Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are ...poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic ...lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43-containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma "horizontal" and bidirectional "vertical" synaptic intercellular transmission and prion-like seeding of TDP-43.
Improved understanding of the genetic basis of adaptation to climate change is necessary for maintaining global biodiversity moving forward. Studies to date have largely focused on sequence ...variation, yet there is growing evidence that suggests that changes in genome structure may be an even more significant source of adaptive potential. The American pika (Ochotona princeps) is an alpine specialist that shows some evidence of adaptation to climate along elevational gradients, but previous work has been limited to single nucleotide polymorphism based analyses within a fraction of the species range. Here, we investigated the role of copy number variation underlying patterns of local adaptation in the American pika using genome-wide data previously collected across the entire species range. We identified 37-193 putative copy number variants (CNVs) associated with environmental variation (temperature, precipitation, solar radiation) within each of the six major American pika lineages, with patterns of divergence largely following elevational and latitudinal gradients. Genes associated (n = 158) with independent annotations across lineages, variables, and/or CNVs had functions related to mitochondrial structure/function, immune response, hypoxia, olfaction, and DNA repair. Some of these genes have been previously linked to putative high elevation and/or climate adaptation in other species, suggesting they may serve as important targets in future studies.
The evolution of complex organismal traits is obvious as a historical fact, but the underlying causes--including the role of natural selection--are contested. Gould argued that a random walk from a ...necessarily simple beginning would produce the appearance of increasing complexity over time. Others contend that selection, including coevolutionary arms races, can systematically push organisms toward more complex traits. Methodological challenges have largely precluded experimental tests of these hypotheses. Using the Avida platform for digital evolution, we show that coevolution of hosts and parasites greatly increases organismal complexity relative to that otherwise achieved. As parasites evolve to counter the rise of resistant hosts, parasite populations retain a genetic record of past coevolutionary states. As a consequence, hosts differentially escape by performing progressively more complex functions. We show that coevolution's unique feedback between host and parasite frequencies is a key process in the evolution of complexity. Strikingly, the hosts evolve genomes that are also more phenotypically evolvable, similar to the phenomenon of contingency loci observed in bacterial pathogens. Because coevolution is ubiquitous in nature, our results support a general model whereby antagonistic interactions and natural selection together favor both increased complexity and evolvability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Designing Public Participation Processes Bryson, John M.; Quick, Kathryn S.; Slotterback, Carissa Schively ...
Public administration review,
January/February 2013, Letnik:
73, Številka:
1
Journal Article
Recenzirano
The purpose of this Theory to Practice article is to present a systematic, cross-disciplinary, and accessible synthesis of relevant research and to offer explicit evidence-based design guidelines to ...help practitioners design better participation processes. From the research literature, the authors glean suggestions for iteratively creating, managing, and evaluating public participation activities. The article takes an evidence-based and design science approach, suggesting that effective public participation processes are grounded in analyzing the context closely, identifying the purposes of the participation effort, and iteratively designing and redesigning the process accordingly.
Invasive alien species (IAS) are among the main causes of global biodiversity loss. Invasive brown (Rattus norvegicus) and black (R. rattus) rats, in particular, are leading drivers of extinction on ...islands, especially in the case of seabirds where >50% of all extinctions have been attributed to rat predation. Eradication is the primary form of invasive rat management, yet this strategy has resulted in a ~10-38% failure rate on islands globally. Genetic tools can help inform IAS management, but such applications to date have been largely reactive, time-consuming, and costly. Here, we developed a Genotyping-in-Thousands by sequencing (GT-seq) panel for rapid species identification and population assignment of invasive brown and black rats (RapidRat) in Haida Gwaii, an archipelago comprising ~150 islands off the central coast of British Columbia, Canada. We constructed an optimized panel of 443 single nucleotide polymorphisms (SNPs) using previously generated double-digest restriction-site associated DNA (ddRAD) genotypic data (27,686 SNPs) from brown (n = 295) and black rats (n = 241) sampled throughout Haida Gwaii. The informativeness of this panel for identifying individuals to species and island of origin was validated relative to the ddRAD results; in all comparisons, admixture coefficients and population assignments estimated using RapidRat were consistent. To demonstrate application, 20 individuals from novel invasions of three islands (Agglomerate, Hotspring, Ramsay) were genotyped using RapidRat, all of which were confidently assigned (>98.5% probability) to Faraday and Murchison Islands as putative source populations. These results indicated that a previous eradication on Hotspring Island was conducted at an inappropriate geographic scale; future management should expand the eradication unit to include neighboring islands to prevent re-invasion. Overall, we demonstrated that RapidRat is an effective tool for managing invasive rat populations in Haida Gwaii and provided a clear framework for GT-seq panel development for informing biodiversity conservation in other systems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Four-dimensional (4D) printing of multi-directionally reinforced preforms has tremendous potential for the development of next generation functional composites by using the capabilities of 3D ...printing technology, 3D textile preform design, and polymer shape memory behavior. This work demonstrates the shape memory behavior and recovery force of 4D printed circular braided tube preforms and their silicone elastomer matrix composites. The preforms were printed by fused deposition modeling using the shape memory polymer (SMP), polylactic acid (PLA). The effects of braiding angle, tube wall thickness, and shape recovery temperature on the shape memory behavior of 4D printed tube preforms and their silicone elastomer matrix composites have been characterized. Measurements of shape recovery forces of the preform and composite were conducted using dynamic mechanical analysis (DMA). The braided microstructural parameters and shape recovery temperature have a significant effect on the preform shape memory behavior. The introduction of the silicone elastomer matrix greatly enhances the shape recovery force, shape recovery ratio, as well as radial compressive failure load of the 4D printed preform/silicone elastomer matrix composite. Building on these results, a potential application for 4D printed textile functional composites is presented.
People who want to tackle tough social problems and achieve beneficial community outcomes are beginning to understand that multiple sectors of a democratic society-business, nonprofits and ...philanthropies, the media, the community, and government-must collaborate to deal effectively and humanely with the challenges. This article focuses on cross-sector collaboration that is required to remedy complex public problems. Based on an extensive review of the literature on collaboration, the article presents a propositional inventory organized around the initial conditions affecting collaboration formation, process, structural and governance components, constraints and contingencies, outcomes, and accountability issues.
This introduction to the special issue on strategic planning has four main parts. First comes a discussion of what makes public-sector strategic planning strategic. This discussion is meant to reduce ...confusion about what strategic planning is and is not. Next, we introduce in detail the five articles in the special issue and note their unique contributions to strategic planning research. Third, we provide a broad assessment of the current state of strategic planning research organized in terms of prominent themes in the literature and our assessment of how the articles address voids related to the themes. The themes are: how should strategic planning be conceptualized and defined? How should it be studied? How does strategic planning work, or not? What are the outcomes of strategic planning? What contributes to strategic planning success? Finally, we offer conclusions and an agenda for future research.
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