Individual Based Model to Simulate the Evolution of Insecticide Resistance

Insecticides play a critical role in agricultural productivity. However, insecticides impose selective pressures on insect populations, so the Darwinian principles of natural selection predict that resistance to the insecticide is likely to form in the insect populations. Insecticide resistance, in turn, severely reduces the utility of the insecticides being used. Thus there is a strong economic incentive to reduce the rate of resistance evolution. Moreover, resistance evolution represents an example of evolution under novel selective pressures, so its study contributes to the fundamental understanding of evolutionary theory. Insecticide resistance often represents a complex interplay of multiple fitness trade-offs for individual insects. Resistant individuals tend to suffer significant decreases in fitness when no insecticide is present, resulting in non-resistant individuals having the tendency to outcompete resistant ones in areas with no insecticide. In the use of standard modeling practices, difficulties arise when trying to incorporate these complexities in a fashion which facilitates the simulation of the model and analyzing the results. Individual based models (IBMs) are one approach to overcoming these difficulties by leveraging modern computational techniques and modern computer power. In an IBM each member of the population is simulated to follow a set of stochastic rules, which includes rules about the behaviors and interactions of individuals. We propose to apply an IBM approach to modeling the evolution of insecticide resistance in an insect species population. The fall armyworm is an economically damaging pest which has recently become invasive in Africa, India, and China. A common type of insecticide used control fall armyworms is Bacillus thuringiensis (Bt). We hypothesize that individuals that are resistant to Bt grow at slower rates than their counterparts. This creates a strong fitness disadvantage when Bt is not present because the fall armyworms are cannibalistic, where smaller individuals have a large disadvantage. Thus we use our IBM to explore the nature of the fitness trade-offs between resistance and growth rate in order to understand how it could be exploited to lessen the rate of resistance evolution in the species. Adviser: Richard Rebarber and Brigitte Tenhumber

DOWNHILL DOMINATION IN GRAPHS

A path π = (v1, v2, . . . , vk+1) iun a graph G = (V, E) is a downhill path if for every i, 1 ≤ i ≤ k, deg(vi) ≥ deg(vi+1), where deg(vi) denotes the degree of vertex vi ∈ V. The downhill domination number equals the minimum cardinality of a set S ⊆ V having the property that every vertex v ∈ V lies on a downhill path originating from some vertex in S. We investigate downhill domination numbers of graphs and give upper bounds. In particular, we show that the downhill domination number of a graph is at most half its order, and that the downhill domination number of a tree is at most one third its order. We characterize the graphs obtaining each of these bounds

An Analysis of the Reflection Component in the EPICS Model of Service Learning

Service learning is a pedagogy providing a structured environment for students to link service with course learning objectives. Key to the service learning experience is critical reflection. This gives students the opportunity to examine their coursework in the context of the service they provide to their community and, in a broader sense, the impact they can have on the world. Research has shown that students participating in service learning have a higher comprehension of the course material and also develop an awareness of their local community and the issues it faces. In engineering, there are many examples of service-learning programs ranging from freshman introductory courses to senior capstone courses. Despite their successes, an area that the engineering education community has yet to fully develop is the reflection component of service learning. This paper addresses the development of reflection activities and materials in the Engineering Projects in Community Service (EPICS) program at Purdue University. EPICS engages students in long-term design projects that provide technical solutions to problems faced by local community service organizations. It is a multidisciplinary (composed of students from 20 majors), vertically integrated (freshman-senior), engineering-based design course. Students design, build, test, and deploy projects meeting the specific needs of their community partners. Reflection has been integrated in the EPICS program through curricular activities and key milestones of the course. These activities guide students through the reflection process on a variety of topics. Critical reflection on the design process and teaming complement those on more traditional areas of ethics and social context to enhance a student\u27s service learning experience. This paper presents an overview of the reflection activities that have been developed, interpretations of student reflections from these activities, and plans to evolve the reflection component in EPICS

Targeted SERS nanosensors measure physicochemical gradients and free energy changes in live 3D tumor spheroids.

Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.Leverhulme Trust (Grant ID: RPG-2012-680), Jamie King Cancer Research FundThis is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C6NR06031

Hydrothermal Chimney Distribution on the Endeavour Segment, Juan de Fuca Ridge

The Endeavour Segment of the Juan de Fuca Ridge is well known for its abundance of hydrothermal vents and chimneys. One-meter scale multibeam mapping data collected by an autonomous undersea vehicle revealed 572 chimneys along the central 14 km of the segment, although only 47 are named and known to be active. Hydrothermal deposits are restricted to the axial graben and the near-rims of the graben above a seismically mapped axial magma lens. The sparse eruptive activity on the segment during the last 4,300 years has not buried inactive chimneys, as occurs at more magmatically robust mid-ocean ridges

Enhancing viscosity control in antibody formulations : a framework for the biophysical screening of mutations targeting solvent-accessible hydrophobic and electrostatic patches

The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. In the current study, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of mutants with modified viscosity profiles accompanied by experimental evaluation. Our observations using a model anti-IL8 antibody reveal that the reduction in viscosity is influenced by the location of hydrophobic interactions, while targeting positively charged patches in mAb1 leads to the most significant viscosity increase compared to the wild-type mAb. We conclude that existing in silico predictions of physicochemical properties exhibit poor correlation with experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the necessity for comprehensive case-by-case evaluations of mAbs. This approach aids in the rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes

Background & AimsPancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice.MethodsWe used KRasG12D p53R172H Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes.ResultsPancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRasG12D p53R172H Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial−mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence.ConclusionsThe actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors

Chronic Thromboembolic Pulmonary Hypertension

The pulmonary hypertension (PH) and right heart dysfunction that results from chronic thromboembolic involvement of the pulmonary vascular bed is potentially curable with surgical endarterectomy. Over the past several decades, growing clinical experience has brought about increased recognition of this treatable form of PH. Moreover, advances in cardiothoracic surgical techniques have given an increasing number of patients with chronic thromboembolic PH (CTEPH) a surgical remedy with decreasing perioperative morbidity and mortality risks. The availability of pulmonary hypertensive—specific medical therapy for CTEPH patients with surgically inaccessible disease also has been a positive therapeutic advance over the past several years. However, despite this progress, chronic thromboembolic disease as a sequela of acute pulmonary emboli continues to be underappreciated. Furthermore, even if CTEPH has been appropriately diagnosed, misinterpretation of diagnostic information may lead to the inappropriate exclusion of patients from surgical consideration. This may result in the prescription of pulmonary hypertensive medical therapy in CTEPH patients with potentially surgically correctable disease. This difficulty arises from a lack of objective criteria as to what constitutes surgical chronic thromboembolic disease, which primarily is a result of the variability in surgical experience in specialty centers in the United States. Consequently, clinicians must be wary about using pulmonary hypertensive medications in CTEPH patients. Before prescription, it is important to exclude patients from surgical consideration by consulting a specialized center with expertise in this discipline