A conceptual and computational framework for modelling and understanding the non-equilibrium gene regulatory networks of mouse embryonic stem cells

The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler's Branching Process Theory (BPT) and on Greaves et al.'s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to "ignite" an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality.This work was performed as part of the CellBranch project, funded by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC, http://www.bbsrc.ac.uk/), project reference BB/L018705/1. Grant holder: SS

Bibliometric Evidence for a Hierarchy of the Sciences

The hypothesis of a Hierarchy of the Sciences, first formulated in the 19(th) century, predicts that, moving from simple and general phenomena (e.g. particle dynamics) to complex and particular (e.g. human behaviour), researchers lose ability to reach theoretical and methodological consensus. This hypothesis places each field of research along a continuum of complexity and "softness", with profound implications for our understanding of scientific knowledge. Today, however, the idea is still unproven and philosophically overlooked, too often confused with simplistic dichotomies that contrast natural and social sciences, or science and the humanities. Empirical tests of the hypothesis have usually compared few fields and this, combined with other limitations, makes their results contradictory and inconclusive. We verified whether discipline characteristics reflect a hierarchy, a dichotomy or neither, by sampling nearly 29,000 papers published contemporaneously in 12 disciplines and measuring a set of parameters hypothesised to reflect theoretical and methodological consensus. The biological sciences had in most cases intermediate values between the physical and the social, with bio-molecular disciplines appearing harder than zoology, botany or ecology. In multivariable analyses, most of these parameters were independent predictors of the hierarchy, even when mathematics and the humanities were included. These results support a "gradualist" view of scientific knowledge, suggesting that the Hierarchy of the Sciences provides the best rational framework to understand disciplines' diversity. A deeper grasp of the relationship between subject matter's complexity and consensus could have profound implications for how we interpret, publish, popularize and administer scientific research

Molecular motors robustly drive active gels to a critically connected state

Living systems often exhibit internal driving: active, molecular processes drive nonequilibrium phenomena such as metabolism or migration. Active gels constitute a fascinating class of internally driven matter, where molecular motors exert localized stresses inside polymer networks. There is evidence that network crosslinking is required to allow motors to induce macroscopic contraction. Yet a quantitative understanding of how network connectivity enables contraction is lacking. Here we show experimentally that myosin motors contract crosslinked actin polymer networks to clusters with a scale-free size distribution. This critical behavior occurs over an unexpectedly broad range of crosslink concentrations. To understand this robustness, we develop a quantitative model of contractile networks that takes into account network restructuring: motors reduce connectivity by forcing crosslinks to unbind. Paradoxically, to coordinate global contractions, motor activity should be low. Otherwise, motors drive initially well-connected networks to a critical state where ruptures form across the entire network.Comment: Main text: 21 pages, 5 figures. Supplementary Information: 13 pages, 8 figure

Eliminating the mystery from the concept of emergence

While some branches of complexity theory are advancing rapidly, the same cannot be said for our understanding of emergence. Despite a complete knowledge of the rules underlying the interactions between the parts of many systems, we are often baffled by their sudden transitions from simple to complex. Here I propose a solution to this conceptual problem. Given that emergence is often the result of many interactions occurring simultaneously in time and space, an ability to intuitively grasp it would require the ability to consciously think in parallel. A simple exercise is used to demonstrate that we do not possess this ability. Our surprise at the behaviour of cellular automata models, and the natural cases of pattern formation they mimic, is then explained from this perspective. This work suggests that the cognitive limitations of the mind can be as significant a barrier to scientific progress as the limitations of our senses

Testing the Goodness of Supplementary Feeding to Enhance Population Viability in an Endangered Vulture

[Background]: Human-predator conflicts are directly or indirectly threatening many species with extinction. Thus, biologists are urged to find simple solutions to complex situations while avoiding unforeseen conservation outcomes. The provision of supplementary food at artificial feeding sites (AFS) is frequently used in the conservation of scavenger bird populations currently suffering from indirect poisoning, although no scientific studies on its effectiveness have been conducted.[Methodology/Principal Findings]: We used a long-term data set of 95 individually marked birds from the largest European core of the endangered bearded vulture (Gypaetus barbatus) to test the long-term effects of specific AFS for bearded vultures on their survival rates (by CMR models) and population dynamics (by Monte Carlo simulations) in an area where fatalities derived from illegal poisoning and the use of other toxics like veterinary drugs have increased over the last several years. Our data support the positive relationship between the use of AFS and survival. However, contrary to theoretical predictions (e.g. high and more stable adult survival among long-lived species), the use of AFS increased only survival of pre-adults. Moreover, AFS buffered the effects of illegal poisoning on this age-class, while adult survival decreased over years. Our simulations predicted a maximum value of extinction probability over a time horizon of 50 years. Population projections run with survival rates expected in scenarios without poisoning predicted the situation of least conservation concern, while including only AFS can maintain a large floater surplus that may delay population decline but fails to reduce poisoning risk among adults.[Conclusions/Significance]: Although AFS are not effective to save bearded vultures from an expected population decline, they delay population extinction and can be a useful tool for prolonging population viability while combating illegal and indirect poisoning. The eradication of different sources of poisoning is of top priority to ensure the long-term viability of this and many other species.Financial support for AM was obtained from the Departament of Medi Ambient i Habitatge of Generalitat de Catalunya and Ministry of Environment. MC was supported by an Excellence post-doctoral contract (Junta de Andalucía).Peer reviewe

Apoptosis and proliferation in the trigeminal placode

The neurogenic trigeminal placode develops from the crescent-shaped panplacodal primordium which delineates the neural plate anteriorly. We show that, in Tupaia belangeri, the trigeminal placode is represented by a field of focal ectodermal thickenings which over time changes positions from as far rostral as the level of the forebrain to as far caudal as opposite rhombomere 3. Delamination proceeds rostrocaudally from the ectoderm adjacent to the rostral midbrain, and contributes neurons to the trigeminal ganglion as well as to the ciliary ganglion/oculomotor complex. Proliferative events are centered on the field prior to the peak of delamination. They are preceded, paralleled and, finally, outnumbered by apoptotic events which proceed rostrocaudally from non-delaminating to delaminating parts of the field. Apoptosis persists upon regression of the placode, thereby exhibiting a massive “wedge” of apoptotic cells which includes the postulated position of the “ventrolateral postoptic placode” (Lee et al. in Dev Biol 263:176–190, 2003), merges with groups of lens-associated apoptotic cells, and disappears upon lens detachment. In conjunction with earlier work (Washausen et al. in Dev Biol 278:86–102, 2005) our findings suggest that apoptosis contributes repeatedly to the disintegration of the panplacodal primordium, to the elimination of subsets of premigratory placodal neuroblasts, and to the regression of placodes

Geomorphic and stratigraphic evidence for an unusual tsunami or storm a few centuries ago at Anegada, British Virgin Islands

© The Author(s), 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Natural Hazards 63 (2012): 51-84, doi:10.1007/s11069-010-9622-6.Waters from the Atlantic Ocean washed southward across parts of Anegada, east-northeast of Puerto Rico, during a singular event a few centuries ago. The overwash, after crossing a fringing coral reef and 1.5 km of shallow subtidal flats, cut dozens of breaches through sandy beach ridges, deposited a sheet of sand and shell capped with lime mud, and created inland fields of cobbles and boulders. Most of the breaches extend tens to hundreds of meters perpendicular to a 2-km stretch of Anegada’s windward shore. Remnants of the breached ridges stand 3 m above modern sea level, and ridges seaward of the breaches rise 2.2–3.0 m high. The overwash probably exceeded those heights when cutting the breaches by overtopping and incision of the beach ridges. Much of the sand-and-shell sheet contains pink bioclastic sand that resembles, in grain size and composition, the sand of the breached ridges. This sand extends as much as 1.5 km to the south of the breached ridges. It tapers southward from a maximum thickness of 40 cm, decreases in estimated mean grain size from medium sand to very fine sand, and contains mud laminae in the south. The sand-and-shell sheet also contains mollusks—cerithid gastropods and the bivalve Anomalocardia—and angular limestone granules and pebbles. The mollusk shells and the lime-mud cap were probably derived from a marine pond that occupied much of Anegada’s interior at the time of overwash. The boulders and cobbles, nearly all composed of limestone, form fields that extend many tens of meters generally southward from limestone outcrops as much as 0.8 km from the nearest shore. Soon after the inferred overwash, the marine pond was replaced by hypersaline ponds that produce microbial mats and evaporite crusts. This environmental change, which has yet to be reversed, required restriction of a former inlet or inlets, the location of which was probably on the island’s south (lee) side. The inferred overwash may have caused restriction directly by washing sand into former inlets, or indirectly by reducing the tidal prism or supplying sand to post-overwash currents and waves. The overwash happened after A.D. 1650 if coeval with radiocarbon-dated leaves in the mud cap, and it probably happened before human settlement in the last decades of the 1700s. A prior overwash event is implied by an inland set of breaches. Hypothetically, the overwash in 1650–1800 resulted from the Antilles tsunami of 1690, the transatlantic Lisbon tsunami of 1755, a local tsunami not previously documented, or a storm whose effects exceeded those of Hurricane Donna, which was probably at category 3 as its eye passed 15 km to Anegada’s south in 1960.The work was supported in part by the Nuclear Regulatory Commission under its project N6480, a tsunami-hazard assessment for the eastern United States

Self-organization of developing embryo using scale-invariant approach

<p>Abstract</p> <p>Background</p> <p>Self-organization is a fundamental feature of living organisms at all hierarchical levels from molecule to organ. It has also been documented in developing embryos.</p> <p>Methods</p> <p>In this study, a scale-invariant power law (SIPL) method has been used to study self-organization in developing embryos. The SIPL coefficient was calculated using a centro-axial skew symmetrical matrix (CSSM) generated by entering the components of the Cartesian coordinates; for each component, one CSSM was generated. A basic square matrix (BSM) was constructed and the determinant was calculated in order to estimate the SIPL coefficient. This was applied to developing <it>C. elegans </it>during early stages of embryogenesis. The power law property of the method was evaluated using the straight line and Koch curve and the results were consistent with fractal dimensions (fd). Diffusion-limited aggregation (DLA) was used to validate the SIPL method.</p> <p>Results and conclusion</p> <p>The fractal dimensions of both the straight line and Koch curve showed consistency with the SIPL coefficients, which indicated the power law behavior of the SIPL method. The results showed that the ABp sublineage had a higher SIPL coefficient than EMS, indicating that ABp is more organized than EMS. The fd determined using DLA was higher in ABp than in EMS and its value was consistent with type 1 cluster formation, while that in EMS was consistent with type 2.</p

Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort

Abstract Introduction Although pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear. Methods Among 52,464 postmenopausal women participating in the California Teachers Study (CTS), 624 were diagnosed with breast carcinoma in situ (CIS) and 2,828 with invasive breast cancer between 1995 and 2007. Multivariable Cox proportional hazards regression methods were used to estimate relative risks associated with parity, age at first full-term pregnancy, breastfeeding, nausea or vomiting during pregnancy, and preeclampsia. Results Compared with never-pregnant women, an increasing number of full-term pregnancies was associated with greater risk reduction for both breast CIS and invasive breast cancer (both P trend &lt; 0.01). Women having four or more full-term pregnancies had a 31% lower breast CIS risk (RR = 0.69, 95% CI = 0.51 to 0.93) and 18% lower invasive breast cancer risk (RR = 0.82, 95% CI = 0.72 to 0.94). Parous women whose first full-term pregnancy occurred at age 35 years or later had a 118% greater risk for breast CIS (RR = 2.18, 95% CI = 1.36 to 3.49) and 27% greater risk for invasive breast cancer (RR = 1.27, 95% CI = 0.99 to 1.65) than those whose first full-term pregnancy occurred before age 21 years. Furthermore, parity was negatively associated with the risk of estrogen receptor-positive (ER+) or ER+/progesterone receptor-positive (PR+) while age at first full-term pregnancy was positively associated with the risk of ER+ or ER+/PR+ invasive breast cancer. Neither of these factors was statistically significantly associated with the risk of ER-negative (ER-) or ER-/PR- invasive breast cancer, tests for heterogeneity between subtypes did not reach statistical significance. No clear associations were detected for other pregnancy-related factors. Conclusions These results provide some epidemiologic evidence that parity and age at first full-term pregnancy are involved in the development of breast cancer among postmenopausal women. The role of these factors in risk of in situ versus invasive, and hormone receptor-positive versus -negative breast cancer merits further exploration