The impact of population size on the evolution of asexual microbes on smooth versus rugged fitness landscapes

<p>Abstract</p> <p>Background</p> <p>It is commonly thought that large asexual populations evolve more rapidly than smaller ones, due to their increased rate of beneficial mutations. Less clear is how population size influences the level of fitness an asexual population can attain. Here, we simulate the evolution of bacteria in repeated serial passage experiments to explore how features such as fitness landscape ruggedness, the size of the mutational target under selection, and the mutation supply rate, interact to affect the evolution of microbial populations of different sizes.</p> <p>Results</p> <p>We find that if the fitness landscape has many local peaks, there can be a trade-off between the rate of adaptation and the potential to reach high fitness peaks. This result derives from the fact that whereas large populations evolve mostly deterministically and often become trapped on local fitness peaks, smaller populations can follow more stochastic evolutionary paths and thus locate higher fitness peaks. We also find that the target size of adaptation and the mutation rate interact with population size to influence the trade-off between rate of adaptation and final fitness.</p> <p>Conclusion</p> <p>Our study suggests that the optimal population size for adaptation depends on the details of the environment and on the importance of either the ability to evolve rapidly or to reach high fitness levels.</p

A System Dynamics based Perspective to Help to Understand the Managerial Big Picture in Respect of Urban Event Dynamics

AbstractIn the PED-community, a lot of conducted work focuses on a detailed aspect of the big picture in respect of pedestrian dynamics and disaster avoidance. Surprisingly, the field of research does not offer a lot of models including a managerial macro perspective to explain – for example – why there are mass gatherings that result in high density pedestrian conditions. To improve the mental models of researchers, managers and policy makers, this paper tries to tackle this research gap, by using the methodology of System Dynamics to explain with causal loop diagrams occurring dynamics of urban events to avoid critical situations beforehand

Impact of an Expeditor on Emergency Department Patient Throughput

Objective: Our hypothesis was that an individual whose primary role was to assist with patient throughput would decrease emergency department (ED) length of stay (LOS), elopements and ambulance diversion. The objective of this study was to measure how the use of an expeditor affected these throughput metrics.Methods: This pre- and post-intervention study analyzed ED patients > 21-years-old between June 2008 and June 2009, at a level one trauma center in an academic medical center with an annual ED census of 40,000 patients. We created the expeditor position as our study intervention in December 2008, by modifying the job responsibilities of an existing paramedic position. An expeditor was on duty from 1PM-1AM daily. The pre-intervention period was June to November 2008, and the post-intervention period was January to June 2009. We used multivariable to assess the impact of the expeditor on throughput metrics after adjusting for confounding variables.Results: We included a total of 13,680 visits in the analysis. There was a significant decrease in LOS after expeditor implementation by 0.4 hours, despite an increased average daily census (109 vs. 121, p<0.001). The expeditor had no impact on elopements. The probability that the ED experienced complete ambulance diversion during a 24-hour period decreased from 55.2% to 16.0% (OR:0.17, 95%CI:0.05-0.67).Conclusion: The use of an expeditor was associated with a decreased LOS and ambulance diversion. These findings suggest that EDs may be able to improve patient flow by using expeditors. This tool is under the control of the ED and does not require larger buy-in, resources, or overall hospital changes. [West J Emerg Med. 2011;12(2):198-203.

Cellular enlargement-A new hallmark of aging?

Years of important research has revealed that cells heavily invest in regulating their size. Nevertheless, it has remained unclear why accurate size control is so important. Our recent study using hematopoietic stem cells (HSCs) in vivo indicates that cellular enlargement is causally associated with aging. Here, we present an overview of these findings and their implications. Furthermore, we performed a broad literature analysis to evaluate the potential of cellular enlargement as a new aging hallmark and to examine its connection to previously described aging hallmarks. Finally, we highlight interesting work presenting a correlation between cell size and age-related diseases. Taken together, we found mounting evidence linking cellular enlargement to aging and age-related diseases. Therefore, we encourage researchers from seemingly unrelated areas to take a fresh look at their data from the perspective of cell size.Peer reviewe

Perturbation-Expression Analysis Identifies RUNX1 as a Regulator of Human Mammary Stem Cell Differentiation

The search for genes that regulate stem cell self-renewal and differentiation has been hindered by a paucity of markers that uniquely label stem cells and early progenitors. To circumvent this difficulty we have developed a method that identifies cell-state regulators without requiring any markers of differentiation, termed Perturbation-Expression Analysis of Cell States (PEACS). We have applied this marker-free approach to screen for transcription factors that regulate mammary stem cell differentiation in a 3D model of tissue morphogenesis and identified RUNX1 as a stem cell regulator. Inhibition of RUNX1 expanded bipotent stem cells and blocked their differentiation into ductal and lobular tissue rudiments. Reactivation of RUNX1 allowed exit from the bipotent state and subsequent differentiation and mammary morphogenesis. Collectively, our findings show that RUNX1 is required for mammary stem cells to exit a bipotent state, and provide a new method for discovering cell-state regulators when markers are not available.National Science Foundation (U.S.). Graduate Research Fellowship (1122374)Smith Family FoundationBreast Cancer Allianc

Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1

PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Unfortunately, chemical inhibitors of PERK's kinase activity cause on-target side effects that have precluded their further development. One strategy for resolving this difficulty would be to target downstream components of the pathway that specifically mediate PERK's pro-invasive and metastatic functions. Here we identify the transcription factor CREB3L1 as an essential mediator of PERK's pro-metastatic functions in breast cancer. CREB3L1 acts downstream of PERK, specifically in the mesenchymal subtype of triple-negative tumors, and its inhibition by genetic or pharmacological methods suppresses cancer cell invasion and metastasis. In patients with this tumor subtype, CREB3L1 expression is predictive of distant metastasis. These findings establish CREB3L1 as a key downstream mediator of PERK-driven metastasis and a druggable target for breast cancer therapy.National Science Foundation (U.S.) (Grant 1122374

Important Historical Efforts at Emergency Department Categorization in the United States and Implications for Regionalization

This article is drawn from a report created for the American College of Emergency Physicians (ACEP) Emergency Department (ED) Categorization Task Force and also reflects the proceedings of a breakout session, “Beyond ED Categorization—Matching Networks to Patient Needs,” at the 2010 Academic Emergency Medicine consensus conference, “Beyond Regionalization: Integrated Networks of Emergency Care.” The authors describe a brief history of the significant national and state efforts at categorization and suggest reasons why many of these efforts failed to persevere or gain wider implementation. The history of efforts to categorize hospital (and ED) emergency services demonstrates recognition of the potential benefits of categorization, but reflects repeated failures to implement full categorization systems or limited excursions into categorization through licensing of EDs or designation of receiving and referral facilities. An understanding of the history of hospital and ED categorization could better inform current efforts to develop categorization schemes and processes.ACADEMIC EMERGENCY MEDICINE 2010; 17:e154–e160 © 2010 by the Society for Academic Emergency MedicinePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79214/1/j.1553-2712.2010.00931.x.pd

The Pacific as the world’s greatest theater of bird migration:Extreme flights spark questions about physiological capabilities, behavior, and the evolution of migratory pathways

The Pacific Basin, by virtue of its vastness and its complex aeroscape, provides unique opportunities to address questions about the behavioral and physiological capabilities and mechanisms through which birds can complete spectacular flights. No longer is the Pacific seen just as a formidable barrier between terrestrial habitats in the north and the south, but rather as a gateway for specialized species, such as shorebirds, to make a living on hemispherically distributed seasonal resources. This recent change in perspective is dramatic, and the research that underpins it has presented new opportunities to learn about phenomena that often challenge a sense of normal. Ancient Polynesians were aware of the seasonal passage of shorebirds and other landbirds over the Pacific Ocean, incorporating these observations into their navigational “tool kit” as they explored and colonized the Pacific. Some ten centuries later, systematic visual observations and tracking technology have revealed much about movement of these shorebirds, especially the enormity of their individual nonstop flights. This invites a broad suite of questions, often requiring comparative studies with bird migration across other ocean basins, or across continents. For example, how do birds manage many days of nonstop exercise apparently without sleep? What mechanisms explain birds acting as if they possess a Global Positioning System? How do such extreme migrations evolve? Through advances in both theory and tracking technology, biologists are poised to greatly expand the horizons of movement ecology as we know it. In this integrative review, we present a series of intriguing questions about trans-Pacific migrant shorebirds and summarize recent advances in knowledge about migratory behavior operating at temporal scales ranging from immediate decisions during a single flight, to adaptive learning throughout a lifetime, to evolutionary development of migratory pathways. Recent advances in this realm should stimulate future research across the globe and across a broad array of disciplines

BCL11B Drives Human Mammary Stem Cell Self-Renewal In Vitro by Inhibiting Basal Differentiation

The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification. Applying this method, we identify a transcription factor, BCL11B, which drives stem cell self-renewal in vitro, by inhibiting differentiation into the basal lineage. To validate BCL11B's functional role, we use two-dimensional colony-forming and three-dimensional tissue differentiation assays to assess the lineage differentiation potential and functional abilities of primary human mammary cells. These findings show that BCL11B regulates mammary cell differentiation and demonstrate the utility of our proposed genome-scale strategy for identifying lineage regulators in mammalian tissues. Miller et al. describe a strategy to identify candidate master regulators of cell lineage specification. This approach identified BCL11B as a key regulator of human mammary stem cell self-renewal in in vitro progenitor and differentiation assays. Using a combination of 2D and 3D primary cell culture techniques, they show that BCL11B drives stem cell self-renewal by inhibiting basal lineage commitment.National Science Foundation (U.S.) (Grant 1122374