Constraints Shape Cell Function and Morphology by Canalizing the Developmental Path along the Waddington's Landscape

Studies performed in absence of gravitational constraint show that a living system is unable to choose between two different phenotypes, thus leading cells to segregate into different, alternative stable states. This finding demonstrates that the genotype does not determine by itself the phenotype but requires additional, physical constraints to finalize cell differentiation. Constraints belong to two classes: holonomic (independent of the system's dynamical states, as being established by the space-time geometry of the field) and non-holonomic (modified during those biological processes to which they contribute in shaping). This latter kind of “constraints”, in which dynamics works on the constraint to recreate them, have emerged as critical determinants of self-organizing systems, by manifesting a “closure of constraints.” Overall, the constraints act by harnessing the “randomness” represented by the simultaneous presence of equiprobable events restraining the system within one attractor. These results cast doubt on the mainstream scientific concept and call for a better understanding of causation in cell biology.     

Plant morphogenesis: A geometrical model for the ramification

A geometrical model is proposed that describes the emergence of a primordium at the shoot apex in Dicotyledons. It is based on recent fundamental results on plant morphogenesis, viz.:

the emergence is preceded by the reorganization of the microtubules of the cortical cytoskeleton, leading to a new orientation of the synthesis of the cell wall microfibrils;

the resulting global stress is related to the general orientation of the cell growth;

The model sums up the continuous interactions that link the microtubules, the microfibrils and the cell growth axis. The paper tries to answer three essential questions:

Why does the principal stem shifts its growth direction after each lateral emergence?

Why do the three axes involved in any ramification (namely the old and the new principal stems and the lateral emergence) exhibit a plane configuration whereas this is an essentially three dimensional phenomenon?

Does phyllotaxis exclusively depend upon the local emergence of a primordium?

An interactive procedure between empirical botanical knowledge and the mathematical model leads to an insight of the compatibility mechanisms that link the various microtubules and microfibrils networks, and the apical dome restoration. A geometrical formalism allows a redefinition of both the “generating centre” and the “organizing centre”, and their field effect.     

Metaphors in search of a target: the curious case of epigenetics

Carrying out research in genetics and genomics and communicating about them would not be possible without metaphors such as “information,” “code,” “letter” or “book.” Genetic and genomic metaphors have remained relatively stable for a long time but are now beginning to shift in the context of synthetic biology and epigenetics. This article charts the emergence of metaphors in the context of epigenetics, first through collecting some examples of metaphors in scientific and popular writing and second through a systematic analysis of metaphors used in two UK broadsheets. Findings show that while source domains for metaphors can be identified, such as our knowledge of electrical switches or of bookmarks, it is difficult to pinpoint target domains for such metaphors. This may be indicative both of struggles over what epigenetics means for scientists (natural and social) and of difficulties associated with talking about this, as yet, young field in the popular press.     

NCI Workshop Report: Clinical and Computational Requirements for Correlating Imaging Phenotypes with Genomics Signatures

The National Cancer Institute (NCI) Cancer Imaging Program organized two related workshops on June 26–27, 2013, entitled “Correlating Imaging Phenotypes with Genomics Signatures Research” and “Scalable Computational Resources as Required for Imaging-Genomics Decision Support Systems.” The first workshop focused on clinical and scientific requirements, exploring our knowledge of phenotypic characteristics of cancer biological properties to determine whether the field is sufficiently advanced to correlate with imaging phenotypes that underpin genomics and clinical outcomes, and exploring new scientific methods to extract phenotypic features from medical images and relate them to genomics analyses. The second workshop focused on computational methods that explore informatics and computational requirements to extract phenotypic features from medical images and relate them to genomics analyses and improve the accessibility and speed of dissemination of existing NIH resources. These workshops linked clinical and scientific requirements of currently known phenotypic and genotypic cancer biology characteristics with imaging phenotypes that underpin genomics and clinical outcomes. The group generated a set of recommendations to NCI leadership and the research community that encourage and support development of the emerging radiogenomics research field to address short-and longer-term goals in cancer research.     

GENETIC AND MORPHOLOGICAL ANALYSES OF THE SOUTHERN BULL KELP DURVILLAEA ANTARCTICA (PHAEOPHYCEAE: DURVILLAEALES) IN NEW ZEALAND REVEAL CRYPTIC SPECIES1

Many macroalgae exhibit considerable intraspecific morphological variation, but whether such variation reflects phenotypic plasticity or underlying genetic differences is often poorly understood. We quantified both morphological and genetic variation of 96 plants from seven field sites across eastern South Island, New Zealand, to assess genetic differences between morphotypes of the southern bull kelp Durvillaea antarctica (Cham.) Har. Consistent DNA sequence differentiation across mitochondrial, plastid, and nuclear loci was correlated with two broadly sympatric morphotypes: “cape” and “thonged.” These ecologically, morphologically, and genetically distinct bull‐kelp lineages were previously considered to be environmentally determined phenotypes with no underlying genetic basis. Interestingly, the sheltered “cape” lineage appears essentially genetically uniform across its South Island range, whereas the exposed “thonged” lineage exhibits marked phylogeographic structure across its range. Results suggest that D. antarctica in New Zealand comprises two reproductively isolated species.     

Rat brain monoamine levels related to behavioral assessment

Randomly selected adult, male, Sprague-Dawley rats exhibit a range of behaviors in an open field. Exploration without defecation or urination is interpreted as stable behavior. On the basis of their open field behavior we selected the five most “emotional” and five most “stable” rats from two separate groups of thirty rats. Norepinephrine (NE), dopamine (DA), and serotonin (5HT) levels were determined in brains from these ten “emotional” and ten “stable” rats. The NE levels of “emotional” rats were elevated about 60 ng/g relative to the “stable” rats. There was no difference in DA levels, but there appeared to be a trend toward elevation of 5HT levels in the “emotional” rats. These findings directly support the hypothesis that elevated central nervous system norepinephrine levels may reflect a factor which contributes to emotionality in the rat, and suggest that brain norepinephrine levels may be a biochemical mechanism which influences performance as seen with the commonly used open field behavioral test of emotionality.     

A curated gene list for expanding the horizons of pigmentation biology

Over the past century, studies of human pigmentary disorders along with mouse and zebrafish models have shed light on the many cellular functions associated with visible pigment phenotypes. This has led to numerous genes annotated with the ontology term “pigmentation” in independent human, mouse, and zebrafish databases. Comparisons among these datasets revealed that each is individually incomplete in documenting all genes involved in integument‐based pigmentation phenotypes. Additionally, each database contained inherent species‐specific biases in data annotation, and the term “pigmentation” did not solely reflect integument pigmentation phenotypes. This review presents a comprehensive, cross‐species list of 650 genes involved in pigmentation phenotypes that was compiled with extensive manual curation of genes annotated in OMIM, MGI, ZFIN, and GO. The resulting cross‐species list of genes both intrinsic and extrinsic to integument pigment cells provides a valuable tool that can be used to expand our knowledge of complex, pigmentation‐associated pathways.     

Organogenesis at the shoot apex: An attempt at modelization

A geometrical model of the emergence of a primordium at the shoot apex in dicotyledons is proposed. It is based on recent fundamental results on plant morphogenesis, i.e.:

1. the emergence is preceded by the reorganization of the microtubules of the cortical cytoskeleton, leading to a new orientation of the synthesis of the cell wall microfibrils;
2. the resulting global stress is related to the general orientation of the cell growth.

So the model sums up the continuous interactions linking the microtubules, the microfibrils and the cell growth axis. This paper tries to answer three questions which are essential from a botanical point of view:

1. Why does the principal stem shift its growth direction after each lateral emergence?
2. Why do the three axes involved in any ramification (namely the old and the new principal stems and the lateral emergence) exhibit a plane configuration whereas this is an essentially three dimensional phenomenon?
3. Does phyllotaxis exclusively depend upon the local emergence of a primordium?

A come and go between the botanical knowledge and the mathematical model leads to an integrated view of the compatibility mechanisms linking the different microtubules and microfibrils networks, without forgetting the apical dome restoration. A geometrical formalism allows a modern redefinition of both the “generating centre” and the “organizing centre” and their field effects.     

Does Aging Have a Purpose?

Ideas of proponents and opponents of programmed aging concerning the expediency of this phenomenon for the evolution of living organisms are briefly considered. We think that evolution has no “gerontological” purpose, because the obligate restriction of cell proliferation during the development of multicellular organisms is a factor that “automatically” triggers aging due to the accumulation of various macromolecular lesions in cells as a result of the suppression, or even complete cessation of emergence of new, intact cells. This leads to the “dilution” of stochastic damage (the most important of which is DNA damage) at the level of the entire cellular population. Some additional arguments in favor of the inexpediency of aging for both species and individuals are also listed.     

Body composition determinants of metabolic phenotypes of obesity in nonobese and obese postmenopausal women

Objective : Although obesity is typically associated with increased cardiovascular risk, a subset of obese individuals display a normal metabolic profile (“metabolically healthy obese,” MHO) and conversely, a subset of nonobese subjects present with obesity‐associated cardiometabolic abnormalities (“metabolically obese nonobese,” MONO). The aim of this cross‐sectional study was to identify the most important body composition determinants of metabolic phenotypes of obesity in nonobese and obese healthy postmenopausal women. Design and Methods : We studied a total of 150 postmenopausal women (age 54 ± 7 years, mean ± 1 SD). Based on a cardiometabolic risk score, nonobese (body mass index [BMI] ≤ 27) and obese women (BMI > 27) were classified into “metabolically healthy” and “unhealthy” phenotypes. Total and regional body composition was assessed with dual‐energy X‐ray absorptiometry (DXA). Results : In both obese and nonobese groups, the “unhealthy” phenotypes were characterized by frequent bodyweight fluctuations, higher biochemical markers of insulin resistance, hepatic steatosis and inflammation, and higher anthropometric and DXA‐derived indices of central adiposity, compared with “healthy” phenotypes. Indices of total adiposity, peripheral fat distribution and lean body mass were not significantly different between “healthy” and “unhealthy” phenotypes. Despite having increased fat mass, MHO women exhibited comparable cardiometabolic parameters with healthy nonobese, and better glucose and lipid levels than MONO. Two DXA‐derived indices, trunk‐to‐legs and abdominal‐to‐gluteofemoral fat ratio were the major independent determinants of the “unhealthy” phenotypes in our cohort. Conclusions : The “metabolically obese phenotype” is associated with bodyweight variability, multiple cardiometabolic abnormalities and an excess of central relative to peripheral fat in postmenopausal women. DXA‐derived centrality ratios can discriminate effectively between metabolic subtypes of obesity in menopause.     

The Play is Now Reality: Affective Turns, Narrative Struggles, and Theorizing Emotion as Practical Experience

Discursive approaches to subjectivity have been critiqued most recently for its dismissal of a living body that moves and senses. While identity as performative has proven invaluable to contemporary cultural theory for its dynamic conceptualization of power in everyday practice, the emergence of what some scholars have named an “affective turn” has prompted calls for configuring the body as more than a complex set of significations, but also a vibrant energy field in perpetual emergence. Centered on an enacted story created by two clinical therapists and two South Asian immigrant domestic violence survivors during a therapeutic support group session, this paper brings the affective turn into dialog with narrative theory. I juxtapose two different readings of this clinical “performance.” One interpretation recognizes affect theory’s value for highlighting sensation and the virtual in moments of transformation. Nonetheless I argue it overlooks a lived history. Thus, using a specifically dramatistic approach to narrative, the second analysis stresses the importance of personal experience and meaning-making in strengthening the link between affect and subjectivity. In doing so, the case study also argues for emotion’s critical link to practical and moral experience.     

DNA Repair: A changing geography? (1964–2008)

This article aims to explain the current state of DNA Repair studies’ global geography by focusing on the genesis of the community. Bibliometric data is used to localize scientific activities related to DNA Repair at the city level. The keyword “DNA Repair” was introduced first by American scientists. It started to spread after 1964 that is to say, after P. Howard-Flanders (Yale University), P. Hanawalt (Stanford University) and R. Setlow (Oak Ridge Laboratories) found evidence for Excision Repair mechanisms. It was the first stage in the emergence of an autonomous scientific community. In this article, we will try to assess to what extent the geo-history of this scientific field is determinant in understanding its current geography. In order to do so, we will localize the places where the first “DNA Repair” publications were signed fifty years ago and the following spatial diffusion process, which led to the current geography of the field. Then, we will focus on the evolution of the research activity of “early entrants” in relation to the activity of “latecomers”. This article is an opportunity to share with DNA Repair scientists some research results of a dynamic field in Science studies: spatial scientometrics.     

Monte Carlo simulation of early molecular evolution in the RNA World

The origin of life remains a highly speculative field, mainly due to the shortage of our knowledge on prebiotic chemistry and basic understanding on the essence of life. In this context, computer simulation is expected to play an important role. For instance, the scenario concerning the genesis of the widely accepted RNA World remains blurry, though we have gathered some circumstantial evidence and fragmented knowledge on several supposed stages, including formation of polynucleotides from a prebiotic nucleotide pool, emergence of RNA replicases (RNA molecules catalyzing their own replication), and evolution of RNA replicases. It is highly valuable to simulate the stages as a continuous process to evaluate the plausibility of the supposition and study the rules involved. Here we construct a computer simulation on the process using Monte Carlo method. It demonstrates that primordial RNA replicases may appear and spread in a nucleotide pool provided they could recognize their own sequence and their complements as catalytic targets, and then may evolve to more efficient RNA replicases. Apart from its indication on the genesis of the RNA World, the vivid simulation of emergence of the “first replicative molecules” and their subsequent evolution is impressive and may help to get insight into “how could self-replication and Darwinian evolution, two key features of life, emerge in a non-life background?” thus improve our understanding of “what is life” when studying origins of life.     

Transgressive Hybrids as Hopeful Monsters

The origin of novelty is a critical subject for evolutionary biologists. Early geneticists speculated about the sudden appearance of new species via special macromutations, epitomized by Goldschmidt’s infamous “hopeful monster”. Although these ideas were easily dismissed by the insights of the Modern Synthesis, a lingering fascination with the possibility of sudden, dramatic change has persisted. Recent work on hybridization and gene exchange suggests an underappreciated mechanism for the sudden appearance of evolutionary novelty that is entirely consistent with the principles of modern population genetics. Genetic recombination in hybrids can produce transgressive phenotypes, “monstrous” phenotypes beyond the range of parental populations. Transgressive phenotypes can be products of epistatic interactions or additive effects of multiple recombined loci. We compare several epistatic and additive models of transgressive segregation in hybrids and find that they are special cases of a general, classic quantitative genetic model. The Dobzhansky-Muller model predicts “hopeless” monsters, sterile and inviable transgressive phenotypes. The Bateson model predicts “hopeful” monsters with fitness greater than either parental population. The complementation model predicts both. Transgressive segregation after hybridization can rapidly produce novel phenotypes by recombining multiple loci simultaneously. Admixed populations will also produce many similar recombinant phenotypes at the same time, increasing the probability that recombinant “hopeful monsters” will establish true-breeding evolutionary lineages. Recombination is not the only (or even most common) process generating evolutionary novelty, but might be the most credible mechanism for sudden appearance of new forms.     

Simulation of gravitational field variation on fluid-filled biological membranes

The knowledge of the behavior of biological organs in a gravitational field is important to understand the functioning of the human body in the aerospace environment. The disturbances in biological transport processes in microgravity have indicated adverse effects on humans engaged in space operations. The relationship between the deformations in the biological organs and the transport phenomena that take place in them has been long established and widely reported in biological sciences and engineering literature. A number of soft tissue organs such as brain, lungs, heart, kidney, bladder, stomach, and the circulatory system can be modeled as fluid-filled membranes. In this investigation, a mathematical model of a fluid-filled biological membrane is developed, and its deformation and spatial configuration in a variable gravitational field are calculated. The variation in the gravitational field in the range 1g to zero-g is simulated by partial submergence of the fluid-filled membrane which, by virtue of buoyancy, gains an effective density as if it is in a different gravitational field. The equations of motion are derived using the theory of large elastic deformations and numerically solved in conjunction with a constitutive equation suitably selected for the biological membrane.     

Extending experimentation: oncology’s fading boundary between research and care

Historians and social scientists view the distinction between research and care as diachronically and synchronically contingent, rather than transcendental, as is often the case in bioethics. Comparing how the notion of total care was used in the 1950s with present-day use of that same term by genomically informed oncology programs, the paper argues that the distinction between research and care needs: to be historicized, by examining its repeated emergence and re-definition, and the shifting relations between these two “ideal-typical” components; and to be problematized, by paying attention to the entities, practices, and institutions that are constitutive of the successive regimens that have punctuated oncology’s development. Shifting to contemporary activities, the paper examines how the recent massive injection of molecular biology and high-throughput genomic technologies in the field of oncology has been accompanied by a reshuffling of the research/care distinction, a process that is leading to new forms of “experimental care”.     

Synthesis of a Smart Gold Nano‐vehicle for Liver Specific Drug Delivery

Targeting drug formulations to specific tissues and releasing the bioactive content in response to a certain stimuli remains a significant challenge in the field of biomedical science. We have developed a nanovehicle that can be used to deliver “drugs” to “specific” tissues. For this, we have simultaneously modified the surface of the nanovehicle with “drugs” and “tissue-specific ligands”. The “tissue-specific ligands” will target the nanovehicle to the correct tissue and release the “drug” of interest in response to specific stimuli. We have synthesised a “lactose surface-modified gold nanovehicle” to target liver cells and release the model fluorescent drug (coumarin derivative) in response to the differential glutathione concentration (between blood plasma and liver cells). Lactose is used as the liver-specific targeting ligand given the abundance of l-galactose receptors in hepatic cells. The coumarin derivative is used as a fluorescent tag as well as a linker for the attachment of various biologically relevant molecules. The model delivery system is compatible with a host of different ligands and hence could be used to target other tissues as well in future. The synthesised nanovehicle was found to be non-toxic to cultured human cell lines even at elevated non-physiological concentrations as high as 100 μg/mL. We discover that the synthesised gold-based nanovehicle shows considerable stability at low extracellular glutathione concentrations; however coumarin is selectively released at high hepatic glutathione concentration.     

Acute exposure to 50 Hz magnetic field does not affect hematologic or immunologic functions in healthy young men: A circadian study

Some epidemiological studies report a relationship between magnetic field exposure and such human diseases as leukemia and immune system disturbances. The few published studies on animals do not demonstrate field exposure-related alterations in hematologic and immune systems. The data presented here are part of a broader study designed to investigate the possible effects of acute exposure to a 50 Hz linearly polarized magnetic field (10 μT) on hematologic and immunologic functions. Thirty-two young men (20–30 years old) were divided into two groups (control group, i.e., sham-exposed, 16 subjects; exposed group, 16 subjects). All subjects participated in two 24 h experiments to evaluate the effects of both continuous and intermittent (1 h “off” and 1 h with the field switched “on” and “off” every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field (generated by three Helmholtz coils per bed) from 23:00 to 08:00 while lying down. Blood samples were collected during each session at 3 h intervals from 11:00 to 20:00 and hourly from 22:00 to 08:00. No significant differences were observed between sham-exposed (control) and exposed men for hemoglobin concentration, hematocrit, red blood cells, platelets, total leukocytes, monocytes, lymphocytes, eosinophils, or neutrophils. Immunologic variables [CD3, CD4, CD8, natural killer (NK) cells and B cells] were unaltered. To our knowledge, this study is the first to document the effects of a 50 Hz magnetic field on the circadian rhythm of human hematologic and immune functions, and it suggests that acute exposure to either a continuous or an intermittent 50 Hz linearly polarized magnetic field of 10 μT, at least under the conditions of our experiment, does not affect either these functions or their circadian rhythms in healthy young men. © 1996 Wiley-Liss, Inc.     

THE EVOLUTION OF PHENOTYPIC CORRELATIONS AND “DEVELOPMENTAL MEMORY”

Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution of phenotypes produced by complex developmental systems can be shaped by past selective environments is poorly understood. Here we investigate the evolution of a network of recurrent nonlinear ontogenetic interactions, such as a gene regulation network, in various selective scenarios. We find that evolved networks of this type can exhibit several phenomena that are familiar in cognitive learning systems. These include formation of a distributed associative memory that can “store” and “recall” multiple phenotypes that have been selected in the past, recreate complete adult phenotypic patterns accurately from partial or corrupted embryonic phenotypes, and “generalize” (by exploiting evolved developmental modules) to produce new combinations of phenotypic features. We show that these surprising behaviors follow from an equivalence between the action of natural selection on phenotypic correlations and associative learning, well‐understood in the context of neural networks. This helps to explain how development facilitates the evolution of high‐fitness phenotypes and how this ability changes over evolutionary time.