Molecular Biology, Misc

Model organisms, the use of green fluorescent proteins, and orthogonal transfer RNA are examples of artificial causes being used in biology. Recent work characterizing the research interests of biologists in terms of a common set of values has ruled out artificial causes as biologically interesting. For instance, Kenneth Waters argues that biologists are primarily interested in causes that actually obtain. Similarly, Marcel Weber argues that biologists are primarily concerned with biologically normal interventions. Both views express a widely received attitude about (...) the interests and goals of biologists as being primarily concerned with the contingent facts of our world. While I agree with this general attitude about the contingent nature of biology, I argue that neither view fully accounts for the diversity that distinguishes the discipline. Along with actual and biologically normal causes, biologists are also interested in artificial causes for technological and observational purposes. I maintain that research interest in artificial causes provides some pragmatic reasons for thinking that research programs in cellular biology aren’t driven by a common core set of values. (shrink)

Several authors have used the notion of causal specificity in order to defend non-parity about genetic causes (Waters 2007, Woodward 2010, Weber 2017, forthcoming). Non-parity in this context is the idea that DNA and some other biomolecules that are often described as information-bearers by biologists play a unique role in life processes, an idea that has been challenged by Developmental Systems Theory (e.g., Oyama 2000). Indeed, it has proven to be quite difficult to state clearly what the alleged special role (...) of genetic causes consists in. In this paper, I show that the set of biomolecules that are normally considered to be information-bearers (DNA, mRNA) can be shown to be the most specific causes of protein primary structure, provided that causal specificity is measured over a relevant space of biological possibilities, disregarding physical as well as logically possible states of the causal variables. (shrink)

Abstraction and idealization are the two notions that are most often discussed in the context of assumptions employed in the process of model building. These notions are also routinely used in philosophical debates such as that on the mechanistic account of explanation. Indeed, an objection to the mechanistic account has recently been formulated precisely on these grounds: mechanists cannot account for the common practice of idealizing difference-making factors in models in molecular biology. In this paper I revisit the debate and (...) I argue that the objection does not stand up to scrutiny. This is because it is riddled with a number of conceptual inconsistencies. By attempting to resolve the tensions, I also draw several general lessons regarding the difficulties of applying abstraction and idealization in scientific practice. Finally, I argue that more care is needed only when speaking of abstraction and idealization in a context in which these concepts play an important role in an argument, such as that on mechanistic explanation. (shrink)

There is no denying the Central Dogma’s impact on the biological sciences. Since the Dogma’s formulation by Francis Crick in 1958, however, many have debated the Dogma’s empirical adequacy. My aim is to move beyond these discussions, and instead consider the Central Dogma’s significance to contemporary biological practice. To do this, I consider four distinct approaches for determining the non-descriptive methodological significance of a scientific principle. I argue that these approaches fail to vindicate the Central Dogma, and that, under many (...) of these approaches, the Dogma amounts to a triviality. (shrink)

This essay considers how scholarly approaches to the development of molecular biology have too often narrowed the historical aperture to genes, overlooking the ways in which other objects and processes contributed to the molecularization of life. From structural and dynamic studies of biomolecules to cellular membranes and organelles to metabolism and nutrition, new work by historians, philosophers, and STS scholars of the life sciences has revitalized older issues, such as the relationship of life to matter, or of physicochemical inquiries to (...) biology. This scholarship points to a novel molecular vista that opens up a pluralist view of molecularizations in the twentieth century and considers their relevance to current science. (shrink)

In the last two decades few topics in philosophy of science have received as much attention as mechanistic explanation. A significant motivation for these accounts is that scientists frequently use the term “mechanism” in their explanations of biological phenomena. While scientists appeal to a variety of causal concepts in their explanations, many philosophers argue or assume that all of these concepts are well understood with the single notion of mechanism. This reveals a significant problem with mainstream mechanistic accounts– although philosophers (...) use the term “mechanism” interchangeably with other causal concepts, this is not something that scientists always do. This paper analyses two causal concepts in biology–the notions of “mechanism” and “pathway”–and how they figure in biological explanation. I argue that these concepts have unique features, that they are associated with distinct strategies of causal investigation, and that they figure in importantly different types of explanation. (shrink)

This article examines how minimal genome research mobilizes philosophical concepts such as minimality and essentiality. Following a historical approach the article aims to uncover what function this terminology plays and which problems are raised by them. Specifically, four historical moments are examined, linked to the work of Harold J. Morowitz, Mitsuhiro Itaya, Eugene Koonin and Arcady Mushegian, and J. Craig Venter. What this survey shows is a historical shift away from historical questions about life or descriptive questions about specific organisms (...) towards questions that explore biological possibilities: what are possible forms of minimal genomes, regardless of whether they exist in nature? Moreover, it highlights a fundamental ambiguity at work in minimal genome research between a universality claim and a standardization claim: does a minimal genome refer to the minimal gene set for any organism whatsoever? Or does it refer rather to a gene set that will provide stable, robust and predictable behaviour, suited for biotechnological applications? Two diagnoses are proposed for this ambiguity: a philosophical diagnosis of how minimal genome research either misunderstands the ontology of biological entities or philosophically misarticulates scientific practice. Secondly, a historical diagnosis that suggests that this ambiguity is part of a broader shift towards technoscience. (shrink)

The Central Dogma of molecular biology, which holds that DNA makes protein and not the other way around, is as influential as it is controversial. Some believe the Dogma has outlived its usefulness, either because it fails to fully capture the ins-and-outs of protein synthesis (Griffiths and Stotz, 2013; Stotz, 2006), because it turns on a confused notion of information (Sarkar, 2004), or because it problematically assumes the unidirectional flow of information from DNA to protein (Gottlieb, 2001). This paper evaluates (...) an underexplored defense of the Dogma, which relies on the assumption that the Dogma and the Inheritance of Acquired Traits, a principle which dates as far back as Jean Baptiste-Lamarck, are incompatible principles (Smith, 1993; Judson, 1979; Dawkins, 1970; Cobb, 2017; Wilkins, 2002; Graur, 2018). By appealing to empirical evidence in molecular science, I argue that this apparent incompatibility is indeed merely apparent. I conclude by briefly demonstrating how these considerations bear on the topic of conceptual pluralism in the philosophy of science (Stencel and Proszewska, 2018; Lu and Bourrat, 2018). (shrink)

Biological order provided by α-helical secondary protein structures is an important resource exploitable by living organisms for increasing the efficiency of energy transport. In particular, self-trapping of amide I energy quanta by the induced phonon deformation of the hydrogen-bonded lattice of peptide groups is capable of generating either pinned or moving solitary waves following the Davydov quasiparticle/soliton model. The effect of applied in-phase Gaussian pulses of amide I energy, however, was found to be strongly dependent on the site of application. (...) Moving solitons were only launched when the amide I energy was applied at one of the α-helix ends, whereas pinned solitons were produced in the α-helix interior. In this paper, we describe a general mechanism that launches moving solitons in the interior of the α-helix through phase-modulated Gaussian pulses of amide I energy. We also compare the predicted soliton velocity based on effective soliton mass and the observed soliton velocity in computer simulations for different parameter values of the isotropy of the exciton-phonon interaction. The presented results demonstrate the capacity for explicit control of soliton velocity in protein α-helices, and further support the plausibility of gradual optimization of quantum dynamics for achieving specialized protein functions through natural selection. (shrink)

The essential biological processes that sustain life are catalyzed by protein nano-engines, which maintain living systems in far-from-equilibrium ordered states. To investigate energetic processes in proteins, we have analyzed the system of generalized Davydov equations that govern the quantum dynamics of multiple amide I exciton quanta propagating along the hydrogen-bonded peptide groups in α-helices. Computational simulations have confirmed the generation of moving Davydov solitons by applied pulses of amide I energy for protein α-helices of varying length. The stability and mobility (...) of these solitons depended on the uniformity of dipole-dipole coupling between amide I oscillators, and the isotropy of the exciton-phonon interaction. Davydov solitons were also able to quantum tunnel through massive barriers, or to quantum interfere at collision sites. The results presented here support a nontrivial role of quantum effects in biological systems that lies beyond the mechanistic support of covalent bonds as binding agents of macromolecular structures. Quantum tunneling and interference of Davydov solitons provide catalytically active macromolecular protein complexes with a physical mechanism allowing highly efficient transport, delivery, and utilization of free energy, besides the evolutionary mandate of biological order that supports the existence of such genuine quantum phenomena, and may indeed demarcate the quantum boundaries of life. (shrink)

Binding specificity is a centrally important concept in molecular biology, yet it has received little philosophical attention. Here I aim to remedy this by analyzing binding specificity as a causal property. I focus on the concept’s role in drug design, where it is highly prized and hence directly studied. From a causal perspective, understanding why binding specificity is a valuable property of drugs contributes to an understanding of causal selection—of how and why scientists distinguish between causes, not just causes from (...) noncauses. In particular, the specificity of drugs is precisely what underwrites their value as experimental interventions on biological processes. (shrink)

Mechanistic explanations are often said to explain because they reveal the causal structure of the world. Conversely, dynamical models supposedly lack explanatory power because they do not describe causal structure. The only way for dynamical models to produce causal explanations is via the 3M criterion: the model must be mapped onto a mechanism. This framing of the situation has become the received view around the viability of dynamical explanation. In this paper, I argue against this position and show that dynamical (...) models can themselves reveal causal structure and consequently produce nonmechanistic, dynamical explanations. Taking the example of cell fates from systems biology, I show how dynamical models, and specifically the attractor landscapes they describe, identify the causes of cell differentiation and explain why cells select particular fates. These dynamical features of the system better fit Woodward’s (2010, 2018) criteria of specificity and proportionality and make them the best candidate causes of cell fates than mechanisms. I also show how these causes are irreducible and inaccessible to mechanistic models, making 3M unworkable and counterproductive in this case. Dynamical models can reveal dynamical causes and thereby provide causal explanations. (shrink)

Machine learning (ML) has been praised as a tool that can advance science and knowledge in radical ways. However, it is not clear exactly how radical are the novelties that ML generates. In this article, I argue that this question can only be answered contextually, because outputs generated by ML have to be evaluated on the basis of the theory of the science to which ML is applied. In particular, I analyze the problem of novelty of ML outputs in the (...) context of molecular biology. In order to do this, I first clarify the nature of the models generated by ML. Next, I distinguish three ways in which a model can be novel (from the weakest to the strongest). Third, I dissect the way ML algorithms work and generate models in molecular biology and genomics. On these bases, I argue that ML is either a tool to identify instances of knowledge already present and codified, or to generate models that are novel in a weak sense. The notable contribution of ML to scientific discovery in the context of biology is that it can aid humans in overcoming potential bias by exploring more systematically the space of possible hypotheses implied by a theory. (shrink)

Philosophy of immunology is a subfield of philosophy of biology dealing with ontological and epistemological issues related to the studies of the immune system. While speculative investigations and abstract analyses have always been part of immune theorizing, until recently philosophers have largely ignored immunology. Yet the implications for understanding the philosophical basis of organismal functions framed by immunity offer new perspectives on fundamental questions of biology and medicine. Developed in the context of history of medicine, theoretical biology, and medical anthropology, (...) philosophy of immunology differs from these related branches of study in its focus on traditional philosophical questions concerning identity, individuality, ecology, cognition, scientific methodology and theory construction. This broad agenda derives from immunology’s multifaceted research program that has developed from its initial clinical challenges of host defense, transplantation, autoimmunity, tumor immunology, and allergy. In addition to these well-established research areas, immunity is now understood to play a central role in other physiological functions, development, ecology, and evolutionary mechanics. Holding together these diverse domains of inquiry lie philosophical commitments oriented by organismal identity. In this regard, pertinent issues are raised concerning cognition (organization of immune perception and information processing), the character of individuality (framed by the ecological context of immune-mediated assimilation and rejection), and the dynamics of complex systems (understood as holistic systems biology). Indeed, immunology, in the context of cognitive science, evolutionary biology, environmental sciences, and development provides multi-focal perspectives for philosophy of science. (shrink)

In this paper I aim to defend a twofold thesis. On one hand, I will sup-port, against Perini [7], the indispensability of diagrams when structurally complex biomolecules are concerned, since it is not possible to satisfactorily use linguistic-sentential representations at that domain. On the other hand, even when diagrams are dispensable I will defend than they will generally be more effective than other representations in encoding biomolecular knowledge, relying on Kulvicki-Shimojima’s diagrammatic effectiveness thesis. Finally, I will ground many epistemic virtues (...) of biomolecular diagrams (understandability, explanatory power, prediction and hypothesis evaluation) on their cognitive-computational indispensability and their semantic-epistemic effectiveness. (shrink)

As technology advances, the demand for innovative instructional materials also increases. As a result, the Department of Education urges teachers to develop instructional materials. This study was conducted at Bulusan National High School, Bulusan, Sorsogon, Philippines SY 2018-2019 which was aimed to develop gamified instructional materials in genetics that would aid in teaching and learning process of grade 12 STEM students. The developed gamified materials were collectively called the GIM in Genetics which is comprised of two parts; namely, Student’s Portfolio (...) and Gamified Lesson Plans. The GIM was anchored on the Teacher’s Guide provided by DepEd. Further, it utilized different game elements, to wit: game mechanics, badges, power cards, scoring system, levels, and leaderboards to deliver innovative teaching strategy and quality education. This paper suggests the development of various innovative teaching strategies and instructional materials as well as its utilization across different fields and subject areas. (shrink)

Jacques Monod (1971) argued that certain molecular processes rely critically on the property of chemical arbitrariness, which he claimed allows those processes to “transcend the laws of chemistry”. It seems natural, as some philosophers have done, to interpret this in modal terms: a biological relationship is chemically arbitrary if it is possible, within the constraints of chemical “law”, for that relationship to have been otherwise than it is. But while modality is certainly important for understanding chemical arbitrariness, understanding its biological (...) role also requires an account of the concrete causal-functional features that distinguish arbitrary from non-arbitrary phenomena. In this paper I elaborate on this under-emphasised aspect by offering a general account of these features: arbitrary relations are instantiated by mechanisms that involve molecular adapters, which causally couple two properties or processes which would otherwise be uncorrelated. Additionally, adapters work by acting as intermediate rather than cooperating causes. (shrink)

For decades, myxobacteria have been spotlighted as exemplars of social “wolf‐pack” predation, communally secreting antimicrobial substances into the shared public milieu. This behavior has been described as cooperative, becoming more efficient if performed by more cells. However, laboratory evidence for cooperativity is limited and of little relevance to predation in a natural setting. In contrast, there is accumulating evidence for predatory mechanisms promoting “selfish” behavior during predation, which together with conflicting definitions of cooperativity, casts doubt on whether microbial “wolf‐pack” predation (...) really is cooperative. Here, it is hypothesized that public‐goods‐mediated predation is not cooperative, and it is argued that a holistic model of microbial predation is needed, accounting for predator and prey relatedness, social phenotypes, spatial organization, activity/specificity/transport of secreted toxins, and prey resistance mechanisms. Filling such gaps in our knowledge is vital if the evolutionary benefits of potentially costly microbial behaviors mediated by public goods are to be properly understood. (shrink)

The applications of machine learning and deep learning to the natural sciences has fostered the idea that the automated nature of algorithmic analysis will gradually dispense human beings from scientific work. In this paper, I will show that this view is problematic, at least when ML is applied to biology. In particular, I will claim that ML is not independent of human beings and cannot form the basis of automated science. Computer scientists conceive their work as being a case of (...) Aristotle’s poiesis perfected by techne, which can be reduced to a number of straightforward rules and technical knowledge. I will show a number of concrete cases where at each level of computational analysis, more is required to ML than just poiesis and techne, and that the work of ML practitioners in biology needs also the cultivation of something analogous to phronesis, which cannot be automated. But even if we knew how to frame phronesis into rules, still this virtue is deeply entrenched in our biological constitution, which computers lack. Whether computers can fully perform scientific practice independently of humans is an ill-posed question. (shrink)

Different cell lineages growing in microgravity undergo a spontaneous transition leading to the emergence of two distinct phenotypes. By returning these populations in a normal gravitational field, the two phenotypes collapse, recovering their original configuration. In this review, we hypothesize that, once the gravitational constraint is removed, the system freely explores its phenotypic space, while, when in a gravitational field, cells are “constrained” to adopt only one favored configuration. We suggest that the genome allows for a wide range of “possibilities” (...) but it is unable per se to choose among them: the emergence of a specific phenotype is enabled by physical constraints that drive the system toward a preferred solution. These findings may help in understanding how cells and tissues behave in both development and cancer. In microgravity, cells undergo spontaneous and reversible transitions between different phenotypes. In the absence of physical constraints, living systems could yield bi-stable decisions. On the contrary, physical ‘boundaries’ constrain cells to acquire only a specific configuration by selecting and shaping different gene expression patterns provided by the intrinsic genetic stochasticity. (shrink)

The structures of protein and DNA were discovered primarily by means of synthesizing component-level information about bond types, lengths, and angles, rather than analyzing X-ray diffraction photographs of these molecules. In this paper, I consider the synthetic and analytic approaches to exemplify alternative heuristics for approaching mid-twentieth-century macromolecular structure determination. I argue that the former was, all else being equal, likeliest to generate the correct structure in the shortest period of time. I begin by characterizing problem solving in these cases (...) as proceeding via the elimination of candidate structures through the successive application of component-level information and interpretations of X-ray diffraction photographs, each of which serves as a kind of constraint on structure. Then, I argue that although each kind of constraint enables the elimination of a considerable proportion of candidate structures, component-level constraints are significantly more likely to do so correctly. Thus, considering them before X-ray diffraction photographs is a better heuristic than one that reverses this order. Because the synthetic approach that resulted in the determination of the protein and DNA structures exemplifies such a heuristic, its use can help account for these discoveries. (shrink)

Much of the recent philosophical debate on causation and causal explanation in the biological and biomedical sciences has focused on the notion of mechanism. Mechanisms, their nature and epistemic roles have been tackled by a range of so-called neo-mechanistic theories, and widely discussed. Without denying the merits of this approach, our paper aims to show how lately it has failed to give proper credit to processes, which are central to the field, especially of contemporary molecular biology. Processes can be summed (...) up in the notion of ‘pathway’, which is far from being just equivalent to that of ‘mechanism’ and has a profound epistemological and explanatory relevance. It is argued that an adequate consideration of pathways impels some rethinking of scientific explanation in molecular biology, namely its functional and contextual features. A number of examples are given to suggest that the focus of philosophical attention in this disciplinary field should shift from the notion of mechanism to the notion of pathway. (shrink)

The theory of evolution of complex, including the humans system and algorithm for its constructing are a synthesis of evolutionary epistemology, philosophical anthropology and concrete scientific empirical basis in modern science,. In other words, natural philosophy is regaining the status bar element theoretical science in the era of technology-driven evolution. The co-evolutionary concept of 3-modal stable evolutionary strategy of Homo sapiens is developed. The concept based on the principle of evolutionary complementarity of anthropogenesis: value of evolutionary risk and evolutionary path (...) of human evolution are defined by descriptive (evolutionary efficiency) and creative-teleological (evolutionary correctly) parameters simultaneously, that cannot be instrumental reduced to others ones. Resulting volume of both parameters define the vectors of biological, social, cultural and techno-rationalistic human evolution by two gear mechanism ˗ genetic and cultural co-evolution and techno-humanitarian balance. The resultant each of them can estimated by the ratio of socio-psychological predispositions of humanization/dehumanization in mentality. Explanatory model and methodology of evaluation of creatively teleological evolutionary risk component of NBIC technological complex is proposed. Integral part of the model is evolutionary semantics (time-varying semantic code, the compliance of the biological, socio-cultural and techno-rationalist adaptive modules of human stable evolutionary strategy). (shrink)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively (...) worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by‐product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI‐1, and (...) MUC1‐C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid – which affect the balance of formaldehyde in the body – may serve as the basis of future anticancer therapy. (shrink)

The repair of chromosomal double‐strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the RecA/Rad51‐mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template to repair the lesion. Here, in reviewing research about DSB repair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination mechanisms.

The ‘managed-metabolism’ hypothesis suggests that a ‘cooperation barrier’ must be overcome if self-producing chemical organizations are to undergo the transition from non-life to life. This dynamical barrier prevents un-managed autocatalytic networks of molecular species from individuating into complex, cooperative organizations. The barrier arises because molecular species that could otherwise make significant cooperative contributions to the success of an organization will often not be supported within the organization, and because side reactions and other ‘free-riding’ processes will undermine cooperation. As a result, (...) the barrier seriously impedes the emergence of individuality, complex functionality and the transition to life. This barrier is analogous to the cooperation barrier that also impedes the emergence of complex cooperation at all levels of living organization. As has been shown at other levels of organization, the barrier can be overcome comprehensively by appropriate ‘management’. Management implements a system of evolvable constraints that can overcome the cooperation barrier by ensuring that beneficial co-operators are supported within the organization and by suppressing free-riders. In this way, management can control and manipulate the chemical processes of a collectively autocatalytic organization, producing novel processes that serve the interests of the organization as a whole and that could not arise and persist in an un-managed chemical organization. Management self-organizes because it is able to capture some of the benefits that are produced when its interventions promote cooperation, thereby enhancing productivity. Selection will therefore favour the emergence of managers that take over and manage chemical organizations so as to overcome the cooperation barrier. The managed-metabolism hypothesis demonstrates that if management is to overcome the cooperation barrier comprehensively, its interventions must be digitally coded. In this way, the hypothesis accounts for the two-tiered structure of all living cells in which a digitally-coded genetic apparatus manages an analogically-informed metabolism.GraphicalOpen image in new window. (shrink)

Mapping the paths that stem and progenitor cells take en route to differentiate and elucidating the underlying molecular controls are key goals in developmental and stem cell biology. However, with population level analyses it is difficult − if not impossible − to define the transition states and lineage trajectory branch points within complex developmental lineages. Single‐cell RNA‐sequencing analysis can discriminate heterogeneity in a population of cells and even identify rare or transient intermediates. In this review, we propose that using these (...) data, one can infer the lineage trajectories of individual stem cells and identify putative branch points. Clonal lineage tracing of stem cells allows one to define the outcome of differentiation. Integrating these single cell‐based approaches provides a robust strategy for establishing and testing models of how an individual stem cell changes through time to differentiate and self‐renew. (shrink)

The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals the (...) existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (shrink)

Proteolysis-targeting chimeric molecules represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological (...) substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. The hetero-bifunctional PROTAC molecules contain a ligand for recruiting an E3 ligase linked with a ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” disease-causing proteins, which are not limited to physiological substrates of the ubiquitin-protease system, suggesting great prospects for therapeutic development. (shrink)

Glycogen is synthesized and stored to maintain postprandial blood glucose homeostasis and to ensure an uninterrupted energy supply between meals. Although the regulation of glycogen turnover has been well studied, the effects of glycogen on aging and disease development have been largely unexplored. In Caenorhabditis elegans fed a high sugar diet, glycogen potentiates resistance to oxidants, but paradoxically, shortens lifespan. Depletion of glycogen by oxidants or inhibition of glycogen synthesis extends the lifespan of worms by an AMPK‐dependent mechanism. Thus, glycogen (...) is not merely an inert storage molecule, but also an active regulator of energy balance and aging. Its depletion by oxidants may be beneficial in the treatment of hyperglycemia and glycogen‐related diseases. (shrink)

Allosteric and transmembrane signaling are among the major questions of structural biology. Here, we review and discuss signal transduction in four-helical TM bundles, focusing on histidine kinases and chemoreceptors found in two-component systems. Previously, piston, scissors, and helical rotation have been proposed as the mechanisms of TM signaling. We discuss theoretically possible conformational changes and examine the available experimental data, including the recent crystallographic structures of nitrate/nitrite sensor histidine kinase NarQ and phototaxis system NpSRII:NpHtrII. We show that TM helices can (...) flex at multiple points and argue that the various conformational changes are not mutually exclusive, and often are observed concomitantly, throughout the TM domain or in its part. The piston and scissoring motions are the most prominent motions in the structures, but more research is needed for definitive conclusions. Models of allosteric transmembrane signaling in microbial sensor histidine kinases and chemoreceptors are discussed in light of recent crystallographic structures. It is shown that the TM α-helices are flexible and various conformational changes are often observed concomitantly. The piston and scissoring motions are the most prominent in the structures. (shrink)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying formation and (...) maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

To decode the function and molecular recognition of several recently discovered cytosine derivatives in the human genome – 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine – a detailed understanding of their effects on the structural, chemical, and biophysical properties of DNA is essential. Here, we review recent literature in this area, with particular emphasis on features that have been proposed to enable the specific recognition of modified cytosine bases by DNA-binding proteins. These include electronic factors, modulation of base-pair stability, flexibility, and radical changes (...) in duplex conformation. We explore these proposals and assess whether or not they are supported by current biophysical data. This analysis is focused primarily on the properties of epigenetically modified DNA itself, which provides a basis for discussion of the mechanisms of recognition by different proteins. 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine have recently been discovered in mammalian DNA and appear to have essential regulatory roles. Here, we summarize recent investigations into their effects on the structural, chemical, and biophysical properties of DNA, an understanding of which is essential to decoding their behavior in the genome. (shrink)

Organogenesis and metamorphosis require the intricate orchestration of multiple types of cellular interactions and signaling pathways. Glutamate (Glu) is an excitatory extracellular signaling molecule in the nervous system, while Ca2+ is a major intracellular signaling molecule. The first Glu receptors to be cloned are Ca2+‐permeable receptors in mammalian brains. Although recent studies have focused on Glu signaling in synaptic mechanisms of the mammalian central nervous system, it is unclear how this signaling functions in development. Our recent article demonstrated that Ca2+‐permeable (...) AMPA‐type Glu receptors (GluAs) are essential for formation of a photosensitive organ, development of some neurons, and metamorphosis, including tail absorption and body axis rotation, in ascidian embryos. Based on findings in these embryos and mammalian brains, we formed several hypotheses regarding the evolution of GluAs, the non‐synaptic function of Glu, the origin of GluA‐positive neurons, and the neuronal network that controls metamorphosis in ascidians. (shrink)

Once dismissed as vestigial organelles, primary cilia have garnered the interest of scientists, given their importance in development/signaling, and for their implication in a new disease category known as ciliopathies. However, many, if not all, “cilia” proteins also have locations/functions outside of the primary cilium. These extraciliary functions can complicate the interpretation of a particular ciliopathy phenotype: it may be a result of defects at the cilium and/or at extraciliary locations, and it could be broadly related to a unifying cellular (...) process for these proteins, such as polarity. Assembly of a cilium has many similarities to the development of other polarized structures. This evolutionarily preserved process for the assembly of polarized cell structures offers a perspective on how the cilium may have evolved. We hypothesize that cilia proteins are critical for cell polarity, and that core polarity proteins may have been specialized to form various cellular protrusions, including primary cilia. (shrink)

Motile eukaryotic cilia and flagella are hair-like organelles responsible for cell motility and mucociliary clearance. Using cryo-electron tomography, it has been shown that the doublet microtubule, the cytoskeleton core of the cilia and flagella, has microtubule inner protein structures binding periodically inside its lumen. More recently, single-particle cryo-electron microscopy analyses of isolated doublet microtubules have shown that microtubule inner proteins form a meshwork inside the doublet microtubule. High-resolution structures revealed new types of interactions between the microtubule inner proteins and the (...) tubulin lattice. In addition, they offered insights into the potential roles of microtubule inner proteins in the stabilization and assembly of the doublet microtubule. Herein, we review our new insights into microtubule inner proteins from the doublet microtubule together with the current body of literature on microtubule inner proteins. High-resolution cryo-electron microscopy structure of the doublet microtubule from Tetrahymena reveals insights into the interactions between microtubule inner proteins with the doublet microtubule tubulin lattice and implication of their functions in the stability and assembly of the doublet microtubule. (shrink)

Centrosomes are the main microtubule organizing centers in animal cells. In particular during embryogenesis, they ensure faithful spindle formation and proper cell divisions. As metazoan centrosomes are eliminated during oogenesis, they have to be reassembled upon fertilization. Most metazoans use the sperm centrioles as templates for new centrosome biogenesis while the egg's cytoplasm re-prepares all components for on-going centrosome duplication in rapidly dividing embryonic cells. We discuss our knowledge and the experimental challenges to analyze zygotic centrosome reformation, which requires genetic (...) experiments to enable scrutinizing respective male and female contributions. Male and female knockout animals and mRNA injection to mimic maternal expression of centrosomal proteins could point a way to the systematic molecular dissection of the process. The most recent data suggest that timely expression of centrosome components in oocytes is the key to zygotic centrosome reformation that uses male sperm as coordinators for de novo centrosome production. Centrosome reformation at fertilization is essential for metazoan development. It requires a complicated interplay of sperm centrioles and the cytoplasm of the oocyte, which has eliminated its centrioles during oogenesis. The male centrioles launch centrosome duplication using female centrosome proteins for the first metazoan cell divisions. (shrink)

We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut (...) dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. (shrink)

In this paper we offer a minimal characterisation of the concept of mechanism in biomedicine, according to which a mechanism is a theoretically described causal pathway. We argue that this conceptionan be drawn from scientific practice, as illustrated by how a central biological and biomedical mechanism, the mechanism of apoptosis, was first identified and characterised. We will use the example of cytological and biochemical theoretical descriptions of the mechanism of apoptosis to draw lessons about the meaning of the concept of (...) mechanism in biomedical contexts and to contrast our preferred account of mechanism with some prominent accounts within the philosophical literature. The main outcome of our discussion will be that commitment to mechanism is first and foremost a methodological stance. (shrink)

ABSTRACT There is a new argument form within theoretical biology. This form takes as input competing explanatory models; it yields as output the conclusion that one of these models is more plausible than the others. The driving force for this argument form is an analysis showing that one model exhibits more parametric robustness than its competitors. This article examines these inferences to the more robust explanation, analysing them as variants of inference to the best explanation. The article defines parametric robustness (...) and distinguishes it from more familiar kinds of robustness. The article also argues that parametric robustness is an explanatory virtue not subsumed by more familiar explanatory virtues, and that the plausibility verdicts in the conclusions of inferences to the more robust explanations are best interpreted as guidance for research activity, rather than claims about likely truth. 1Introducing Inference to the More Robust Explanation 2Inference to the More Robust Explanation in the Study of Apoptosis 2.1Regulating apoptosis 2.2Competing models and evidential indecision 2.3Measuring robustness 2.4Robustness as a guide to plausibility 2.5Varieties of robustness 3Inference to the More Robust Explanation as Inference to the Best Explanation 3.1The structure of inference to the best explanation 3.2Parametric robustness as an explanatory virtue rather than an explanandum 3.3Relation of parametric robustness to other explanatory virtues 4Epistemological Significance of Inference to the More Robust Explanation 4.1Plausibility in practice 4.2Plausibility in principle 5Conclusion. (shrink)

Life is perpetuated through a single-cell bottleneck between generations in many organisms. Here, I highlight that this cell holds information in two distinct stores: in the linear DNA sequence that is replicated during cell divisions, and in the three-dimensional arrangement of molecules that can change during development but is recreated at the start of each generation. These two interdependent stores of information – one replicating with each cell division and the other cycling with a period of one generation – coevolve (...) while perpetuating an organism. Unlike the genome sequence, the arrangement of molecules, including DNA, RNAs, proteins, sugars, lipids, etc., is not well understood. Because this arrangement and the genome sequence are transmitted together from one generation to the next, analysis of both is necessary to understand evolution and origins of inherited diseases. Recent developments suggest that tools are in place to examine how all the information to build an organism is encoded within a single cell, and how this cell code is reproduced in every generation. Life relies on the information for making organisms that is encoded in single cells and transmitted between generations. These cell codes include interdependent stores of information that replicate and that cycle. Understanding evolution and the origins of inherited diseases requires analysis of cell codes. (shrink)

In human cancers, histone methyltransferase SETDB1 (SET domain, bifurcated 1) is frequently overexpressed but its significance in carcinogenesis remains elusive. A recent study shows that SETDB1 downregulation induces de‐repression of retroelements and innate immunity in cancer cells. The possibility of SETDB1 functioning as a surveillant of retroelement expression is discussed in this study: the cytoplasmic presence of retroelement‐derived nucleic acids (RdNAs) drives SETDB1 into the nucleus by the RNA‐interference route, rendering the corresponding retroelement transcriptionally inert. These RdNAs could, therefore, be (...) signals of genome instability sent out for SETDB1 present in the cytoplasm to maintain genome integrity. (shrink)