Shared Prosperity, Stronger Regions: An Agenda for Rebuilding America's Older Core Cities

Explores opportunities for community collaborations to promote economic development and neighborhood revitalization, and offers strategies for public/private investment. Includes case studies in Baltimore, Cleveland, Detroit, Philadelphia, and Pittsburgh

The inheritance of heterogeneity

INTRODUCTION: One important characteristic of solid tumors is heterogeneity at multiple levels of genetic and non-genetic organization. This can include gene mutations, epigenetic alterations, copy number changes, and chromosomal aberrations. Collectively, these alterations contribute as parts of a genome-defined system. Thus, when genetic information is passed from mother to daughter cell in the context of cancer evolution, in contrast to normal cellular processes, an altered system inheritance is often transmitted. When the genome of a somatic cell is highly unstable, such as during certain phases of cancer initiation and progression, many novel alterations to the genome can be introduced in a short timeframe, effectively resulting in the macro-evolution of the somatic cell population (i.e., through the transition stages of cancer, including transformation, metastasis, and drug resistance). Unfortunately, these continually introduced, non-clonal alterations to the cell’s genetic information have often been described as background “noise” that does not function significantly in cancer. Rather, the driving force of cancer has largely been attributed to the accumulation of gene mutations in several key, driver genes. Despite the presumed significance of these driver genes by the gene mutation and clonal evolutionary theories of cancer, recent sequencing efforts have failed to identify common driver genes in the majority of cancer types. Based on this fact, and on the overwhelming presence of non-clonal alterations at multiple levels of organization in the cells comprising tumors, the paradigm of cancer research requires re-examination. A better understanding of genome-level heterogeneity is necessary, as the genome, rather than individual genes, defines system boundaries and unifies the diverse individual molecular mechanisms of cancer through their contribution to major evolutionary transitions. Because inheritance is traditionally defined as a precise process of relaying bio-information with extreme low frequencies of errors, it is challenging to explain how genetics work in cancer evolution. It is thus timely to consider that potentially novel processes of inheritance occur in many types of cancer. The maintenance of a massive extent of multi-level heterogeneity in the cells of solid tumors over generations suggests that a less precise process is taking place. We have described this with a new term, “fuzzy inheritance,” wherein a range of variants, rather than specific variants (such as specific gene mutations or chromosomal aberrations), is recapitulated in the cell division process. This study aimed to elucidate the mechanism of fuzzy inheritance by examining the relationship between genome instability-linked karyotypic heterogeneity and growth heterogeneity, based on single-cell analysis of an in vitro cell culture model. By demonstrating that increased genome-level heterogeneity is reflected by increased and more variable levels of growth heterogeneity, it was hoped to establish that fuzzy inheritance correctly explains the maintenance of high levels of heterogeneity in these somatic cell populations. An example of this phenomenon was also studied in giant cancer cells, as they undergo division processes which appear to contribute to and facilitate genome instability. METHODS: To examine these concepts, various cellular profiling methods were used, including in-situ cell growth, cellular morphological comparison, and karyotype analysis. We first quantified the extent of variation in the growth rates of single cells; by selecting the fastest- and slowest-growing colonies from the parent population, and examining the extent to which growth heterogeneity was passed in subsequent generations of cells, the correlation between genome-level heterogeneity (as reflected by the karyotype) and growth heterogeneity was determined. We then examined an extreme example of fuzzy inheritance, wherein giant cancer cells containing massive amounts of DNA undergo extremely abnormal cell division events, yielding many normal-sized daughter cells with genomes significantly different from those of both the parent cell and other daughter cells. By studying the frequency and other aspects of these cells in two unequally stable cell lines, we sought to gain insight on one specific mechanism of fuzzy inheritance. RESULTS: The data suggested that fuzzy inheritance can be demonstrated in multiple cell culture models. The extent and variability of karyotypic heterogeneity was reflected by those of growth heterogeneity, indicating the karyotype’s importance in facilitating cancer evolutionary processes. Moreover, the cells with giant nuclei can generate diverse genome-level heterogeneity. DISCUSSION: Because fuzzy inheritance allows for the less precise passage of bio-information over generations in cancer cell populations, and for the effective introduction of numerous alterations to the genome in often brief spans of time, the cell population can constantly increase its evolutionary potential, which is essential for the major transition steps of cancer evolution. The mechanism of fuzzy inheritance should be explored further, due to its clear importance in the processes underlying cancer initiation, progression, and drug resistance

Development of a Weaned Pig Model of Enterotoxigenic E.coli-induced Environmental Enteropathy

Environmental enteropathy is chronic inflammatory disease of the small intestine that hinders the childhood development in impoverished countries. As it assumes a large role in the malnutrition as well as stunting of growth in the early stages of life. This is correlated with an increased likelihood of contracting a chronic disease in adulthood. A specific culprit of the disease is unknown but it is assumed that an enteric pathogen plays a role as fecal-oral contamination and poor living conditions are the primary routes to infection. Weaned pigs experience similar symptoms to that of humans in a disease known as post weaning diarrhea. The aim of this study was to develop a model of environmental enteropathy that can be utilized for the research of new interventions. Twenty-four weaned piglets at approximately 14lbs were randomly assigned to one of three treatments. The pigs were housed 2 pigs per pen with a total of 4 pens per treatment. The treatments were as follows: 1) Control (sham challenged with PBS) 2) Acute (received one dose of ATCC 23545) and 3) Chronic (received a daily dose of ATCC 23545). After 2 d of acclimation, pigs were challenged with the respective treatment on d 1. Feed disappearance, body weight, blood and fecal samples were taken on d 0, 1, 3, and 6. Blood and fecal samples were analyzed for inflammatory markers. All pigs were necropsied on d 7 for the collection of intestinal samples for histology and determination of Enterotoxigenic Eschericia coli counts. The ETEC 23545 treatment had no effect on ADG, ADFI, or G:F throughout the duration of the trial (P≥.18 ) A treatment interaction was seen on d 6 serum levels of IL-6 (P<0.05) but an effect was not seen in the d 6 serum levels of IL-8. The fecal calprotectin levels did not have a treatment (P=.95) day (P=.48) or treatment x day (P=.95) effect. However, the fecal colony counts experienced a treatment effect (P<.0001). The acutely challenged pigs most closely mimicked environmental enteropathy in children with highest fecal shedding of E.coli, elevated colonization of small intestine and elevated levels of serum IL-6

Bringing Solar Energy to Low- and Moderate-Income Communities

The U.S. solar photovoltaics industry has taken off over the past decade, but without deliberate action low- and moderate-income communities could be left behind in the transition to clean energy. Drawing on substantial literature related to multiple dimensions of low-income solar finance and interviews with key informants in the field, authors Eric Hangen, Rebecca Regan, and Sarah Boege recommend public investments and policy changes that could help scale the provision of equitable solar finance

Scaling Equitable Solar Finance

The U.S. solar photovoltaics industry has taken off over the past decade, but without deliberate action low- and moderate-income communities could be left behind in the transition to clean energy. Drawing on substantial literature related to multiple dimensions of low-income solar finance and interviews with key informants in the field, authors Eric Hangen, Rebecca Regan, and Sarah Boege recommend public investments and policy changes that could help scale the provision of equitable solar finance

Development of a Weaned Pig Model of Enterotoxigenic E.coli-induced Environmental Enteropathy

Environmental enteropathy is chronic inflammatory disease of the small intestine that hinders the childhood development in impoverished countries. As it assumes a large role in the malnutrition as well as stunting of growth in the early stages of life. This is correlated with an increased likelihood of contracting a chronic disease in adulthood. A specific culprit of the disease is unknown but it is assumed that an enteric pathogen plays a role as fecal-oral contamination and poor living conditions are the primary routes to infection. Weaned pigs experience similar symptoms to that of humans in a disease known as post weaning diarrhea. The aim of this study was to develop a model of environmental enteropathy that can be utilized for the research of new interventions. Twenty-four weaned piglets at approximately 14lbs were randomly assigned to one of three treatments. The pigs were housed 2 pigs per pen with a total of 4 pens per treatment. The treatments were as follows: 1) Control (sham challenged with PBS) 2) Acute (received one dose of ATCC 23545) and 3) Chronic (received a daily dose of ATCC 23545). After 2 d of acclimation, pigs were challenged with the respective treatment on d 1. Feed disappearance, body weight, blood and fecal samples were taken on d 0, 1, 3, and 6. Blood and fecal samples were analyzed for inflammatory markers. All pigs were necropsied on d 7 for the collection of intestinal samples for histology and determination of Enterotoxigenic Eschericia coli counts. The ETEC 23545 treatment had no effect on ADG, ADFI, or G:F throughout the duration of the trial (P≥.18 ) A treatment interaction was seen on d 6 serum levels of IL-6 (P<0.05) but an effect was not seen in the d 6 serum levels of IL-8. The fecal calprotectin levels did not have a treatment (P=.95) day (P=.48) or treatment x day (P=.95) effect. However, the fecal colony counts experienced a treatment effect (P<.0001). The acutely challenged pigs most closely mimicked environmental enteropathy in children with highest fecal shedding of E.coli, elevated colonization of small intestine and elevated levels of serum IL-6

Touch the Wind: Simultaneous Airflow, Drag and Interaction Sensing on a Multirotor

Disturbance estimation for Micro Aerial Vehicles (MAVs) is crucial for robustness and safety. In this paper, we use novel, bio-inspired airflow sensors to measure the airflow acting on a MAV, and we fuse this information in an Unscented Kalman Filter (UKF) to simultaneously estimate the three-dimensional wind vector, the drag force, and other interaction forces (e.g. due to collisions, interaction with a human) acting on the robot. To this end, we present and compare a fully model-based and a deep learning-based strategy. The model-based approach considers the MAV and airflow sensor dynamics and its interaction with the wind, while the deep learning-based strategy uses a Long Short-Term Memory (LSTM) neural network to obtain an estimate of the relative airflow, which is then fused in the proposed filter. We validate our methods in hardware experiments, showing that we can accurately estimate relative airflow of up to 4 m/s, and we can differentiate drag and interaction force.Comment: The first two authors contributed equall

Progress on the introduction of supervisory ward manager roles since the Francis report recommendations

Recommendation 195 of the Francis report suggested that the introduction of supervisory ward managers into clinical practice could improve the quality of patient care in England. The Department of Health and NHS Commissioning Board's vision and strategy Compassion in Practice in 2012 restated the recommendation in action area four, with trusts required to publish progress. With the aim of identifying whether the lessons of the Francis report had been learned, a review of the published literature since 2012 retrieved only five articles on the subject, with many anecdotal accounts of its implementation in local trusts. The three subsequent update reports of Compassion in Practice stopped backing recommendation 195 and promoted black and ethnic minority leadership, a laudable initiative, but not a recommendation of the Francis report. The authors suggest recommendation 195 and Compassion in Practice's original action area four should be promoted again to ensure public safety and address the notion that lessons learned are less likely to be repeated

The supervisory ward manager's role: progress on Compassion in Practice action area four

In 2012, the Department of Health published Compassion in Practice, which included six areas for action. Action area four suggests that ward managers and leaders should be supervisory, and not included in ward staff numbers. The recommendation has recently been changed to promote black and minority ethnic (BME) leadership in the NHS. This article examines the literature on supervisory nurse leader roles between 2007 and 2017 to identify what, if any, progress has been made. Although supervisory status can improve care at ward level, and was endorsed by the Francis Report, it seems that few care providers in England have invested in this, possibly because it is voluntary, rather than a statutory requirement. The article argues that, rather than focusing on BME leadership, commissioners and providers should consider implementing the original action four to support the lessons learned in the Francis Report. [Abstract copyright: ©2012 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

Self-Assembling Protein Surfaces for In Situ Capture of Cell-Free-Synthesized Proteins

We present a new method for the surface capture of proteins in cell-free protein synthesis (CFPS). We demonstrate the spontaneous self-assembly of the protein BslA into functionalizable surfaces on the surface of a CFPS reaction chamber. We show that proteins can be covalently captured by such surfaces, using “Catcher/Tag” technology. Importantly, proteins of interest can be captured either when synthesised in situ by CFPS above the BslA surfaces, or when added as pure protein. The simplicity and cost efficiency of this method suggest that it will find many applications in cell-free-based methods