Almost all biomedical research to date has relied upon mean measurements from cell populations, however it is well established that what it is observed at this macroscopic level can be the result of many interactions of several different single cells. Thus, the observable macroscopic ‘average’ cannot outright be used as representative of the ‘average cell’. Rather, it is the resulting emerging behaviour of the actions and interactions of many different cells. Single‐cell RNA sequencing (scRNA‐Seq) enables the comparison of the transcriptomes (...) of individual cells. This provides high‐resolution maps of the dynamic cellular programmes allowing us to answer fundamental biological questions on their function and evolution. It also allows to address medical questions such as the role of rare cell populations contributing to disease progression and therapeutic resistance. Furthermore, it provides an understanding of context‐specific dependencies, namely the behaviour and function that a cell has in a specific context, which can be crucial to understand some complex diseases, such as diabetes, cardiovascular disease and cancer. Here, we provide an overview of scRNA‐Seq, including a comparative review of emerging technologies and computational pipelines. We discuss the current and emerging applications and focus on tumour heterogeneity a clear example of how scRNA‐Seq can provide new understanding of a complex disease. Additionally, we review the limitations and highlight the need of powerful computational pipelines and reproducible protocols for the broader acceptance of this technique in basic and clinical research. (shrink)

Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non‐linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings also (...) suggest the existence of alternative competing hypotheses, such as a non‐linearity between cell death and cell size. While we find that the proposed non‐linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology. (shrink)

Here, we propose that the heterogeneity of mutational types in populations underpins alternative pathways of evolutionary adaptation. Point mutations, deletions, insertions, transpositions and duplications cause different biological effects and provide distinct adaptive possibilities. Experimental evidence for this notion comes from the mutational origins of adaptive radiations in large, clonal bacterial populations. Independent sympatric lineages with different phenotypes arise from distinct genetic events including gene duplication, different insertion sequence movements and several independent point mutations. The breadth of the mutational spectrum (...) in the ancestral population should be viewed as a form of bet‐hedging, reducing the risk of evolutionary dead ends and complementing the phenotypic and epigenetic heterogeneities that improve the survival capabilities of a population. Different mutational events arise from distinct cellular processes and are subject to separate environmental impacts, so the availability of any particular type of mutation may constrain or promote adaptive pathways in populations. (shrink)

Supply networks as complex systems are significant challenges for decision-makers in predicting the evolution of cooperation among firms. The impact of environmental heterogeneity on firms is critical. Environment-based preference selection plays a pivotal role in clarifying the existence and maintenance of cooperation in supply networks. This paper explores the implication of the heterogeneity of environment and environment-based preference on the evolution of cooperation in supply networks. Cellular automata are considered to examine the synchronized evolution of cooperation and (...) defection across supply networks. The Prisoner’s Dilemma Game and Snowdrift Game reward schemes have been formed, and the heterogeneous environment and environmental preference have been applied. The results show that the heterogeneous environment’s degree leads to higher cooperation for both Prisoner’s Dilemma Game and Snowdrift Game. We also probe into the impact of the environmental preference on the evolution of cooperation, and the results of which confirm the usefulness of preference of environment. This work offers a valuable perspective to improve the level of cooperation among firms and understand the evolution of cooperation in supply networks. (shrink)

Non‐genetic forms of antimicrobial (drug) resistance can result from cell‐to‐cell variability that is not encoded in the genetic material. Data from recent studies also suggest that non‐genetic mechanisms can facilitate the development of genetic drug resistance. We speculate on how the interplay between non‐genetic and genetic mechanisms may affect microbial adaptation and evolution during drug treatment. We argue that cellular heterogeneity arising from fluctuations in gene expression, epigenetic modifications, as well as genetic changes contribute to drug resistance at (...) different timescales, and that the interplay between these mechanisms enhance pathogen resistance. Accordingly, developing a better understanding of the role of non‐genetic mechanisms in drug resistance and how they interact with genetic mechanisms will enhance our ability to combat antimicrobial resistance. Also see the video abstract here: https://youtu.be/aefGpdh-bgU. (shrink)

Age‐related and cancer‐related epigenomic modifications have been associated with enhanced cell‐to‐cell gene expression variability that characterizes increased cellular stochasticity. Since gene expression variability appears to be highly reduced by—and epigenetic and phenotypic stability acquired through—direct or long‐range cellular interactions during cell differentiation, we propose a common origin for aging and cancer in the failure to control cellular stochasticity by cell–cell interactions. Tissue‐disruption‐induced cellular stochasticity associated with epigenetic drift would be at the origin of organ dysfunction because (...) of an increase in phenotypic variation among cells, ultimately leading to cell death and organ failure through a loss of coordination in cellular functions, and eventually to cancerization. We propose mechanistic research perspectives to corroborate this hypothesis and explore its evolutionary consequences, highlighting a positive correlation between the median age of mass loss onset (a proxy for the onset of organ aging) and the median age at cancer diagnosis. (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent with (...) clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at (...) quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings. (shrink)

The establishment of distinct cellular identities was pivotal during the evolution of Metazoa, enabling the emergence of an array of specialized tissues with different functions. In most animals including vertebrates, cell specialization occurs in response to a combination of intrinsic (e.g., cellular ontogeny) and extrinsic (e.g., local environment) factors that drive the acquisition of unique characteristics at the single‐cell level. The first functional organ system to form in vertebrates is the cardiovascular system, which is lined by a network (...) of endothelial cells whose organ‐specific characteristics have long been recognized. Recent genetic analyses at the single‐cell level have revealed that heterogeneity exists not only at the organ level but also between neighboring endothelial cells. Thus, how endothelial heterogeneity is established has become a key question in vascular biology. Drawing upon evidence from multiple organ systems, here we will discuss the role that lineage history may play in establishing endothelial heterogeneity. (shrink)

Cellular 3D structures, for example, organoids, are an excellent model for studying and developing treatments for various diseases, including hereditary ones. Therefore, they are increasingly being used in biomedical research. From the point of view of safety and efficacy, recombinant adeno‐associated viral (rAAV) vectors are currently most in demand for the delivery of various transgenes for gene replacement therapy or other applications. The delivery of transgenes using rAAV vectors to various types of organoids is an urgent task, however, it (...) is associated with a number of problems that are discussed in this review. Cellular heterogeneity and specifics of cultivation of 3D structures determine the complexity of rAAV delivery and are sometimes associated with low transduction efficiency. This review surveys the main ways to solve emerging problems and increase the efficiency of transgene delivery using rAAVs to organoids. A clear understanding of the stage of development of the organoid, its cellular composition and the presence of surface receptors will allow obtaining high levels of organoid transduction with existing rAAV vectors. (shrink)

A recent single cell mRNA sequencing study by Dueck et al. compares neuronal transcriptomes to the transcriptomes of adipocytes and cardiomyocytes. Single cell ‘omic approaches such as those used by the authors are at the leading edge of molecular and biophysical measurement. Many groups are currently employing single cell sequencing approaches to understand cellular heterogeneity in cancer and during normal development. These single cell approaches also are beginning to address long‐standing questions regarding nervous system diversity. Beyond an innate (...) interest in cataloging cell type diversity in the brain, single cell neuronal diversity has important implications for neurotypic neural circuit function and for neurological disease. Herein, we review the authors’ methods and findings, which most notably include evidence of unique expression profiles in some single neurons. (shrink)

Cellular differentiation is often accompanied by the expression of specialized plasma membrane proteins which accumulate in discrete regions. The biogenesis of these specialized membrane domains involves the assembly and co‐localisation of a spectrin‐based membrane skeleton. While the constituents of the membrane skeleton in non‐erythroid cells are often immunologically related to erythroid spectrin, ankyrin, and protein 4.1, there are structural and functional differences between the isoforms of these membrane skeleton polypeptides, as well as highly variable patterns of expression during (...) class='Hi'>cellular differentiation. We consider this heterogeneity of structure and expression during development in the context of the hypothesis that non‐erythroid spectrin, ankyrin, and protein 4.1 are involved in the formation of specialized membrane domains. (shrink)

Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet‐hedging are identical or rather display distinct features. Here we argue that bet‐hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet‐hedging strategies in cancer originate from (...) a hijacking of the normal developmental bet‐hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet‐hedging strategies of cancer cells. (shrink)

The integration of cellular networks and vehicular networks is complex and heterogeneous. Synchronization among vehicles in heterogeneous vehicular clusters plays an important role in effective data sharing and the stability of the cluster. This synchronization depends on the smooth exchange of information between vehicles and remote servers over the Internet. The remote servers predict road traffic patterns by adopting deep learning methods to help drivers on the roads. At the same time, local data processing at the vehicular cluster level (...) may increase the capabilities of remote servers. However, global positioning system signal interruption, especially in the urban environment, plays a big part in the detritions of synchronization among the vehicles that lead to the instability of the cluster. Instability of connections is a major hurdle in developing cost-effective solutions for deriving assistance and route planning applications. To solve this problem, a self-localization scheme within the vehicular cluster is proposed. The proposed self-localization scheme handles GPS signal interruption to the vehicle within the cluster. A unique clustering criterion and a synchronization mechanism for sharing traffic information system data among multiple vehicles are developed. The developed scheme is simulated and compared with existing known approaches. The results show the better performance of our proposed scheme over others. (shrink)

Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. (...) An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. Epigenetic and transcriptional variability mediate phenotypic plasticity, enabling adaptation to changing environments. In this review, we describe the sources of inter- and intra-individual variability and discuss epigenetic regulators of gene expression variability, including DNA methylation and chromatin structure. Understanding these molecular mechanisms will improve therapeutic approaches and personalized medicine. (shrink)

What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted. This is due to the high cost of accuracy, the greater number of damage forms (...) compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world. This strategy also applies to cancer cells, which are particularly dependent on damage dilution. Imposing restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing both damage composition and the rate of damage accumulation. Thus, heterogeneity leading to myriad mild damage forms represents the cause of aging, whereas the processes that affect the damage landscape and damage accumulation are lifespan regulators. (shrink)

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this (...) article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms. (shrink)

Most eukaryotes possess many copies of rDNA. Organismal selection alone cannot maintain rRNA function because the effects of mutations in one rDNA are diluted by the presence of many other rDNAs. rRNA quality is maintained by processes that increase homogeneity of rRNA within, and heterogeneity among, germ cells thereby increasing the effectiveness of cellular selection on ribosomal function. A successful rDNA repeat will possess adaptations for spreading within tandem arrays by intranuclear selection. These adaptations reside in the non‐coding (...) regions of rDNA. Single‐copy genes are predicted to manage processes of intranuclear and cellular selection in the germline to maintain the quality of rRNA expressed in somatic cells of future generations. (shrink)

El desarrollo acelerado de la ciencia y la técnica ha proporcionado nuevos conocimientos, entre ellos los relacionados con la biología molecular y celular y particularmente con el descubrimiento del factor de crecimiento epidérmico y su capacidad para estimular la formación de tejido de granulación y acelerar la reepitelización en las úlceras del pie diabético. Los Estudios Sociales de la Ciencia y la Tecnología constituyen un campo caracterizado por la heterogeneidad de tendencias que han ido configurando un enfoque más integral, interdisciplinario (...) y responsable de la reflexión sobre la actividad científico-tecnológica. El artículo tiene como objetivo fundamentar el impacto social del Heberprot-P como fruto de una Tecnociencia, mediante un análisis teórico del tema. The quick development of science and technology has provided new knowledge about different matters, such as those related with the molecular and cellular biology and particularly with the discovery of the factor of epidermal growth and its capacity to stimulate the formation of granulation tissue and to accelerate the re-epithelisation in ulcers of diabetic foot. The Social Studies of Science and Technology constitute a field characterized by heterogeneity of tendencies that have been giving shape to a more integral and interdisciplinary focus responsible for the reflection on the scientific-technological activity. This article is aimed at basing the social impact of Heberprot-P as a result of a technoscience, by means of a theoretical analysis on the topic. (shrink)

The macrophage plays an important role in host development and physiology, and in pathogenesis of many infectious, immunologic and degenerative disease processes. It displays marked heterogeneity of phenotype in different tissues, reflecting local interactions with other cell types, and contributes to host homeostasis through a varied repertoire of plasma membrane and secretory molecules. Upon isolation from the body it continues to express special, as well as general, features of cellular organisation and function, which make it a delight to (...) study in cell culture. (shrink)

Certain sections ofJosiah Willard Gibbs's thermodynamics papers might be applicable to biological equilibrium and growth, normal or abnormal.Gibbs added terms⌆ Μ i dm i to the differential of the internal energy dε=tdη−pdΝ, where μi=δεδmi is the potential of substancem i , to provide for chemical as well as thermal and mechanical equilibrium. In this article a further generalization is suggested, to include biological equilibrium by adding to de terms of the form GdN, the variableN being the number of cells, where (...) G=δεδN is a “growth potential” that measures exactly the resistance toward spontaneous growth. The functionG, likeΜ i is intensive in nature except for a conversion factor dMdN ,M=⌆m i , affording possible insight into why incipient abnormal growth is often independent of the number of cells. Useful applications might follow from identities between δGδη,δGδv , or δGδmi and δtδN,−δpδN or δμiδN respectively. The following new function is studied, ζ¯=ζ−GN , a natural generalization of theGibbs free energy function ζ, the possibility of measuring it electrically, and comparison of its role with that of ζ for the possible experimental determination ofG. Gibbs's necessary and sufficient conditions for heterogeneous equilibrium ofn components inm phases are generalized and also modified to include broader restraining conditions like ∑mi=1δNj⩾o ,j=1,f,n, the > being characteristic of only living cellular phases. Careful appraisal of the term “biological stability” is followed by new criteria for stability, instability, and limits of stability, in terms of derivatives ofG, with possible medical applications. Three different sections of Gibbs's works tend to indicate that, for a biological phase, lower pressure usually increases its stability. The equation p′′−p′=σ , where σ=surface tension,p′, p′ = pressures,r, r′=radii of curvature, is applied to possible control of tissue growth at interfaces. Methods of altering the equilibrum between three phasesA, B, C by varying the interfacial tensionsσ AB ,σ BC ,σ AC , using relations like AB <σ AC + BC for stability of theA, B interface, suggest different means for shifting biological equilibrium between normal and abnormal cells through the introduction of new third phases at the interface. Various devices are mentioned for possible control of growth through proper channeling of surface or other equivalent forms of energy. (shrink)

The 2013 Rostock Symposium on Systems Biology and Bioinformatics in Aging Research was again dedicated to dissecting the aging process using in silico means. A particular focus was on ontologies, as these are a key technology to systematically integrate heterogeneous information about the aging process. Related topics were databases and data integration. Other talks tackled modeling issues and applications, the latter including talks focussed on marker development and cellular stress as well as on diseases, in particular on diseases of (...) kidney and skin. (shrink)

Whenever the state of a biological system is not determined solely by present conditions but depends on its past history, we can say that the system has memory. Bacteria and bacteriophage use a variety of memory mechanisms, some of which seem to convey adaptive value. A genetic type of heritable memory is the programmed inversion of specific DNA sequences, which causes switching between alternative patterns of gene expression. Heritable memory can also be based on epigenetic circuits, in which a system (...) with two possible steady states is locked in one or the other state by a positive feedback loop. Epigenetic states have been observed in a variety of cellular processes, and are maintained by diverse mechanisms. Some of these involve alternative DNA methylation patterns that are stably transmitted to daughter molecules and can affect DNA–protein interactions (e.g., gene transcription). Other mechanisms exploit autocatalytic loops whereby proteins establish the proper conditions for their continued synthesis. Template polymers other than nucleic acids (e.g., components of the cell wall) may also propagate epigenetic states. Non‐heritable memory is exemplified by parasitic organisms that bear a signature of their previous host, such as host‐controlled modification of phage DNA or porin hitchhiking in predatory bacteria. The heterogeneous nature of the examples known may be indicative of widespread occurrence of memory mechanisms in bacteria and phage. However, the actual extent, variety and potential selective value of prokaryotic memory devices remain open questions, still to be addressed experimentally. BioEssays 24:512–518, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Chondrogenesis is a key process in skeletogenesis since endochondral ossification requires the formation of a cartilaginous template. Knowledge of molecular mechanisms regulating chondrogenesis is extremely valuable not only to understand many human disorders but also in regenerative medicine. Embryonic skeletogenesis is an excellent model to study this mechanism. Most cartilages share the cellular basis underlying chondrogenesis but the high heterogeneity in morphologies of the different skeletal elements appears to be generated by differential participation of a variety of chondrogenic (...) signals. Here we overview the regulatory factors responsible for chondrogenesis concluding that early chondrogenic signals for the digit cartilages differ from those implicated in the formation of other axial and appendicular skeletal components. BioEssays 29:725–737, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This book is a colorful journey into the fascinatingly diverse world of interneurons, an important class of highly heterogeneous cells found in all cortical neuronal networks. Interneurons are known to play key roles in many brain functions, from sensory processing to neuronal oscillations linked to learning and memory. The central aim of the volume is to provide new insights into the striking degree of cellular diversity found in interneuronal microcircuits. The book discusses the history of research into interneuronal variability, (...) the developmental origins of interneuronal diversity, the functional roles of heterogeneity in neuronal circuits, contemporary interneuronal classification systems, and the genetic and homeostatic mechanisms that shape the degree of cell to cell variability within interneuronal populations. It elaborates on new ideas about interneuronal diversity that rest upon theoretical and experimental results, with arguments touching upon evolution, animal behavior, and the mathematical theory of small world networks. This engaging volume is invaluable to neuroscientists and others interested in how neuronal newtworks function; electrical engineers, computational modelers, and physicists interested in neuronal network theory; neurologists and psychiatrists working on mechanisms of neurological and psychiatric disorders; and students and trainees in all of these fields. (shrink)

O‐glycosylation is the post‐translational process whereby carbohydrate is added to hydroxylated amino acids of proteins. The major O‐glycosylation pathway in animal cells is involved in the synthesis of oligosaccharides linked by N‐acetylgalactosamine to serine or threonine residues in ‘mucin‐type’ proteins or their analogs. In this review, we discuss the evidence for the cellular localization of the biosynthetic steps in this pathway and propose a simplified, consensus version. We also propose variations of the simple pathway to account for its (...) class='Hi'>heterogeneity and variability in different cell types and differentiation states. (shrink)

The autosomal recessive genetic disease, Fanconi anaemia, is perceived as another manifestation of defective cellular DNA repair, just as in the autosomal recessive disease Xeroderma pigmentosum. The biochemistry and cellular biology of Xeroderma pigmentosum have been convincingly elucidated, but the same has not been true for Fanconi anaemia. In this review we consider the pleiotropic nature of Fanconi anaemia, its clinical and cellular variability and its genetic heterogeneity. We take into account the wealth of experimental findings (...) available and offer a novel hypothesis involving feedback control of DNA replication during S phase of the cell cycle to explain the basic defect in the disease. (shrink)

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound (...) motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient‐derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis. (shrink)

The conventional description of biography as a form of nonfiction narrative begs questions about the stories biographies tell, the facts that constitute their raw material, and the language in which they are cast. These questions are seen as central for students of the arts and humanities and are addressed as three interrelated issues as exemplified in literary biography. First, it is argued that biographies have a cellular structure that derives from the imposition of a master narrative over the subject’s (...) life, one that creates continuity and coherence from the heterogeneous accumulation of mininarratives found in the biographer’s sources. The factual status of these sources is shown to be complex due to the ambiguous nature of the subject’s literary works considered as data; to be unstable due to unavoidable features such as archival gaps, and the selectivity, speculation, and error that are inherent in the biographical process; and to be malleable because of the particular agenda that motivates every biography. Finally, the “literariness” of biographical language is shown to be fundamental in the rhetorical evocation of the subject. Art and artifice combine in a genre that provokes questions about the relationship between the life stories biographers construct and the narratives by which we make sense of life. (shrink)

This article is concerned with the problem of the relation between the genetic information contained in the DNA and the emergence of visible structure in multicellular animals. The answer is sought in a reappraisal of the data of experimental embryology, considering molecular, cellular and organismal aspects. The presence of specific molecules only confers a tissue identity on the cells when their concentration exceeds the threshold of differentiation. When this condition is not fulfilled the activity of the genes that code (...) for the specific molecules in question only confers on them a histogenetic potency, i.e. the capacity to form the corresponding tissue in further development (or to transdifferentiate to that tissue). The progressive restriction of histogenetic potencies during development reflects the irreversible repression of more and more genes. The establishment of a given tissue identity under the influence of an inducing tissue (or a morphogenetic hormone) is only possible when the cells have acquired the competence to respond. Tissue differentiation proceeds progressively during development thanks to the cytoplasmic memory that cells retain collectively (or sometimes individually) of the items of information successively registered by their ancestors cells. The increasing complexity of visible structure emerging during development results only from the progression of tissue differentiation. This involves continual exchange of information among the cells and leads to (1) cell displacements and rearrangements, particularly during organogenesis and (2) extreme diversification of cell individualities within tissues, particularly during postembryonic growth. A mutation (just as a teratogenic factor) evokes an anomaly that is localized in both space and time because it alters a certain aspect of cell behaviour (particularly cell surface adhesiveness or mitotic activity) at the time when this is involved in the establishment of a particular structural trait. Neither the organization of the adult nor the modalities of development are encoded in the DNA. The automatic concatenation of cell interactions in the embryo and the structural amplification it entails is conditioned by the specific biochemical composition of the cytoplasm of the egg and by the heterogeneous distribution of its inclusions. (shrink)

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair‐covered skin. Dermal adipocytes cycle through de‐differentiation and re‐differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de‐differentiation of dermal adipocytes in the catagen phase of the hair follicle cycle. (...) Both caveolin‐1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin‐1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen (...) in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. (shrink)

As the title of this article suggests, the concept of the interface needs to be revisited in the context of biological media in order to infer some implications for the post-biological culture. A direct comparison of our media culture to the environmental notion of the media and the natural partitioning of the media by biological membranes becomes possible if we expand on the notions of media and interfaces in our technologically conditioned realities. The question of periphery and permeability of a (...) biological membrane will be addressed in the context of the theory of aesthetics. Although at first glance we are dealing only with subtle changes in the degree of permeability of an interface, suddenly selectiveness in permeability arises, and though an interface is considered simply peripheral, at a slight touch with an opposing media its role swiftly becomes central. Taking into account the functioning of a biological membrane, a remarkably resourceful technology, associations stem from the culture on the cellular level to the culture of human society, where the human being should not be limited to the concept of self, but operatively diffused into collective awareness. The technologies that we develop, and the media we employ and inhabit always meet at an interface. But there is more to the face-to-face meeting of media than a mere inert surface. Such a surface as a membrane is not abstractly thin but more like ‘infrathin’ – the term invented by the artist Marcel Duchamp. What happens at such confrontation of media of different kinds, of incomparable qualities, will be further discussed in the article. The dynamics of permeability at the periphery adjust the tension between heterogeneous qualities of the media to allow for coexistence, even for the emergence of new meanings. This heterogeneity can be experienced only within the interface, and therefore an inner view is proposed instead of a view from above, an inner view that prevents reduction of processes to commensurable, quantifiable objects. Since interface occurs at every interaction with the world, as explained in the theory of endophysics by biochemist Otto E. Rössler, we have to be aware of the problematics of this phenomenon, and we must rethink its potential. The interface is at the same time an opportunity, the interval we are given, where our drive to act is suppressed and our will to speculate prevails. By contemplating intricate biological solutions, this article hopes to further encourage the turn towards post-biological evolution of our awareness. (shrink)

Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as (...) a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases. (shrink)

Unlike eggs and diatoms, most single cells in nature do not have structured shells to provide extensive protection. It is a challenge to artificially confer shell structures on living cells to improve their inherent properties and functions. We discuss four different types of cellular shellizations: man‐made hydrogels, sol‐gels, polyelectrolytes, and mineral shells. We also explore potential applications, such as cell storage, protection, delivery, and therapy. We suggest that shellization could provide another means to regulate and functionalize cells. Specifically, the (...) integration of living cells and non‐living functional shells may be developed as a novel strategy to create “super” or intelligent cells. Unlike biological approaches, this material‐based bio‐interface regulation is inexpensive, effective, and convenient, opening up a novel avenue for cell‐based technologies and practices. (shrink)

In some recent papers (G. ‘t Hooft and others), it has been argued that quantum mechanics can arise from classical cellular automata. Nonetheless, G. Shpenkov has proved that the classical wave equation makes it possible to derive a periodic table of elements, which is very close to Mendeleyev’s one, and describe also other phenomena related to the structure of molecules. Hence the classical wave equation complements Schrödinger’s equation, which implies the appearance of a cellular automaton molecular model starting (...) from classical wave equation. The other studies show that the microworld is constituted as a tessellation of primary topological balls. The tessellattice becomes the origin of a submicrospic mechanics in which a quantum system is subdivided to two subsystems: the particle and its inerton cloud, which appears due to the interaction of the moving particle with oncoming cells of the tessellattice. The particle and its inerton cloud periodically change the momentum and hence move like a wave. The new approach allows us to correlate the Klein-Gordon equation with the deformation coat that is formed in the tessellatice around the particle. The submicroscopic approach shows that the source of any type of wave movements including the Klein-Gordon, Schrödinger, and classical wave equations is hidden in the tessellattice and its basic exciations – inertons, carriers of mass and inert properies of matter. We also discuss possible correspondence with Konrad Zuse’s calculating space. (shrink)

Imagination has been assigned an important explanatory role in a multitude of philosophical contexts. This paper examines four such contexts: mindreading, pretense, our engagement with fiction, and modal epistemology. Close attention to each of these contexts suggests that the mental activity of imagining is considerably more heterogeneous than previously realized. In short, no single mental activity can do all the explanatory work that has been assigned to imagining.

Many writers have commented on the heterogeneity of the socially responsible investment (SRI) movement. However, few have actually tried to understand and explain it, and even fewer have discussed whether the opposite – standardisation – is possible and desirable. In this article, we take a broader perspective on the issue of the heterogeneity of SRI. We distinguish between four levels on which heterogeneity can be found: the terminological, definitional, strategic and practical. Whilst there is much talk about (...) the definitional ambiguities of SRI, we suggest that there is actually some agreement on the definitional level. There are at least three explanations which we suggest can account for the heterogeneity on the other levels: cultural and ideological differences between different regions, differences in values, norms and ideology between various SRI stakeholders, and the market setting of SRI. Discussing the implications of the three explanations for the SRI market, we suggest that there is reason to be sceptical about the possibilities of standardisation if not standardisation is imposed top-down. Whether this kind of standardisation is desirable or not, we argue, depends on what the motives for it would be. To the extent that standardisation may facilitate the mainstreaming of SRI, it could be a good thing – but we entertain doubts about whether mainstreaming really requires standardisation. (shrink)

Cellular automata (henceforth: CA) are discrete, abstract computational systems that have proved useful both as general models of complexity and as more specific representations of non-linear dynamics in a variety of scientific fields. Firstly, CA are (typically) spatially and temporally discrete: they are composed of a finite or denumerable set of homogeneous, simple units, the atoms or cells. At each time unit, the cells instantiate one of a finite set of states. They evolve in parallel at discrete time steps, (...) following state update functions or dynamical transition rules: the update of a cell state obtains by taking into account the states of cells in its local neighborhood (there are, therefore, no actions at a distance). Secondly, CA are abstract, as they can be specified in purely mathematical terms and implemented in physical structures. Thirdly, CA are computational systems: they can compute functions and solve algorithmic problems. Despite functioning in a different way from traditional, Turing machine-like devices, CA with suitable rules can emulate a universal Turing machine, and therefore compute, given Turing's Thesis, anything computable.... (shrink)

We argue that prediction success maximization is a basic objective of cognition and cortex, that it is compatible with but distinct from prediction error minimization, that neither objective requires subtractive coding, that there is clear neurobiological evidence for the amplification of predicted signals, and that we are unconvinced by evidence proposed in support of subtractive coding. We outline recent discoveries showing that pyramidal cells on which our cognitive capabilities depend usually transmit information about input to their basal dendrites and amplify (...) that transmission when input to their distal apical dendrites provides a context that agrees with the feedforward basal input in that both are depolarizing, i.e., both are excitatory rather than inhibitory. Though these intracellular discoveries require a level of technical expertise that is beyond the current abilities of most neuroscience labs, they are not controversial and acclaimed as groundbreaking. We note that this cellular cooperative context-sensitivity greatly enhances the cognitive capabilities of the mammalian neocortex, and that much remains to be discovered concerning its evolution, development, and pathology. (shrink)

Cells live in dynamic environments that necessitate perpetual adaptation. Since cells have limited resources to monitor external inputs, they are required to maximize the information content of perceived signals. This challenge is not unique to microscopic life: Animals use senses to perceive inputs and adequately respond. Research showed that sensory‐perception is actively shaped by learning and expectation allowing internal cognitive models to “fill in the blanks” in face of limited information. We propose that cells employ analogous strategies and use internal (...) models shaped through the long process of evolutionary adaptation. Given this perspective, we postulate that cells are prone to “misperceptions,” analogous to visual illusions, leading them to incorrectly decode patterns of inputs that lie outside of their evolutionary experience. Mapping cellular misperception can serve as a fundamental approach for dissecting regulatory networks and could be harnessed to modulate cell behavior, a potentially new avenue for therapy. (shrink)

Since Tolman’s paper in 1948, psychologists and neuroscientists have argued that cartographic representations play an important role in cognition. These empirical findings align with some theoretical works developed by philosophers who promote a pluralist view of representational vehicles, stating that cognitive processes involve representations with different formats. However, the inferential relations between maps and representations with different formats have not been sufficiently explored. Thus, this paper is focused on the inferential relations between cartographic and linguistic representations. To that effect, we (...) appeal to heterogeneous inference with ordinary maps and sentences. In doing so, we aim to build a model to bridge the gap between cartographic and linguistic thought. (shrink)

This book presents the deterministic view of quantum mechanics developed by Nobel Laureate Gerard 't Hooft. Dissatisfied with the uncomfortable gaps in the way conventional quantum mechanics meshes with the classical world, 't Hooft has revived the old hidden variable ideas, but now in a much more systematic way than usual. In this, quantum mechanics is viewed as a tool rather than a theory. The book presents examples of models that are classical in essence, but can be analysed by the (...) use of quantum techniques, and argues that even the Standard Model, together with gravitational interactions, might be viewed as a quantum mechanical approach to analysing a system that could be classical at its core. He shows how this approach, even though it is based on hidden variables, can be plausibly reconciled with Bell's theorem, and how the usual objections voiced against the idea of 'superdeterminism' can be overcome, at least in principle. This framework elegantly explains - and automatically cures - the problems of the wave function collapse and the measurement problem. Even the existence of an "arrow of time" can perhaps be explained in a more elegant way than usual. As well as reviewing the author's earlier work in the field, the book also contains many new observations and calculations. It provides stimulating reading for all physicists working on the foundations of quantum theory. (shrink)

Recall that for any Boolean algebra (BA) A, the cellularity of A is c(A) = sup{|X| : X is a pairwise-disjoint subset of A}. A pseudo-tree is a partially ordered set (T, ≤) such that for every t in T, the set {r ∊ T : r ≤ t} is a linear order. The pseudo-tree algebra on T, denoted Treealg(T), is the subalgebra of ℘(T) generated by the cones {r ∊ T : r ≥ t}, for t in T. We (...) characterize the cellularity of pseudo-tree algebras in terms of cardinal functions on the underlying pseudo-trees. For T a pseudo-tree, c(Treealg(T)) is the maximum of four cardinals c\sbT, ι\sbT, φ\sbT, and μ\sbT : roughly, c\sbT measures the "tallness" of the pseudo-tree T; ι\sbT the "breadth"; φ\sbT the number of "finite branchings"; and μ\sbT the number of places where T "does not branch." We give examples to demonstrate that all four of these cardinals are needed. (shrink)

The paper introduces an extension of the proposal according to which conceptual representations in cognitive agents should be intended as heterogeneous proxytypes. The main contribution of this paper is in that it details how to reconcile, under a heterogeneous representational perspective, different theories of typicality about conceptual representation and reasoning. In particular, it provides a novel theoretical hypothesis - as well as a novel categorization algorithm called DELTA - showing how to integrate the representational and reasoning assumptions of the theory-theory (...) of concepts with the those ascribed to the prototype and exemplars-based theories. (shrink)

The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review (...) much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD+ and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age‐related pathologies, which are caused by or exacerbated by senescent cells in vivo. (shrink)

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA‐protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non‐depressed persons, which may contribute to the observed unfavorable somatic health outcomes in (...) the depressed population. Some small‐scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere‐lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere‐telomerase system and debates whether depression‐related cellular aging should be considered a reversible process or permanent damage. (shrink)