.’s reconstruction became known as the “Out of Africa” hypothesis. Since mtDNA is inherited exclusively through the maternal line, the common ancestor who was first branded African (...) Eve later became known as Mitochondrial Eve (mtEve, for short). -/- In this paper, I show that mtEve was not a single, successful, or purely scientific discovery. Instead, she was produced many times and in many ways, each of which informed the next. Importantly, though Wilson and colleagues heralded mitochondrial DNA as a source of certainty, objectivity, and consensus for evolutionary inference, their productions of Mitochondrial Eve depended as much on popular assumptions about the certainty of maternal inheritance as they did on new molecular and computational tools. This recognition lets us reevaluate the complex consequences of these productions, which, like mtEve herself, could not be confined to a purely social, material, or scientific dimension. (shrink)

In the year 1714, Johann Christian Lange published a baroque textbook about a logic machine, supposed to simulate human cognitive abilities such as perception, judgement, and reasoning. From today’s perspective, it can be argued that this blueprint is based on an inference engine applied to a strict ontology which serves as a knowledge base. In this paper, I will first introduce Lange’s approach in the period of baroque logic and then present a diagrammatic modernization of Lange’s principles, entitled Calculus CL. (...) Finally, I would like to discuss the possibilities of how to apply CL to modern cases of concern by using an example from epidemiology. (shrink)

Review of William B Irvine's "You: A Natural History".

Eshel Ben-Jacob’s manuscript entitled ‘Bacterial wisdom, Gödel’s theorem and creative genomic webs’ summarizes decades of work demonstrating adaptive mutagenesis in bacterial genomes. Bacterial genomes, each an essential part of a Kantian whole that is a single bacterium, are thus not independent of the environment as sensed; and a single bacterium is therefore a semiotic entity. Ben-Jacob suggests this but errs in 1) assigning autonomy to the genome, and 2) analogizing through computation without making clear whether he is doing so for (...) illustrative purposes or making committed ontological propositions. We reinterpret adaptive mutagenesis and related phenomena in ways both metaphysically rigorous and revealing. We conclude that bacteria are much farther removed from the ‘self-organizing’ world of inanimate process than from the Peircian world of signs; and a critical reappraisal of existing knowledge can enhance our understanding of selfhood, semiosis, and the roots of subjective experience. (shrink)

In 1926, Haldane published an essay titled 'On Being the Right Size' in which he argued that the structure, function, and behavior of an organism are strongly conditioned by the physical forces that exert the greatest impact at the scale at which it exists. This chapter puts Haldane’s insight to work in the context of contemporary cell and molecular biology. Owing to their minuscule size, cells and molecules are subject to very different forces than macroscopic organisms. In a sense, macroscopic (...) and microscopic entities inhabit different “worlds”: the former is ruled by gravity and inertia, whereas the latter is governed by Brownian motion. One implication is that we should be extremely skeptical of models and analogies that seek to explain properties of microscopic entities by appealing to properties of macroscopic ones. Unfortunately, this is precisely what the appeal to engineering metaphors in molecular biology attempts to do. Molecular biologists routinely resort to such metaphors because they are familiar and intuitively intelligible. But if our machines were the size of molecules it would be impossible for them to function the way they do. It follows that we should avoid distorting biological reality by construing it in engineering terms. In this chapter I examine four key metaphors in molecular biology – “genetic program,” “cellular circuitry,” “molecular machine,” and “molecular motor” – and I argue that their deficiencies derive from their neglect of scale. I also try to explain why many biologists today appear to have forgotten the importance of scale that Haldane drew attention to in his essay. I suggest that the reason has to do with the influence of Schrödinger’s argument in 'What is Life?' regarding the stability of the gene. (shrink)

This Element presents a philosophical exploration of the concept of the 'model organism' in contemporary biology. Thinking about model organisms enables us to examine how living organisms have been brought into the laboratory and used to gain a better understanding of biology, and to explore the research practices, commitments, and norms underlying this understanding. We contend that model organisms are key components of a distinctive way of doing research. We focus on what makes model organisms an important type of model, (...) and how the use of these models has shaped biological knowledge, including how model organisms represent, how they are used as tools for intervention, and how the representational commitments linked to their use as models affect the research practices associated with them. This title is available as Open Access on Cambridge Core. (shrink)

CONTENT 1. Misconceptions of Darwin's Theory of Evolution 2. Darwinism against Essentialism and the Concept of Species 3. Function and Biological Explanation 4. The Gene 목차 1. 다윈의 진화론에 대한 오해들 2. 본질주의에 대한 진화론의 반대와 종(Species)의 개념 3. 기능(function)과 생명과학적 설명 4. 유전자 맺음말.

죽고 다시 태어나는 반복의 과정을 논하는 불교의 윤회설은 끊임없이 변화하는 생명현상의 본래 모습을 그대로 보여준다. 어느 생명체도 변하지 않고 영구한 것은 없다. 오래된 개체의 삶이 끝나고 새로운 삶이 시작되는 반복의 자연현상이 윤회이다. 본고는 윤회를 생명과학적으로 해석하며 삼라만상에서 일어나는 윤회란 개체들뿐만 아니라 세포와 분자선상에서도 일어나는 자연스런 생명현상임을 밝히겠다.

This dissertation proposes a new working model of reductionism for biology and a new concept of the gene based on the new reduction model. My project aims to help biologists and philosophers understand what reductionism in biology really is, or, should be. Historical debates about reductionism testify us that the classical reduction model, i.e., Ernest Nagel's bridge-law model, offers us neither an appropriate ontological reductionism nor a reductive explanation about biological phenomena. Casting doubts on the received view of the layered (...) hierarchical model of ontology, I suggest that many interesting biological properties be construed as second-order functional properties and their first-order realizers. Providing for reduction finely-analyzed biological properties, I offer a new model for reductionism in biology - localized functional reductionism - which evolved from Jaegwon Kim's view of reductionism presented for the problems of mental causation. My localized functional reductionism shows that a localized functional property is reduced to its base/structural property. I emphasize that researchers in biology do not deal with abstract general properties but always localized, structure-specific biological properties. A localized functional property and the structure-specific biological property as its base property are what we are interested in and this is what makes biological properties appropriate for research and meaningful for philosophical discussion. The localized functional reduction model, which is actually a case of token reduction model, integrates the fine-grained ontological hierarchies of both macro/micro-levels and higher/lower-orders, and it also synthesizes functional reductionism and token identity thesis. In my localized functional reductionism, functional biological properties are not eliminated but they exist with their own causal powers and true explanatory powers. I also argue that the gene, construed as a second-order functional property, must be understood as gene expression network-specific. The gene, when it is realized on a given occasion, is reduced to, and is identical with, one of its genomic realizers on the given occasion, that is, the gene expression network. A new dynamic approach to the concept of the gene as the gene expression network vindicates reductionism. (shrink)

The theory of concepts advanced in the dissertation aims at accounting for a) how a concept makes successful practice possible, and b) how a scientific concept can be subject to rational change in the course of history. Traditional accounts in the philosophy of science have usually studied concepts in terms only of their reference; their concern is to establish a stability of reference in order to address the incommensurability problem. My discussion, in contrast, suggests that each scientific concept consists of (...) three components of content: 1) reference, 2) inferential role, and 3) the epistemic goal pursued with the concept's use. I argue that in the course of history a concept can change in any of these three components, and that change in one component—including change of reference—can be accounted for as being rational relative to other components, in particular a concept's epistemic goal.This semantic framework is applied to two cases from the history of biology: the homology concept as used in 19th and 20th century biology, and the gene concept as used in different parts of the 20th century. The homology case study argues that the advent of Darwinian evolutionary theory, despite introducing a new definition of homology, did not bring about a new homology concept (distinct from the pre-Darwinian concept) in the 19th century. Nowadays, however, distinct homology concepts are used in systematics/evolutionary biology, in evolutionary developmental biology, and in molecular biology. The emergence of these different homology concepts is explained as occurring in a rational fashion. The gene case study argues that conceptual progress occurred with the transition from the classical to the molecular gene concept, despite a change in reference. In the last two decades, change occurred internal to the molecular gene concept, so that nowadays this concept's usage and reference varies from context to context. I argue that this situation emerged rationally and that the current variation in usage and reference is conducive to biological practice.The dissertation uses ideas and methodological tools from the philosophy of mind and language, the philosophy of science, the history of science, and the psychology of concepts. (shrink)

Contemporary biological research has suggested that some host–microbiome multispecies systems (referred to as “holobionts”) can in certain circumstances evolve as unique biological individual, thus being a unit of selection in evolution. If this is so, then it is arguably the case that some biological adaptations have evolved at the level of the multispecies system, what we call hologenomic adaptations. However, no research has yet been devoted to investigating their nature, or how these adaptations can be distinguished from adaptations at the (...) species-level (genomic adaptations). In this paper, we cover this gap by investigating the nature of hologenomic adaptations. By drawing on the case of the evolution of sanguivory diet in vampire bats, we argue that a trait constitutes a hologenomic adaptation when its evolution can only be explained if the holobiont is considered the biological individual that manifests this adaptation, while the bacterial taxa that bear the trait are only opportunistic beneficiaries of it. We then use the philosophical notions of emergence and inter-identity to explain the nature of this form of individuality and argue why it is special of holobionts. Overall, our paper illustrates how the use of philosophical concepts can illuminate scientific discussions, in the trend of what has recently been called metaphysics of biology. (shrink)

The subject of this edited volume is the idea of levels of organization: roughly, the idea that the natural world is segregated into part-whole relationships of increasing spatiotemporal scale and complexity. The book comprises a collection of essays that raise the idea of levels into its own topic of analysis. Owing to the wide prominence of the idea of levels, the scope of the volume is aimed at theoreticians, philosophers, and practicing researchers of all stripes in the life sciences. The (...) volume’s contributions reflect this diversity, and draw from fields such as developmental biology, evolutionary biology, molecular biology, ecology, cell biology, and neuroscience. The book presents wide-ranging novel insights on causation and levels, the hierarchical structure of evolution, the role of levels in biological theory, and more. (shrink)

This book is divided in two parts, the first of which shows how, beyond paleontology and systematics, macroevolutionary theories apply key insights from ecology and biogeography, developmental biology, biophysics, molecular phylogenetics, and even the sociocultural sciences to explain evolution in deep time. In the second part, the phenomenon of macroevolution is examined with the help of real life-history case studies on the evolution of eukaryotic sex, the formation of anatomical form and body-plans, extinction and speciation events of marine invertebrates, hominin (...) evolution and species conservation ethics. The book brings together leading experts, who explain pivotal concepts such as Punctuated Equilibria, Stasis, Developmental Constraints, Adaptive Radiations, Habitat Tracking, Turnovers, (Mass) Extinctions, Species Sorting, Major Transitions, Trends, and Hierarchies – key premises that allow macroevolutionary epistemic frameworks to transcend microevolutionary theories that focus on genetic variation, selection, migration and fitness. Along the way, the contributing authors review ongoing debates and current scientific challenges; detail new and fascinating scientific tools and techniques that allow us to cross the classic borders between disciplines; demonstrate how their theories make it possible to extend the Modern Synthesis; present guidelines on how the macroevolutionary field could be further developed; and provide a rich view of just how it was that life evolved across time and space. In short, this book is a must-read for active scholars and, because the technical aspects are fully explained, it is also accessible for non-specialists. Understanding evolution requires a solid grasp of above-population phenomena. Species are real biological individuals, and abiotic factors impact the future course of evolution. Beyond observation, when the explanation of macroevolution is the goal, we need both evidence and theory that enable us to explain and interpret how life evolves at the grand scale. (shrink)

Biologists are nearing the creation of the first fully synthetic eukaryotic genome. Does this mean that we still soon be able to create genomes that are parts of an existing genetic lineage? If so, it might be possible to bring back extinct species. But do genomes that are synthetically assembled, no matter how similar they are to native genomes, really belong to the genetic lineage on which they were modelled? This article will argue that they are situated within the same (...) genetic lineage. To see why requires closely examining whether material overlap between parents and offspring is a necessary feature of biological reproduction. The processes used to create synthetic genomes shows that these processes are a form of scaffolded reproduction because they use external machinery and take ownership of the material parts used to create synthetic genomes. Closely examining these processes also reveals, surprisingly, that ‘synthetic reproduction’ can take place between entities that don’t participate in the same biological lineages. 1Introduction2The Argument for Lineage-less Genomes3Synthetic Eukaryotic Chromosomes and Material Overlap4Biological Reproduction, Material, and Information5Synthetic Reproductive Processes and Their Implications. (shrink)

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non-secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep-wake cycle shares some common mechanisms with these disorders. Here we review (...) recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca2+-dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization balance in psychiatric and neurodevelopmental disorders. How animals implement sleep homeostasis is a great mystery. Here, we review recent studies with highlighting the hypothesis that the slow Ca2+-dependent hyperpolarization pathway regulates sleep homeostasis via modifying the fast pathway; the activity of CaMKIIα/β increases during wakefulness, which triggers sleep by phosphorylating the components in the fast pathway. (shrink)

The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons (...) in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. (shrink)

Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in (...) vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. Cellular microenvironment can regularly change, hence the need for a dynamic modulation of transcriptional programs by the epigenome. In the current review, we highlight novel emerging aspects of epigenetic memory controlled by PcG proteins and the evolution of specialized functions to convey plasticity and adaptability to environmental changes. (shrink)

Messenger RNA is a flexible tool box that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. Our understanding about the landscape of RNA modifications is still rudimentary in contrast to DNA and histone modifications. The major obstacle has been the lack of sensitive detection methods since they are (...) non-editing events. However, with the advent of next-generation sequencing techniques, RNA modifications are being identified precisely at single nucleotide resolution. In recent years, methylation at the N6 position of adenine has gained the attention of RNA biologists. The m6A modification has a set of writers, erasers, and readers. Here, we provide a summary of interesting facts, conflicting findings, and recent advances in the technical and functional aspects of the m6A epitranscriptome. The recent outburst of studies has brought the key role of mRNA N6-methyladenosine modification in post-transcriptional processing steps into the limelight. This review summarizes the current progress and the future prospective of m6A methylome. We addressed the debatable function of m6A modification and related modifiers in tumorigenesis and tumor progression. (shrink)

In the last few years, biologists and computer scientists have claimed that the introduction of data science techniques in molecular biology has changed the characteristics and the aims of typical outputs (i.e. models) of such a discipline. In this paper we will critically examine this claim. First, we identify the received view on models and their aims in molecular biology. Models in molecular biology are mechanistic and explanatory. Next, we identify the scope and aims of data science (machine learning in (...) particular). These lie mainly in the creation of predictive models which performances increase as data set increases. Next, we will identify a tradeoff between predictive and explanatory performances by comparing the features of mechanistic and predictive models. Finally, we show how this a priori analysis of machine learning and mechanistic research applies to actual biological practice. This will be done by analyzing the publications of a consortium—The Cancer Genome Atlas—which stands at the forefront in integrating data science and molecular biology. The result will be that biologists have to deal with the tradeoff between explaining and predicting that we have identified, and hence the explanatory force of the ‘new’ biology is substantially diminished if compared to the ‘old’ biology. However, this aspect also emphasizes the existence of other research goals which make predictive force independent from explanation. (shrink)

Definition of the problem: The ELSI (Ethical, Legal, and Social Issues) program of the Human Genome Project is the biggest bioethical research project to date. However, it has met with fairly critical reception. Arguments: ELSI is nevertheless an important element in current bioethics. We can learn not just from the results and methodology of the numerous studies that received ELSI funding, but also by looking at the pros and cons of its close institutional integration into the Human Genome Project. Finally, (...) excellent didactic resources have been developed, providing helpful tools for the improvement of medical ethics teaching. Conclusion: A critical analysis of the ELSI program can be instrumental in developing new perspectives in medical ethics. (shrink)

The proteasome family of proteases comprises oligomeric assemblies of very different symmetry. In different sizes, it features ring‐like oligomers with dihedral symmetry that allow the stacking of further rings of regulatory subunits as observed in the modular proteasome system, but also less symmetric helical assemblies. Comprehensive sequence and structural analyses of proteasome homologs reveal a parsimonious scenario of how symmetry may have emerged from a monomeric ancestral precursor and how it may have evolved throughout the proteasome family. The four characterized (...) representatives—ancestral β subunit (Anbu), HslV, betaproteobacterial proteasome homolog (BPH), and the 20S proteasome—are outlasting cornerstones in the family's evolutionary history, each marking a transition in symmetry. This article contextualizes the evolutionary and functional key aspects of these symmetry transitions, explaining how they facilitated the diversification and concurrent evolution of independent proteolytic systems side by side, each with its customized network of auxiliary interactors. -/- . (shrink)

In sexual organisms, haploid gametes are produced from diploid germ cells through meiosis. Chromosome reassortment and recombination generate ample genetic variation, augmented by newly arising mutations. Meiotic mutations are associated with recombination, initiated by DNA breakage, and may lead to faster evolution and sequence heterogeneity around recombination hotspots. More details can be found in the Review article 1800235 by Ayelet Arbel‐Eden and Giora Simchen, Elevated Mutagenicity in Meiosis and Its Mechanism, DOI: 10.1002/bies.201970041.

Diploid germ cells produce haploid gametes through meiosis, a unique type of cell division. Independent reassortment of parental chromosomes and their recombination leads to ample genetic variability among the gametes. Importantly, new mutations also occur during meiosis, at frequencies much higher than during the mitotic cell cycles. These meiotic mutations are associated with genetic recombination and depend on double‐strand breaks (DSBs) that initiate crossing over. Indeed, sequence variation among related strains is greater around recombination hotspots than elsewhere in the genome, (...) presumably resulting from recombination‐associated mutations. Significantly, enhanced mutagenicity in meiosis may lead to faster divergence during evolution, as germ‐line mutations are the ones that are transmitted to the progeny and thus have an evolutionary impact. The molecular basis for mutagenicity in meiosis may be related to the repair of meiotic DSBs by polymerases, or to the exposure of single‐strand DNA to mutagenic agents during its repair. (shrink)

The fate of cellular RNAs is largely dependent on their structural conformation, which determines the assembly of ribonucleoprotein (RNP) complexes. Consequently, RNA‐binding proteins (RBPs) play a pivotal role in the lifespan of RNAs. The advent of highly sensitive in cellulo approaches for studying RNPs reveals the presence of unprecedented RNA‐binding domains (RBDs). Likewise, the diversity of the RNA targets associated with a given RBP increases the code of RNA–protein interactions. Increasing evidence highlights the biological relevance of RNA conformation for recognition (...) by specific RBPs and how this mutual interaction affects translation control. In particular, noncanonical RBDs present in proteins such as Gemin5, Roquin‐1, Staufen, and eIF3 eventually determine translation of selective targets. Collectively, recent studies on RBPs interacting with RNA in a structure‐dependent manner unveil new pathways for gene expression regulation, reinforcing the pivotal role of RNP complexes in genome decoding. (shrink)

Short (“seed”) or extended base pairing between microRNAs (miRNAs) and their target RNAs enables post‐transcriptional silencing in many organisms. These interactions allow the computational prediction of potential targets. In model organisms, predicted targets are frequently validated experimentally; hence meaningful miRNA‐regulated processes are reported. However, in non‐models, these reports mostly rely on computational prediction alone. Many times, further bioinformatic analyses such as Gene Ontology (GO) enrichment are based on these in silico projections. Here such approaches are reviewed, their caveats are highlighted (...) and the ease of picking false targets from predicted lists is demonstrated. Discoveries that shed new light on how miRNAs evolved to regulate targets in various phyletic groups are discussed, in addition to the pitfalls of target identification in non‐model organisms. The goal is to prevent the misuse of bioinformatic tools, as they cannot bypass the biological understanding of miRNA–target regulation. (shrink)

No cure yet exists for devastating Alzheimer's disease (AD), despite many years and humongous efforts to find efficacious pharmacological treatments. So far, neither designing drugs to disaggregate amyloid plaques nor tackling solely inflammation turned out to be decisive. Mesenchymal stem cells (MSCs) and, in particular, extracellular vesicles (EVs) originating from them could be proposed as an alternative, strategic approach to attack the pathology. Indeed, MSC‐EVs—owing to their ability to deliver lipids/proteins/enzymes/microRNAs endowed with anti‐inflammatory, amyloid‐β degrading, and neurotrophic activities—may be exploited (...) as therapeutic tools to restore synaptic function, prevent neuronal death, and slow down memory impairment in AD. Herein the results presented in the most recently published studies on this topic are critically evaluated, providing a strong rationale for possible employment of MSC‐EVs in AD. (shrink)