The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on ‘what regulates cell size’, the question ‘why cell size needs to be maintained’ has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative (...) cell surface area impose biophysical limitations on cells, which can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity. Cell size is intimately connected to metabolism and growth rate, which are influenced by mitochondrial activity and biophysical constraints. We discuss that cellular fitness is often cell-size dependent. While the current evidence relies largely on proliferating cells, this connection from cell size to fitness may also help explain metabolic diseases. (shrink)

Unstable Accumulating Activator models for cellular size control propose an activator that accumulates in a size-dependent manner and triggers cell cycle progression once it has reached a certain threshold. Having a short half life makes such an activator responsive to changes in cell size and makes specific predictions for how cells respond to perturbation. In particular, it explains the curious phenomenon of excess mitotic delay. Excess mitotic delay, first observed in Tetrahymena in the '50s, is (...) a phenomenon in which a pulse of protein synthesis inhibition causes a delay in mitotic entry that is longer than the pulse and that gets longer the later in the cell cycle the pulse is delivered. The interpretation of this phenomenon championed by Zeuthen and Mitchison in the '60s and '70s is that an unstable activator of mitosis is degraded during the pulse and has to be resynthesized to a threshold level to trigger mitosis; small cells have more time to resynthesize the activator before mitosis and so suffer less excess delay, whereas, large cells have less time thus suffer greater excess delay. Fifty years later, with our detailed understanding of cell cycle biochemistry, we can identify and test candidate Unstable Accumulating Activators. Here I review the field and further develop this concept. Excess mitotic delay, the phenomenon in which inhibition of protein synthesis causes a longer delay than the pulse of inhibition, is consistent with cell size control by an unstable accumulating activator, but not a stable activator. (shrink)

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number of recent (...) observations suggesting that the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB‐ and S6K‐deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. BioEssays 24:65–71, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Graphical AbstractOrganelles are reaction vessels containing metabolic pathways. As in a chemical factory, the size of the reaction vessels limits the rate of product formation. Organelle size is tuned to metabolic needs, hence reprogramming organelle size could be a novel therapeutic strategy as well as a new tool for metabolic engineering.

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)

Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also its mass. Numerous studies in cells ranging from yeast to mammals have shown that cellular growth, stimulated by nutrients and/or growth factor signaling, is a prerequisite for cell cycle progression in most types of cells. The textbook view of growth‐regulated cell cycles is that growth signaling activates the transcription of G1 Cyclin genes to induce cell proliferation, and also stimulates (...) anabolic metabolism and cell growth in parallel. However, genetic knockout tests in model organisms indicate that this is not the whole story, and new studies show that additional, “smarter” mechanisms help to coordinate the cell cycle with growth itself. Here we summarize recent advances in this field, and discuss current models in which growth signaling regulates cell proliferation by targeting core cell cycle regulators via non‐transcriptional mechanisms. (shrink)

Among all organisms, the size of each body part or organ scales with overall body size, a phenomenon called allometry. The study of shape and form has attracted enormous interest from biologists, but the genetic, developmental and physiological mechanisms that control allometry and the proportional growth of parts have remained elusive. Recent progress in our understanding of body‐size regulation provides a new synthetic framework for thinking about the mechanisms and the evolution of allometric scaling. In particular, insulin/IGF (...) signaling, which plays major roles in longevity, diabetes and the regulation of cell, organ and body size, might also be centrally involved in regulating organismal shape. Here we review recent advances in the fields of growth regulation and endocrinology and use them to construct a developmental model of static allometry expression in insects. This model serves as the foundation for a research program that will result in a deeper understanding of the relationship between growth and form, a question that has fascinated biologists for centuries. BioEssays 29:536–548, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid (...) class='Hi'>cell division are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Honey bees are eusocial insects and the workers inform their nestmates of information regarding the location of food source using symbolic communication, called ‘dance communication’, that are based on their highly advanced learning abilities. Mushroom bodies (MBs), a higher-order center in the honey bee brain, comprise some subtypes/populations of interneurons termed Kenyon cells (KCs) that are distinguished by their cell body size and location in the MBs, as well as their gene expression profiles. Although the role of MBs (...) in learning ability has been studied extensively in the honey bee, the roles of each KC subtype and their evolution in hymenopteran insects remain mostly unknown. This mini-review describes recent progress in the analysis of gene/protein expression profiles and possible functions of KC subtypes/populations in the honey bee. Especially, the discovery of novel KC subtype/population, ‘middle-type KCs’ and ‘KC population expressing FoxP’, necessitated a redefinition of the KC subtype/population. Analysis of the effects of inhibiting gene function in a KC subtype-preferential manner revealed the function of the gene product as well as of the subtype where it is expressed. Genes expressed in a KC subtype/population-preferential manner can be used to trace the differentiation of KC subtypes during the honey bee ontogeny and the possible evolution of KC subtypes in hymenopteran insects. Current findings suggest that the three KC subtypes are unique characteristics to the aculeate hymenopteran insects. Finally, recent application of genome editing for the study of KC subtype functions in the honey bee is described. Genes expressed in a KC subtype-preferential manner can be good candidate target genes for genome editing, because they are likely related to highly advanced brain functions and some of them are dispensable for normal development and sexual maturation in honey bees. (shrink)

From cytological examination, the size and form of the chromosomes in the eukaryotic nucleus are invariant across generations, leading to the expectation that constancy of inheritance likely depends on constancy of the chromosomal DNA molecule conveying the constant phenotype. Indeed, except for rare mutations, major phenotypic traits appear largely without change from generation to generation. Thus, when it was discovered that the inheritance of traits for bacteria, mitochondria and chloroplasts was also constant, it was assumed that chromosomes in those (...) locations were also constant. Such has not turned out to be the case, however; those chromosomes are highly variable in structure. I propose, therefore, that only for the nucleus is there a requirement that a chromosome be “finished” (contain only fully replicated genomes) before it may segregate to daughter cells. This requirement does not apply to the variable chromosomes among chloroplasts, mitochondria and bacteria. BioEssays 29:474–483, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

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

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

Early embryogenesis is marked by a frail Spindle Assembly Checkpoint (SAC). The time of SAC acquisition varies depending on the species, cell size or a yet to be uncovered developmental timer. This means that for a specific number of divisions, biorientation of sister chromatids occurs unsupervised. When error‐prone segregation is an issue, an aneuploidy‐selective apoptosis system can come into play to eliminate chromosomally unbalanced cells resulting in healthy newborns. However, aneuploidy content can be too great to overcome, endangering (...) viability.SAC generates a diffusible signal to lengthen time spent in mitosis if needed, ensuring correct chromosome segregation, a fundamental factor in the generation of euploid cells. Thus, it remains puzzling what benefit could come from delaying SAC acquisition till later in the development. In this review, we describe what is known on SAC acquisition in distinct species and highlight pending research as well as potential applications for such knowledge. (shrink)

During balanced growth of cells in culture all extensive properties of the culture — e.g. cell number, total mass, total DNA content — increase exponentially at the same specific growth rate. Therefore, in some average sense, each component of a cell must double between birth and division. For DNA there exists an elaborate mechanism to ensure precise replication of the genetic material and accurate partitioning of identical copies of the genome to the two daughter cells. Do cells possess (...) another mechanism that intentionally relates the timing of cell division to overall increase in cell size, or is the coordination of growth and division an incidental consequence of size‐independent rules for progress through the cell cycle?. (shrink)

Plant cells are caged within a distended polymeric network (the cell wall), which enlarges by a process of stress relaxation and slippage (creep) of the polysaccharides that make up the load‐bearing network of the wall. Protein mediators of wall creep have recently been isolated and characterized. These proteins, called expansins, appear to disrupt the noncovalent adhesion of matrix polysaccharides to cellulose microfibrils, thereby permitting turgor‐driven wall enlargement. Expansin activity is specifically expressed in the growing tissues of dicotyledons and monocotyledons. (...) Sequence analysis of cDNAs indicates that expansins are novel proteins, without previously known functional motifs. Comparison of expansin cDNAs from cucumber, pea, Arabidopsis and rice shows that the proteins are highly conserved in size and amino acid sequence. Phylogenetic analysis of expansin sequences suggests that this multigene family diverged before the evolution of angiosperms. Speculation is presented about the role of this gene family in plant development and evolution. (shrink)

Hydrogen fuel cells are likely to begin replacing conventional internal combustion engines as a power generation method for transportation applications in the near future. A life cycle analysis of a hydrogen fuel cell was performed to examine the major environmental impacts of such an engine in comparison with an internal combustion engine. To quantify the emissions, material consumption and energy consumption were identified by carrying out mass and energy balances, respectively. Wherever possible, a “well-to-wheel” approach was adopted to identify (...) all the processes involved. The size of the hydrogen fuel cell engine selected was 60 kW, which would power a small automobile weighing around 800 kg. This report briefly describes the materials and processes involved in assembling such an engine, with their respective environmental impacts. Different technologies to build a hydrogen economy also are discussed because hydrogen is an integral part of most fuel cell engines. The main conclusion is that if an environmentally sustainable system of hydrogen production is found, the use of hydrogen and, in turn, hydrogen fuel cell cars would be highly beneficial. Thus, the theoretical potential of fuel cells is great for environmental benefits, but practical applications might prove otherwise. (shrink)

Microfluidic technology – the manipulation of fluids at micrometer scales – has revolutionized many areas of synthetic biology. The bottom‐up synthesis of “minimal” cell models has traditionally suffered from poor control of assembly conditions. Giant unilamellar vesicles (GUVs) are good models of living cells on account of their size and unilamellar membrane structure. In recent years, a number of microfluidic approaches for constructing GUVs has emerged. These provide control over traditionally elusive parameters of vesicular structure, such as (...) class='Hi'>size, lamellarity, membrane composition, and internal contents. They also address sophisticated cellular functions such as division and protein synthesis. Microfluidic techniques for GUV synthesis can broadly be categorized as continuous‐flow based approaches and droplet‐based approaches. This review presents the state‐of‐the‐art of microfluidic technology, a robust platform for recapitulating complex cellular structure and function in synthetic models of biological cells. (shrink)

Gene therapies to treat sickle cell disease are in development and are expected to have high costs. The large eligible population size — by far, the largest for a gene therapy — poses daunting budget challenges and threatens to exacerbate health disparities for Black patients, who make up the vast majority of American sickle cell patients.

The fitness of any evolutionary unit can be understood in terms of its two basic components: fecundity (reproduction) and viability (survival). Trade-offs between these fitness components drive the evolution of life-history traits in extant multicellular organisms. We argue that these trade-offs gain special significance during the transition from unicellular to multicellular life. In particular, the evolution of germ–soma specialization and the emergence of individuality at the cell group (or organism) level are also consequences of trade-offs between the two basic (...) fitness components, or so we argue using a multilevel selection approach. During the origin of multicellularity, we study how the group trade-offs between viability and fecundity are initially determined by the cell level trade-offs, but as the transition proceeds, the fitness trade-offs at the group level depart from those at the cell level. We predict that these trade-offs begin with concave curvature in single-celled organisms but become increasingly convex as group size increases in multicellular organisms. We argue that the increasingly convex curvature of the trade-off function is driven by the cost of reproduction which increases as group size increases. We consider aspects of the biology of the volvocine green algae – which contain both unicellular and multicellular members – to illustrate the principles and conclusions discussed. (shrink)

A fundamental goal of biology is to understand how novel phenotypes evolved through changes in existing genes. The Dictyostelia or social amoebas represent a simple form of multicellularity, where starving cells aggregate to build fruiting structures. This review summarizes efforts to provide a framework for investigating the genetic changes that generated novel morphologies in the Dictyostelia. The foundation is a recently constructed molecular phylogeny of the Dictyostelia, which was used to examine trends in the evolution of novel forms and in (...) the divergence of genes that shape these forms. There is a major trend towards the formation of large unbranched fruiting bodies, which is correlated with the use of cyclic AMP (cAMP) as a secreted signal to coordinate cell aggregation. The role of cAMP in aggregation arose through co‐option of a pathway that originally acted to coordinate fruiting body formation. The genotypic changes that caused this innovation and the role of dynamic cAMP signaling in defining fruiting body size and pattern throughout social amoeba evolution are discussed. BioEssays 29:635–644, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Philosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy (...) of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations. (shrink)

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

A marked feature of eukaryotic programmed cell death is an early drop in mitochondrial transmembrane potential. This results from the opening of permeability transition pores, which are composed of adenine nucleotide translocators and mitochondrial porins. The latter share striking similarites with bacterial porins, (including down‐regulation of their pore size by purine nucleotides), suggesting a common origin. The porins of some invasive bacteria play a crucial role during their accommodation inside the host cell and this co‐existence resembles the (...) endosymbiotic origin of mitochondria. The above observations suggest that early in eukaryotic evolution, former invaders may have used porin‐type channels to enter their host and to induce its death when the levels of its cytoplasmic purine nucleotides were dropped. The appearance of adenosine nucleotide translocators in the primitive eukaryotes, which permitted usage of the oxidative metabolism of the invaders, provided the basis for the permeability transition phenomena, now linked to the apoptotic process. Bcl‐2‐type molecules, being able to modulate the permeability transition pores by interaction with adenosine nucleotide translocators, may have played an essential role in conferring a means of controlling apoptosis. (shrink)

The Schaechter–Maaløe–Kjeldgaard papers, which have their 50th anniversary this year, have major implications for understanding the cell cycle, control of cell growth, control of cell size, metabolic control, the basic bacterial growth curve, and myriad other bacterial and eukaryotic growth phenomena. These ideas have broad applications that should be considered in current studies of the cell cycle. In particular, the emphasis on steady‐state growth conditions, and clear and sharp changes in growth conditions were fundamental to (...) their experiments and have been codified in the principles of the Copenhagen School of Microbiology. BioEssays 30:1019–1024, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Studies on the development of cell populations are often based on results of the theory of stochastic birth- and death-processes (continuous or discrete (seee.g. references inVogel, Niewisch &Matioli (1969), in some cases, death may be interpreted not as actual death of the cell bute.g. as a recruitment of the cell considered into another cell compartment, etc.). It is usually assumed that the conditions for the development are homogeneous,i.e. that the probabilities of births and deaths are independent (...) on the time. However, in most situations, this assumption is not fulfilled (owing to the maturation and differentiation of cells, changes of the microenvironment, inducing factors, etc.). Then it is necessary to study the development of cell populations under non-homogeneous conditions. In this paper, some properties of appropriate birth- and death-processes under nonhomogeneous conditions are studied; formulae given in section 4 permit calculation of some characteristics describing the cell population size distribution at individual discrete epochs (at individual generations) during the development of the cell population considered. (shrink)

The Drosophila Bolwig organs are small photoreceptor bundles that facilitate the phototactic behavior of the larva. Comparative literature suggests that these highly reduced visual organs share evolutionary ancestry with the adult compound eye. A recent molecular genetic study produced the first detailed account of the mechanisms controlling differential opsin expression and photoreceptor subtype determination in these enigmatic eyes of the Drosophila larva. Here, the evolutionary implications are examined, taking into account the dynamic diversification of opsin genes and the spatial regulation (...) of opsin homolog expression in other insects. It is concluded that, consistent with their common evolutionary roots, the Drosophila larval and adult eyes use the same mechanisms for the regulation of opsin expression and photoreceptor cell fate specification. Strikingly, the structurally highly derived Bolwig organs retained a more ancestral state of opsin expression and regulation. Inconspicuous in size, the Drosophila larval eyes deliver useful lessons in the reconstruction of homology between neuronal cell types with gene expression data, and on the conservative nature of gene regulatory network evolution during the emergence of novel organs from ancestral templates. BioEssays 30:980–993, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The ability to improve diagnosis and refine prognosis in children with acute leukaemia is improving steadily. A growing number of tests can and are being performed on leukaemic cells. These include surface-marker analysis, DNA content, cytogenetics and studies of gene rearrangements. Increasingly large bone-marrow samples, now usually obtained under general anaesthesia, are required to make secure diagnoses. Ethical issues arise from three major areas. 1) Current research on leukaemia cells requested by the Medical Research Council is considered by local research (...) ethics committees, but parents are not regularly given detailed information about or asked specifically to consent to such research; 2) substantial quantities of excess cells are stored indefinitely. This archive of stored material is a valuable resource for research but there has been little consideration of the ethical issues which arise from this practice, and 3) there is a potential for pressure to obtain increasingly large samples. 'Creeping growth' in sample size is likely to continue unless ethics committees consider future research proposals in more detail. These issues deserve attention in order that worthwhile research and its publication are not impeded for want of ethical consideration. The implications extend beyond the field of childhood leukaemia. (shrink)

The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous (...) normal cells is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem‐like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of “order in the large over heterogeneity in the small”. BioEssays 28: 515–524, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Many feel the Common Rule treats an unwieldy range of activities identically under the monolithic label "human subjects research." Past objections centering on the conflation of biomedical and behavioral research have gained new currency with the increase in biobanking and Internet-based research. A more nuanced approach to research is overdue. Regulation will no doubt remain a major component of any new approach. But in some research contexts, investigators and subjects should be permitted to reach voluntary, informed agreements about certain aspects (...) of their relationship.Consider the National Institutes of Health's new "Guidelines for Human Stem Cell Research."1 The guidelines owe their existence to the NIH's .. (shrink)

Segmentation of the medical image plays a significant role when it comes to diagnosis using computer aided system. This article focuses on the human corneal endothelium’s health, which is one of the filed research interests, especially in the human cornea. Various pathological environments fasten the extermination of the endothelial cells, which in turn decreases the cell density in an abnormal manner. Dead cells worsen the hexagonal design. The mutilated endothelial cells can no longer revive back and that gives room (...) for neighbouring cells to migrate and expand so that they can fill in the space. The latter results in cell elongation that is unpredictable as well as increase in size and thinning. Cell density and shape are therefore considered major parameters when it comes to explaining the health condition attributed to corneal endothelium. In this study, medical feature extraction was obtained depending on the segmentation of the endothelial cell boundary, and the task of segmentation of such objects especially the thin, transparent, and unclear cell boundary is considered challenging due to the nature of the image capture during endothelium layer examination by ophthalmologists using confocal or specular microscopy. The resulting image suffers from various issues that affect the quality of the image. Low quality is due to non-uniformity of illumination and the presence of a lot of noise and artefacts resulting from high amounts of distortion, and most of these limitations are present because of the nature of the imaging modality. Usually, images contain certain kind of noise and also continuous shadow. Furthermore, the cells are separated by poor border, thereby leading to great difficulty in the segmentation of the images. The irregular shape of cell and also the contrast of such images seem to be low as they possess blurry boundaries with diverse objects existing in addition to the lack of homogeneity. The main aim of the study is to propose and develop a totally automatic, robust, and real-time model for the segmentation of endothelial cells of the human cornea obtained by in vivo microscopy and computation of different clinical features of endothelial cells. To achieve the aim of this study a new scheme of image enhancement was proposed such as the Contrast-Limited Adaptive Histogram Equalisation technique to enhance contrast. After that, a new image denoising technique called Wavelet Transform Filter and Butterworth Bandpass for Segmentation is used. Subsequently, brightness level correction is applied by using the moving average filter and the CLAHE to reduce the effects of the non-uniform image lighting produced as a result of the previous step. The main aim of this article is the segmentation of endothelial cells, which involves precise detection of the endothelial contours. So a new segmentation model was proposed such that the shape of the cells will be extracted, and the contours were highlighted. This stage is followed by clinical feature extraction and uses the features for diagnosis. In this stage, several relevant clinical features such as pleomorphism mean cell perimeter, mean cell density, mean cell area, and polymegathism are extracted. The role of these clinical features is crucial for the early detection of corneal pathologies as well as the evaluation of the health of the corneal endothelium layer. The findings of this study were promising. (shrink)

The transparent sea urchin embryo provides a laboratory for study of morphogenesis. The calcareous endoskeleton is formed by a syncytium of mesenchyme cells in the blastocoel. The locations of mesenchyme in the blastocoel, the size of the skeleton, and even the branching pattern of the skeletal rods, are governed by interactions with the blastula wall. Now Guss and Ettensohn(1) show that the rate of deposition of CaCO3 in the skeleton is locally controlled in the mesenchymal syncytium, as is the (...) pattern of expression of three genes involved in skeleton formation. They propose that short range signals emanating from the blastula wall regulate many aspects of the biomineralization process. (shrink)

The set of 60 real rays in four dimensions derived from the vertices of a 600-cell is shown to possess numerous subsets of rays and bases that provide basis-critical parity proofs of the Bell-Kochen-Specker (BKS) theorem (a basis-critical proof is one that fails if even a single basis is deleted from it). The proofs vary considerably in size, with the smallest having 26 rays and 13 bases and the largest 60 rays and 41 bases. There are at least (...) 90 basic types of proofs, with each coming in a number of geometrically distinct varieties. The replicas of all the proofs under the symmetries of the 600-cell yield a total of almost a hundred million parity proofs of the BKS theorem. The proofs are all very transparent and take no more than simple counting to verify. A few of the proofs are exhibited, both in tabular form as well as in the form of MMP hypergraphs that assist in their visualization. A survey of the proofs is given, simple procedures for generating some of them are described and their applications are discussed. It is shown that all four-dimensional parity proofs of the BKS theorem can be turned into experimental disproofs of noncontextuality. (shrink)

The origin of mitosis and the nuclear envelope were the pivotal processes in the evolutionary origin of the nucleus; they probably occurred in a wall‐less mutant bacterium that evolved a cytoskeleton and phagocytosis about 1500 million years ago. Principles of intracellular coevolution clarify their origin, as well as that of nucleosomes, spliceosomes, and the evolution of genome size.

Constraining collective cell migration in vitro using different types of engineered substrates such as microstructured surfaces or adhesive patterns of different shapes and sizes often leads to the emergence of specific patterns of motion. Recently, analogies between the behavior of cellular assemblies and that of active fluids have enabled significant advances in our understanding of collective cell migration; however, the physiological relevance and potential functional consequences of the resulting migration patterns remain elusive. Here we describe the different patterns (...) of collective cell migration that have been reported in vitro in response to geometrical constraints, explore the in vivo pertinence of the in vitro systems used to impose the geometrical constraints, and discuss the potential physiological ramifications of the collective migration patterns that emerge as a result of physical constraints. We conclude by highlighting key upcoming challenges in the exciting field of constrained collective cell migration. (shrink)

The aim of this work is twofold. First, we survey the techniques developed in Perthame and Zubelli (Inverse Probl 23(3):1037–1052, 2007 ), Doumic et al. (Inverse Probl 25, 2009 ) to reconstruct the division (birth) rate from the cell volume distribution data in certain structured population structured population models. Secondly, we implement such techniques on experimental cell volume distributions available in the literature so as to validate the theoretical and numerical results. As a proof of concept, we use (...) the experimental data experimental data reported in the classical work of Kubitschek (Biophys J 9(6):792–809, 1969 ) concerning Escherichia coli in vitro experiments measured by means of a Coulter transducer-multichannel analyzer system (Coulter Electronics, Inc., Hialeah, FL, USA). Despite the rather old measurement technology, the reconstructed division rates still display potentially useful biological features. (shrink)

Oncogenic hyperplasia is the first and inevitable stage of formation of a (solid) tumor. This stage is also the core of many other proliferative diseases. The present work proposes the first minimal model that combines homeorhesis with oncogenic hyperplasia where the latter is regarded as a genotoxically activated homeorhetic dysfunction. This dysfunction is specified as the transitions of the fluid of cells from a fluid, homeorhetic state to a solid, hyperplastic-tumor state, and back. The key part of the model is (...) a nonlinear reaction-diffusion equation (RDE) where the biochemical-reaction rate is generalized to the one in the well-known Schlögl physical theory of the non-equilibrium phase transitions. A rigorous analysis of the stability and qualitative aspects of the model, where possible, are presented in detail. This is related to the spatially homogeneous case, i.e. when the above RDE is reduced to a nonlinear ordinary differential equation. The mentioned genotoxic activation is treated as a prevention of the quiescent G0-stage of the cell cycle implemented with the threshold mechanism that employs the critical concentration of the cellular fluid and the nonquiescent-cell-duplication time. The continuous tumor morphogeny is described by a time-space-dependent cellular-fluid concentration. There are no sharp boundaries (i.e. no concentration jumps exist) between the domains of the homeorhesis- and tumor-cell populations. No presumption on the shape of a tumor is used. To estimate a tumor in specific quantities, the model provides the time-dependent tumor locus, volume, and boundary that also points out the tumor shape and size. The above features are indispensable in the quantitative development of antiproliferative drugs or therapies and strategies to prevent oncogenic hyperplasia in cancer and other proliferative diseases. The work proposes an analytical-numerical method for solving the aforementioned RDE. A few topics for future research are suggested. (shrink)

Stomata are microscopic pores on the surface of land plants used for gas and water vapor exchange. A pair of highly specialized guard cells surround the pore and adjust pore size. Studies in Arabidopsis have revealed that cell–cell communication is essential to coordinate the asymmetric cell divisions required for proper stomatal patterning. Initial research in this area identified signaling molecules that negatively regulate stomatal differentiation. However, genes promoting cell‐fate transition leading to mature guard cells remained (...) elusive. Now, three closely related basic helix–loop–helix (bHLH) proteins, SPEECHLESS, MUTE and FAMA have been identified as positive regulators that direct three consecutive cell‐fate decisions during stomatal development. The identification of these genes opens a new direction to investigate the evolution of stomatal development and the conserved functions of bHLH proteins in cell type differentiation adopted by plants and animals. BioEssays 29:861–870, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Ischemic stroke involves numerous and complex pathophysiological mechanisms including blood flow reduction, ionic exchanges, spreading depressions and cell death through necrosis or apoptosis. We used a mathematical model based on these phenomena to study the influences of intensity and duration of ischemia on the final size of the infarcted area. This model relies on a set of ordinary and partial differential equations. After a sensibility study, the model was used to carry out in silico experiments in various ischemic (...) conditions. The simulation results show that the proportion of apoptotic cells increases when the intensity of ischemia decreases, which contributes to the model validation. The simulation results also show that the influence of ischemia duration on the infarct size is more complicated. They suggest that reperfusion is beneficial when performed in the early stroke but may be either inefficacious or even deleterious when performed later after the stroke onset. This aggravation could be explained by the depolarisation waves which might continue to spread ischemic damage and by the speeding up of the apoptotic process leading to cell death. The effect of reperfusion on cell death through these two phenomena needs to be further studied in order to develop new therapeutic strategies for stroke patients. (shrink)

Cells and tissue within injured organs undergo a complicated healing process that still remains poorly understood. Interestingly, smaller organisms respond to injury with tissue regeneration and restoration of function, while humans and other large organisms respond to injury by forming dysfunctional, fibrotic scar tissue. Over the past few decades, allometric scaling principles have been well established to show that larger organisms experience exponentially higher tissue forces during movement and locomotion and throughout the organism's lifespan. How these evolutionary adaptations may affect (...) tissue injury has not been thoroughly investigated in humans. We discuss how these adapations may affect healing and demonstrate that blocking the most evolutionary conserved biologic force sensor enables large organisms to heal after injury with true tissue regeneration. Future strategies to disrupt tissue force sensors may unlock the key to regenerating after injury in a wide range of organ systems. (shrink)

The production, distribution and use of electricity can generate low frequency electric and magnetic fields (50–60 Hz). Considering that some studies showed adverse effects on pancreatic β-cells exposed to these fields; the present study aimed to analyze the effects of 60 Hz electric fields on membrane potential during the silent and burst phases in pancreatic β-cells using a mathematical model. Sinusoidal 60 Hz electric fields with amplitude ranging from 0.5 to 4 mV were applied on pancreatic β-cells model. The sinusoidal (...) electric field changed burst duration, inter-burst intervals (silent phase) and spike sizes. The parameters above presented dose-dependent response with the voltage amplitude applied. In conclusion, theoretical analyses showed that a 60 Hz electric field with low amplitudes changes the membrane potential in pancreatic β-cells. (shrink)

Cellular pattern formations of some epithelia are believed to be governed by the direct lateral inhibition rule of cell differentiation. That is, initially equivalent cells are all competent to differentiate, but once a cell has differentiated, the cell inhibits its immediate neighbors from following this pathway. Such a differentiation repeats until all non-inhibited cells have differentiated. The cellular polygonal patterns can be characterized by the numbers of undifferentiated cells and differentiated ones. When the differentiated cells become large (...) in size, the polygonal pattern is deformed since more cells are needed to enclose the large cell. An actual example of such a cellular pattern was examined. The pupal wing epidermis of a butterfly Pieris rapae shows a transition of the equivalent-size cell pattern to the pattern involving large cells. The process of the transition was analyzed by using the method of weighted Voronoi tessellation that is useful for treatment of irregularly sized polygons. The analysis supported that the pattern transition of the early stage of the pupal wing epidermis is governed by the lateral inhibition rule. The differentiation takes place in order of largeness, but not smallness, of the apical polygonal area in the differentiating region of the pupal wing. (shrink)

This book is about how big is the universe and how small are quarks, and what are the sizes of dozens of things between these two extremes. It describes the sizes of atoms and planets, quarks and galaxies, cells and sequoias. It is a romp through forty-five orders of magnitude from the smallest sub-nuclear particles we have measured, to the edge of the observed universe. It also looks at time, from the epic age of the cosmos to the fleeting lifetimes (...) of ethereal particles. It is a narrative that trips its way from stellar magnitudes to the clocks on GPS satellites, from the nearly logarithmic scales of a piano keyboard through a system of numbers invented by Archimedes and on to the measurement of the size of an atom. (shrink)

A flurry of technological advances in molecular, cellular and developmental biology during the past decade has provided a clearer understanding of mechanisms underlying phenotypic diversification. Building upon such momentum, a recent paper tackles one of the foremost topics in evolution, that is the origin of species‐specific beak morphology in Darwin's finches.1 Previous work involving both domesticated and wild birds implicated a well‐known signaling pathway (i.e. bone morphogenetic proteins) and one population of progenitor cells in particular (i.e. cranial neural crest), as (...) primary factors for establishing beak size and shape. But these results were limited in their ability to explain fully the morphogenetic bases of patterned outgrowth. So in a quest to identify novel genes whose expression correlated with differences in beak anatomy among Darwin's finches, a DNA microarray approach was undertaken using tissues harvested from the Galápagos Islands. The results are striking and point to a protein called calmodulin, which is a mediator of cellular calcium signaling, as a key determinant of beak length. BioEssays 29: 1–6, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

hiCLIP (RNA hybrid and individual‐nucleotide resolution ultraviolet cross‐linking and immunoprecipitation), is a novel technique developed by Sugimoto et al. (2015). Here, the use of different adaptors permits a controlled ligation of the two strands of a RNA duplex allowing the identification of each arm in the duplex upon sequencing. The authors chose a notoriously difficult to study double‐stranded RNA‐binding protein (dsRBP) termed Staufen1, a mammalian homolog of Drosophila Staufen involved in mRNA localization and translational control. Using hiCLIP, they discovered a (...) dominance of intramolecular RNA duplexes compared to the total RNA duplexes identified. Importantly, the authors discovered two different types of intramolecular duplexes in the cell: highly translated mRNAs with long‐range duplexes in their 3′‐UTRs and poorly translated mRNAs with duplexes in their coding region. In conclusion, the authors establish hiCLIP as an important novel technique for the identification of RNA secondary structures that serve as in vivo binding sites for dsRBPs. (shrink)

Cell size is an important determinant of body size. While the genetic mechanisms of cell size regulation have been well studied in yeast, this process has only recently been addressed in multicellular organisms. One recent report by Wang et al. (2002) shows that in the nematode C. elegans, the TGFβ‐like pathway acts in the hypodermis to regulate cell size and consequently body size.1 This finding is an exciting step in discovering the molecular (...) mechanisms that control cell and body size. BioEssays 25:305–308, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Two main attempts have been suggested for the biological significance of endopolyploidy: (i) provision of high DNA amounts to support high synthetic demands in certain cells and (ii) compensation for a lack of nuclear DNA in species with small genomes. However, in seed plants, the positive correlation between DNA content and cell volume of endopolyploid cells suggests other possibilities. Cell size paralleled by the endopolyploidy level has an impact on growth and development. Endopolyploidy levels in turn are (...) characteristic for a given species and even families, reflecting the adaptation to certain habitats during phylogeny. Furthermore, endopolyploidy levels vary to some degree between individuals of one species in response to different environmental conditions. In addition, endopolyploidy differs between different tissues suggests that a certain cell size is advantageous for a given cell function. This article reviews these findings and discusses more conclusive possible functions of endopolyploidy. BioEssays 28: 271–281, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Diatoms are a species‐rich group of photosynthetic eukaryotes, with enormous ecological significance and great potential for biotechnology. During the last decade, diatoms have begun to be studied intensively using modern molecular techniques and the genomes of four diatoms have been wholly or partially sequenced. Although new insights into the biology and evolution of diatoms are accumulating rapidly due to the availability of reverse genetic tools, the full potential of these molecular biological approaches can only be fully realized if experimental control (...) of sexual crosses becomes firmly established and widely accessible to experimental biologists. Here we discuss the issue of choosing new models for diatom research, by taking into account the broader context of diatom mating systems and the place of sex in relation to the intricate cycle of cell size reduction and restitution that is characteristic of most diatoms. We illustrate the results of our efforts to select and develop experimental systems in diatoms, using species with typical life cycle attributes, which could be used as future model organisms to complement existing ones. BioEssays 30:692–702, 2008. © 2008 Wiley Periodicals, Inc. (shrink)