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Commercialization of 2,4-D–tolerant crops is a major concern for sweetpotato producers because of potential 2,4-D drift that can cause severe crop injury and yield reduction. A field study was initiated in 2014 and repeated in 2015 to assess impacts of reduced rates of 2,4-D, glyphosate, or a combination of 2,4-D with glyphosate on sweetpotato. In one study, 2,4-D and glyphosate were applied alone and in combination at 1/10, 1/100, 1/250, 1/500, 1/750, and 1/1,000 of anticipated field use rates (1.05 kg ha−1 for 2,4-D and 1.12 kg ha−1 for glyphosate) to ‘Beauregard’ sweetpotato at storage root formation (10 days after transplanting [DAP]). In a separate study, all these treatments were applied to ‘Beauregard’ sweetpotato at storage root development (30 DAP). Injury with 2,4-D alone or in combination with glyphosate was generally equal or greater than with glyphosate applied alone at equivalent herbicide rates, indicating that injury is attributable mostly to 2,4-D in the combination. There was a quadratic increase in crop injury and quadratic decrease in crop yield (with respect to most yield grades) with increased rate of 2,4-D applied alone or in combination with glyphosate applied at storage root development. However, neither the results of this relationship nor of the significance of herbicide rate were observed on crop injury or sweetpotato yield when herbicide application occurred at storage root formation, with a few exceptions. In general, crop injury and yield reduction were greatest at the highest rate (1/10×) of 2,4-D applied alone or in combination with glyphosate, although injury observed at lower rates was also a concern after initial observation by sweetpotato producers. However, in some cases, yield reduction of U.S. no.1 and marketable grades was also observed after application of 1/250×, 1/100×, or 1/10× rates of 2,4-D alone or with glyphosate when applied at storage root development.
OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.
A major concern of sweetpotato producers is the potential negative effects from herbicide drift or sprayer contamination events when dicamba is applied to nearby dicamba-resistant crops. A field study was initiated in 2014 and repeated in 2015 to assess the effects of reduced rates of N,N-Bis-(3-aminopropyl)methylamine (BAPMA) or diglycloamine (DGA) salt of dicamba, glyphosate, or a combination of these individually in separate trials with glyphosate on sweetpotato. Reduced rates of 1/10, 1/100, 1/250, 1/500, 1/750, and 1/1,000 of the 1× use rate of each dicamba formulation at 0.56 kg ha−1, glyphosate at 1.12 kg ha−1, and a combination of the two at aforementioned rates were applied to ‘Beauregard’ sweetpotato at storage root formation (10 d after transplanting) in one trial and storage root development (30 d after transplanting) in a separate trial. Injury with each salt of dicamba (BAPMA or DGA) applied alone or with glyphosate was generally equal to or greater than glyphosate applied alone at equivalent rates, indicating that injury is most attributable to the dicamba in the combination. There was a quadratic increase in crop injury and a quadratic decrease in crop yield (with respect to most yield grades) observed with an increased herbicide rate of dicamba applied alone or in combination with glyphosate applied at storage root development. However, with a few exceptions, neither this relationship nor the significance of herbicide rate was observed on crop injury or sweetpotato yield when herbicide application occurred at the storage root formation stage. In general, crop injury and yield reduction were greatest at the highest rate (1/10×) of either salt of dicamba applied alone or in combination with glyphosate, although injury observed at lower rates would be cause for concern after initial observation by sweetpotato producers. However, in some cases yield reduction of No.1 and marketable grades was observed following 1/250×, 1/100×, or 1/10× application rates of dicamba alone or with glyphosate when applied at storage root development.
Landscapes are defined as ‘an area, as perceived by people, whose character is the result of the action and interaction of natural and/or human factors’ (Council of Europe, 2000). Cultural landscapes are defined by the UNESCO World Heritage Convention (1992) as distinct geographical areas or properties uniquely ‘represent[ing] the combined work of nature and of man’. It also describes cultural landscapes as a ‘diversity of manifestations of the interaction between humankind and its natural environment’, and that the protection of traditional cultural landscapes can contribute to maintaining biological diversity. Indeed, Pilgrim and Pretty (2010) propose that the resilience of ecocultural systems is at its strongest when biological and cultural diversity can be considered as an interdependent whole.
The solutions must be context-sensitive; for example, even within Sweden it was clear from this survey (Sang & Ode-Sang, 2015) that there was considerable variance in the financial resources, skills and requirements of different local authorities. This said, there are also certain issues in common which we believe will have some general relevance elsewhere, at least in so far as some hierarchy of government exists whereby local government has responsibility for granting or denying permission to specific developments of smaller scale and national authorities are involved in decisions over key infrastructure and strategic planning as well as regulatory and financial frame works. Not all the suggestions will fit equally to all domains, such as land versus marine, but we hope, in bringing together the views of all authors here, to provide some general principles by which greater capacity for scenario modelling may be built. Of course, these represent the views of modellers and academics, albeit ones with considerable collective experience of working with practitioners, policy makers, citizens and other stakeholder groups. Some of these recommendations may be ‘easier said than done’ and few are exclusively the responsibility of any one party, efforts must be coordinated, but we nonetheless believe it is of value to set out as plainly as possible the tasks at hand and where these might be most fruitfully begun.
This paper presents the results of the work of the new field initiative launched by the British Museum at the Darband-i Rania pass in the Kurdistan Region of Iraq. The pass is located at the northeastern corner of Lake Dokan, where, though now subsumed into the lake, the Lower Zab flows from the Peshdar into the Rania Plain. It is a strategic location on a major route from Mesopotamia into Iran, and control of both the road and the river must always have been important. The aim of the work, which commenced in autumn of 2016, is to explore a cluster of sites that commanded the pass, with a particular focus on the first millennium b.c. Excavation is being carried out principally at two sites: Qalatga Darband, a large fortified site at the western end of the pass, and Usu Aska, a fort inside the pass itself. The occupations of these two sites are predominantly Parthian and Assyrian respectively. Smaller operations have also been carried out at Murad Rasu, a multi-period site situated on a headland across the waters on the southern shore of Lake Dokan. The results have included the discovery at Qalatga Darband of a monumental complex built of stone and roofed with terracotta roof tiles containing the smashed remains of Hellenistic statuary. Other features indicative of Hellenistic material culture are Mediterranean-type oil-presses and Corinthian column bases and capitals. At Usu Aska remains are being uncovered of an Assyrian fortification of massive proportions.
This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation.
We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children’s hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls.
All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences −30.13 mg/cm3 (p = 0.041), −0.31 mm (p = 0.043), and −6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were −0.46 ± 1.1 and −0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex.
In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.
The transmission rate of methicillin-resistant Staphylococcus aureus (MRSA) to gloves or gowns of healthcare personnel (HCP) caring for MRSA patients in a non–intensive care unit setting was 5.4%. Contamination rates were higher among HCP performing direct patient care and when patients had detectable MRSA on their body. These findings may inform risk-based contact precautions.
Why has Sidgwick's political philosophy fallen into oblivion while his ethics continues to be celebrated? Not because his performance in that field was inferior, nor because his choice of topics has become outdated, nor because his conclusions were largely conservative. Instead the problem stems from the weight he attached to common sentiments and beliefs in his application of the utility principle, illustrated by his treatment of topics such as secession and colonialism. Moreover his Elements of Politics is arranged in such a way that he never has to confront the basic question of what makes states legitimate. This means that neither political moralists, who want to see the utility principle applied in more radical fashion, nor political realists, for whom the problem of establishing political order is central, find much to commend in his political philosophy.
We examine first language (L1) attrition among 30 L1 Spanish – L2 English speakers living in the United Kingdom. We also tested 30 recently-arrived Spaniards to the UK as a baseline. We present several key findings: 1) attrition fluctuates over time and does not affect all individuals equally; 2) entropy can explain said fluctuation of attritional affects over time such that while length of residence and age of arrival may affect the depth of attrition, how often one is exposed to her native language, how often she uses it and for how long each day, who her friends are, and to which types of input she is regularly exposed, seemingly aid in the maintenance or loss of linguistic knowledge; 3) though offline scalar interpretations among bilinguals were predicted by canonical sociolinguistic variables, the online data revealed an overall insensitivity to pragmatic violations. Thus, offline and online methods combine to be more explanatory regarding the comprehension and processing of implicature generating quantifiers.
In this chapter I examine the criteria that it is legitimate for liberal states to use when selecting refugees for admission. My aim is not to provide detailed policy guidance. Refugee policy, like immigration policy generally, is a complex matter, and states have evolved different selection practices to suit their particular circumstances and the demands for admission that they face. Nevertheless, we can readily agree that some selection criteria are inadmissible – selection on grounds of race, for example. In particular, I want to explore whether in setting their policies, states have simply to respond to the weight of the moral claim that each refugee can make to be admitted, or whether they also have some scope to shape these policies to reflect the preferences and interests of their own citizens. In relation to the former, what gives one refugee a stronger claim than another to be granted admission, on either a temporary or a permanent basis? In relation to the latter, how far, if at all, is it permissible for states to allow considerations of national culture, economic advantage, social cohesion and so forth to influence their refugee selection policies?
Of the cast of characters who populate the contemporary world, none is more familiar than the figure of the refugee. He or she is visible to us mainly as a person on the move, the victim of war or ethnic cleansing. We see her sitting surrounded by her life’s possessions in a battered truck crossing the wasteland; we see him strapped into an orange lifejacket and crammed precariously on an inflatable raft; we see her waiting sorrowfully in front of a border fence hoping that a guard will one day let her cross. But our remotely acquired visual impressions can mislead. Refugees who are actively in flight make up only a small fraction of the number who qualify for that designation at any moment. The vast majority – some 25 million – are more or less stationary, living largely out of our sight in the global South, in encampments that are purpose-built or home-made, or on the margins of cities like Beirut or Peshawar. They exist in a kind of limbo, often unwelcome visitors in the countries that have little choice but to house them, but unable to return to their homelands while conditions there remain hostile or unsafe. Many would prefer to be resettled in rich, developed countries – typically more than half a million apply to do so each year. But the number who succeed is only a fraction of this, since the governments of these countries set quotas for accepting refugees and go to considerable lengths to enforce them. The events of 2015, when more than a million migrants, including many refugees, entered Europe directly and found sanctuary there, were unprecedented in the recent past, and are unlikely to be repeated. Yet, for citizens in Europe and North America, it is the minority who attempt to settle in the global North who capture most of their attention, and philosophical reflection on the moral and political claims of the refugee, of the kind that occupies this book, has also focussed mainly on those who seek admission to rich developed countries.
Clonal Mycobacterium mucogenicum isolates (determined by molecular typing) were recovered from 19 bronchoscopic specimens from 15 patients. None of these patients had evidence of mycobacterial infection. Laboratory culture materials and bronchoscopes were negative for Mycobacteria. This pseudo-outbreak was caused by contaminated ice used to provide bronchoscopic lavage. Control was achieved by transitioning to sterile ice.
Uninsured patients are more likely than the general population to use tobacco and less likely to quit.
To determine if the mode of delivering the PHS Guidelines influenced the effectiveness of smoking cessation among patients in a safety net setting.
Six free clinics were randomly assigned to a training program delivered by an academic physician or community partner plus video support. A repeated cross-sectional survey of patients was conducted at three waves to assess effectiveness to promote quitting.
Tobacco use was triple the rate of the US population: 57.7% (Wave 1), 44.7% (Wave 2), and 48.9% (Wave 3). Patients were more likely to report receipt of at least one evidence-based strategy to promote quitting at Wave 2 (AOR = 2.33, 95% CI (1.18–4.58)). Patients treated in clinics trained by the community partner were significantly more likely to report receiving cessation assistance at Wave 2 (AOR 2.54, 95%CI 1.29–5.00) and the trend was similar, but not significant at Wave 3. Patients in the community partner-led arm were significantly less likely to report tobacco use at Wave 3 (AOR 0.59, 95% CI 0.35–0.99).
Implementation of the PHS Guidelines in free clinics demonstrates preliminary efficacy, with delivery by community partners offering greater scalability.
How to assess and deal with the claims of millions of displaced people to find refuge and asylum in safe and prosperous countries is one of the most pressing issues of modern political philosophy. In this timely volume, fresh insights are offered into the political and moral implications of refugee crises and the treatment of asylum seekers. The contributions illustrate the widening of the debate over what is owed to refugees, and why it is assumed that national state actors and the international community owe special consideration and protection. Among the specific issues discussed are refugees' rights and duties, refugee selection, whether repatriation can be encouraged or required, and the ethics of sanctuary policies.