Complexity in cancer stem cells and tumor evolution: towards precision medicine

In this review, we discuss recent advances on the plasticity of cancer stem cells and highlight their relevance to understand the metastatic process and to guide therapeutic interventions. Recent results suggest that the strict hierarchical structure of cancer cell populations advocated by the cancer stem cell model must be reconsidered since the depletion of cancer stem cells leads the other tumor cells to switch back into the cancer stem cell phenotype. This plasticity has important implications for metastasis since migrating cells do not need to be cancer stem cells in order to seed a metastasis. We also discuss the important role of the immune system and the microenvironment in modulating phenotypic switching and suggest possible avenues to exploit our understanding of this process to develop an effective strategy for precision medicine.Comment: 2 Figures, to appear in Seminars in Cancer Biology, Available online 23 February 201

Energy-Efficient selective activation in Femtocell Networks

Provisioning the capacity of wireless networks is difficult when peak load is significantly higher than average load, for example, in public spaces like airports or train stations. Service providers can use femtocells and small cells to increase local capacity, but deploying enough femtocells to serve peak loads requires a large number of femtocells that will remain idle most of the time, which wastes a significant amount of power. To reduce the energy consumption of over-provisioned femtocell networks, we formulate a femtocell selective activation problem, which we formalize as an integer nonlinear optimization problem. Then we introduce GREENFEMTO, a distributed femtocell selective activation algorithm that deactivates idle femtocells to save power and activates them on-the-fly as the number of users increases. We prove that GREENFEMTO converges to a locally Pareto optimal solution and demonstrate its performance using extensive simulations of an LTE wireless system. Overall, we find that GREENFEMTO requires up to 55% fewer femtocells to serve a given user load, relative to an existing femtocell power-saving procedure, and comes within 15% of a globally optimal solution

Conformational mechanism for the stability of microtubule-kinetochore attachments

Regulating the stability of microtubule(MT)-kinetochore attachments is fundamental to avoiding mitotic errors and ensure proper chromosome segregation during cell division. While biochemical factors involved in this process have been identified, its mechanics still needs to be better understood. Here we introduce and simulate a mechanical model of MT-kinetochore interactions in which the stability of the attachment is ruled by the geometrical conformations of curling MT-protofilaments entangled in kinetochore fibrils. The model allows us to reproduce with good accuracy in vitro experimental measurements of the detachment times of yeast kinetochores from MTs under external pulling forces. Numerical simulations suggest that geometrical features of MT-protofilaments may play an important role in the switch between stable and unstable attachments

Legal determinants of external finance revisited : the inverse relationship between investor protection and societal well-being

This paper investigates relationships between corporate governance traditions and quality of life as measured by a number of widely reported indicators. It provides an empirical analysis of indicators of societal health in developed economies using a classification based on legal traditions. Arguably the most widely cited work in the corporate governance literature has been the collection of papers by La Porta et al. which has shown, inter alia, statistically significant relationships between legal traditions and various proxies for investor protection. We show statistically significant relationships between legal traditions and various proxies for societal health. Our comparative evidence suggests that the interests of investors may not be congruent with the interests of wider society, and that the criteria for judging the effectiveness of approaches to corporate governance should not be restricted to financial metrics

Volume changes during active shape fluctuations in cells

Cells modify their volume in response to changes in osmotic pressure but it is usually assumed that other active shape variations do not involve significant volume fluctuations. Here we report experiments demonstrating that water transport in and out of the cell is needed for the formation of blebs, commonly observed protrusions in the plasma membrane driven by cortex contraction. We develop and simulate a model of fluid mediated membrane-cortex deformations and show that a permeable membrane is necessary for bleb formation which is otherwise impaired. Taken together our experimental and theoretical results emphasize the subtle balance between hydrodynamics and elasticity in actively driven cell morphological changes.Comment: Phys. Rev. Lett. in press. 13 pages 4 figures, 9 supplementary figure

Cholesterol impairment contributes to neuroserpin aggregation

Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol regulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.Comment: 7 figure

Mechanical Properties of Growing Melanocytic Nevi and the Progression to Melanoma

Melanocytic nevi are benign proliferations that sometimes turn into malignant melanoma in a way that is still unclear from the biochemical and genetic point of view. Diagnostic and prognostic tools are then mostly based on dermoscopic examination and morphological analysis of histological tissues. To investigate the role of mechanics and geometry in the morpholgical dynamics of melanocytic nevi, we study a computation model for cell proliferation in a layered non-linear elastic tissue. Numerical simulations suggest that the morphology of the nevus is correlated to the initial location of the proliferating cell starting the growth process and to the mechanical properties of the tissue. Our results also support that melanocytes are subject to compressive stresses that fluctuate widely in the nevus and depend on the growth stage. Numerical simulations of cells in the epidermis releasing matrix metalloproteinases display an accelerated invasion of the dermis by destroying the basal membrane. Moreover, we suggest experimentally that osmotic stress and collagen inhibit growth in primary melanoma cells while the effect is much weaker in metastatic cells. Knowing that morphological features of nevi might also reflect geometry and mechanics rather than malignancy could be relevant for diagnostic purpose

Ecological effects of the European barbel Barbus barbus (L., 1758) (Cyprinidae) invasion on native barbel populations in the Tiber River basin (Italy)

The purpose of this study was to investigate the effects of the European barbel Barbus barbus (L., 1758) invasion in the Tiber River basin (Italy) on the native Tiber barbel Barbus tyberinus Bonaparte, 1839, verifying whether the co-occurrence played a negative impact on growth rate and relative weight. Fish census data were collected during three periods (2000–2005, 2006–2010, 2011–2015) at 158 sampling sites. Since its first record in 1998, European barbel rapidly spread in the study area: it was present in more than 20% of the monitoring sites, where it is leading to the gradual replacement of Tiber barbel by widening its distribution in the Tiber River and in the downstream reaches of the main tributaries. By contrast, Tiber barbel has suffered from this competition, as demonstrated by the fact that the mean value of the relative weight was significantly higher where European barbel was absent. The results obtained suggested that this non-native species could be a serious threat to the conservation status of endemic Tiber barbel, and constitute the premise to underpin conservation strategies aiming to preserve native freshwater biodiversity

You're the Coach: A Guide for Parents of New Drivers, December 8, 2015

This publication is a guide for parents and guardians of teenagers learning to drive. It should be used with the Iowa Driver’s Manual to aid you in instructing your new driver about how to safely and responsibly operate a motor vehicle. Since the task of driving is affected by changing conditions, this manual does not attempt to cover all situations that may arise