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1.
Nature ; 596(7871): 268-272, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107529

RESUMO

The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Ad26COVS1 , Adolescente , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Humanos , Imunidade Celular , Imunidade Humoral , Pessoa de Meia-Idade , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
2.
J Allergy Clin Immunol ; 153(6): 1655-1667, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38154666

RESUMO

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.


Assuntos
COVID-19 , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Hospedeiro Imunocomprometido/imunologia , Adulto , Idoso , Linfócitos T/imunologia , Vacinas contra COVID-19/imunologia , Imunocompetência/imunologia
3.
Proc Natl Acad Sci U S A ; 118(44)2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34697238

RESUMO

Pest management practices in modern industrial agriculture have increasingly relied on insurance-based insecticides such as seed treatments that are poorly correlated with pest density or crop damage. This approach, combined with high invertebrate toxicity for newer products like neonicotinoids, makes it challenging to conserve beneficial insects and the services that they provide. We used a 4-y experiment using commercial-scale fields replicated across multiple sites in the midwestern United States to evaluate the consequences of adopting integrated pest management (IPM) using pest thresholds compared with standard conventional management (CM). To do so, we employed a systems approach that integrated coproduction of a regionally dominant row crop (corn) with a pollinator-dependent specialty crop (watermelon). Pest populations, pollination rates, crop yields, and system profitability were measured. Despite higher pest densities and/or damage in both crops, IPM-managed pests rarely reached economic thresholds, resulting in 95% lower insecticide use (97 versus 4 treatments in CM and IPM, respectively, across all sites, crops, and years). In IPM corn, the absence of a neonicotinoid seed treatment had no impact on yields, whereas IPM watermelon experienced a 129% increase in flower visitation rate by pollinators, resulting in 26% higher yields. The pollinator-enhancement effect under IPM management was mediated entirely by wild bees; foraging by managed honey bees was unaffected by treatments and, overall, did not correlate with crop yield. This proof-of-concept experiment mimicking on-farm practices illustrates that cropping systems in major agricultural commodities can be redesigned via IPM to exploit ecosystem services without compromising, and in some cases increasing, yields.


Assuntos
Agricultura/métodos , Conservação dos Recursos Naturais , Controle de Insetos/métodos , Insetos , Inseticidas , Polinização , Agricultura/economia , Animais , Biomassa , Citrullus , Controle de Insetos/economia , Resíduos de Praguicidas/análise , Pólen/química , Zea mays
4.
Clin Infect Dis ; 76(3): e60-e70, 2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35959897

RESUMO

BACKGROUND: The burden and duration of persistent symptoms after nonsevere coronavirus disease 2019 (COVID-19) remains uncertain. This study aimed to assess postinfection symptom trajectories in home-isolated COVID-19 cases compared with age- and time- matched seronegative controls, and investigate immunological correlates of long COVID. METHODS: A prospective case-control study included home-isolated COVID-19 cases between February 28 and April 4, 2020, and followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive controls. We collected clinical data at baseline, 6, 12, and 18 months postinfection, and blood samples at 2, 4, 6, and 12 months for analysis of SARS-CoV-2-specific humoral and cellular responses. RESULTS: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared with controls, adult cases had a high risk of fatigue (27% excess risk, sex, and comorbidity adjusted odds ratio [aOR] 5.86; 95% confidence interval [CI], 3.27-10.5), memory problems (21% excess risk; aOR 7.42; CI, 3.51-15.67), concentration problems (20% excess risk; aOR 8.88; 95% CI, 3.88-20.35), and dyspnea (10% excess risk; aOR 2.66; 95% CI, 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%; 95% CI, 1.5-21.5; P = .024) and among women (excess risk 18.7%; 95% CI, 4.4-32.9; P = .010). Longitudinal spike immunoglobulin G was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4+ T-cell receptor ß depth was significantly associated with both dyspnea and number of symptoms at 12 months. CONCLUSIONS: This study documents a high burden of persisting symptoms after mild COVID-19 and suggests that infection induced SARS-CoV-2-specific immune responses may influence long-term symptoms.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Feminino , Humanos , Síndrome de COVID-19 Pós-Aguda , Estudos de Casos e Controles , Dispneia , Transtornos da Memória
5.
Planta ; 257(6): 106, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37127808

RESUMO

MAIN CONCLUSION: Cucurbita argyrosperma domestication affected plant defence by downregulating the cucurbitacin synthesis-associated genes. However, tissue-specific suppression of defences made the cultivars less attractive to co-evolved herbivores Diabrotica balteata and Acalymma spp. Plant domestication reduces the levels of defensive compounds, increasing susceptibility to insects. In squash, the reduction of cucurbitacins has independently occurred several times during domestication. The mechanisms underlying these changes and their consequences for insect herbivores remain unknown. We investigated how Cucurbita argyrosperma domestication has affected plant chemical defence and the interactions with two herbivores, the generalist Diabrotica balteata and the specialist Acalymma spp. Cucurbitacin levels and associated genes in roots and cotyledons in three wild and four domesticated varieties were analysed. Domesticated varieties contained virtually no cucurbitacins in roots and very low amounts in cotyledons. Contrastingly, cucurbitacin synthesis-associated genes were highly expressed in the roots of wild populations. Larvae of both insects strongly preferred to feed on the roots of wild squash, negatively affecting the generalist's performance but not that of the specialist. Our findings illustrate that domestication results in tissue-specific suppression of chemical defence, making cultivars less attractive to co-evolved herbivores. In the case of squash, this may be driven by the unique role of cucurbitacins in stimulating feeding in chrysomelid beetles.


Assuntos
Cucurbita , Herbivoria , Animais , Domesticação , Insetos/fisiologia , Plantas , Cucurbitacinas
6.
Clin Infect Dis ; 75(12): 2079-2087, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-35521791

RESUMO

BACKGROUND: While diagnostic, therapeutic, and vaccine development in the coronavirus disease 2019 (COVID-19) pandemic has proceeded at unprecedented speed, critical gaps in our understanding of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unaddressed by current diagnostic strategies. METHODS: A statistical classifier for identifying prior SARS-CoV-2 infection was trained using >4000 SARS-CoV-2-associated T-cell receptor (TCR) ß sequences identified by comparing 784 cases and 2447 controls from 5 independent cohorts. The T-Detect COVID (Adaptive Biotechnologies) assay applies this classifier to TCR repertoires sequenced from blood samples to yield a binary assessment of past infection. Assay performance was assessed in 2 retrospective (n = 346; n = 69) and 1 prospective cohort (n = 87) to determine positive percent agreement (PPA) and negative percent agreement (NPA). PPA was compared with 2 commercial serology assays, and pathogen cross-reactivity was evaluated. RESULTS: T-Detect COVID demonstrated high PPA in individuals with prior reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection (97.1% 15+ days from diagnosis; 94.5% 15+ days from symptom onset), high NPA (∼100%) in presumed or confirmed SARS-CoV-2 negative cases, equivalent or higher PPA than 2 commercial serology tests, and no evidence of pathogen cross-reactivity. CONCLUSIONS: T-Detect COVID is a novel T-cell immunosequencing assay demonstrating high clinical performance for identification of recent or prior SARS-CoV-2 infection from blood samples, with implications for clinical management, risk stratification, surveillance, and understanding of protective immunity and long-term sequelae.


Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Teste para COVID-19 , Estudos Retrospectivos , Estudos Prospectivos , Técnicas de Laboratório Clínico , Sensibilidade e Especificidade , Receptores de Antígenos de Linfócitos T
7.
Proc Biol Sci ; 289(1986): 20221279, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36350210

RESUMO

Insect pests and pollinators can interact directly and indirectly to affect crop production; however, impacts of these interactions on marketable yield are little known. Thus, the evaluation of interactions between pests and pollinators are needed to best prioritize management efforts. Over 2 years, we evaluated the impact of pollinator visitation and/or beetle (Acalymma vittatum) infestation on fruit set and yield in seedless watermelon production. In 2020, we tested the main effect of pollinator visitation: two or eight honeybee visits, two wild bee visits, hand pollinated and open pollinated. In 2021, we crossed wild and managed pollinator visitation (two or four honeybee visits, two or four wild bee visits, hand pollinated and open pollinated) with varying beetle infestation levels (0, 3, 6 and 9 beetles/plant). In both years, wild bees contributed significantly to high fruit yields, and exclusive visitation from wild bees increased yield by a factor of 1.5-3 compared to honeybees. In 2021, pollination was the only significant factor for fruit set and marketable yield even when compared to the varying beetle infestation levels. These data advocate for a reprioritization of management, to conserve and protect wild bee pollination, which could be more critical than avoiding pest damage for ensuring high yields.


Assuntos
Citrullus , Besouros , Abelhas , Animais , Produtos Agrícolas , Polinização , Insetos , Flores
8.
Plant Cell ; 31(12): 2947-2972, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31628167

RESUMO

Flowers are essential but vulnerable plant organs, exposed to pollinators and florivores; however, flower chemical defenses are rarely investigated. We show here that two clustered terpene synthase and cytochrome P450 encoding genes (TPS11 and CYP706A3) on chromosome 5 of Arabidopsis (Arabidopsis thaliana) are tightly coexpressed in floral tissues, upon anthesis and during floral bud development. TPS11 was previously reported to generate a blend of sesquiterpenes. By heterologous coexpression of TPS11 and CYP706A3 in yeast (Saccharomyces cerevisiae) and Nicotiana benthamiana, we demonstrate that CYP706A3 is active on TPS11 products and also further oxidizes its own primary oxidation products. Analysis of headspace and soluble metabolites in cyp706a3 and 35S:CYP706A3 mutants indicate that CYP706A3-mediated metabolism largely suppresses sesquiterpene and most monoterpene emissions from opening flowers, and generates terpene oxides that are retained in floral tissues. In flower buds, the combined expression of TPS11 and CYP706A3 also suppresses volatile emissions and generates soluble sesquiterpene oxides. Florivory assays with the Brassicaceae specialist Plutella xylostella demonstrate that insect larvae avoid feeding on buds expressing CYP706A3 and accumulating terpene oxides. Composition of the floral microbiome appears also to be modulated by CYP706A3 expression. TPS11 and CYP706A3 simultaneously evolved within Brassicaceae and form the most versatile functional gene cluster described in higher plants so far.plantcell;31/12/2947/FX1F1fx1.


Assuntos
Alquil e Aril Transferases/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Flores/metabolismo , Terpenos/antagonistas & inibidores , Alquil e Aril Transferases/genética , Animais , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/microbiologia , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/genética , Flores/genética , Flores/microbiologia , Expressão Gênica , Larva , Microbiota , Modelos Moleculares , Simulação de Acoplamento Molecular , Monoterpenos/metabolismo , Mariposas , Família Multigênica , Filogenia , Sesquiterpenos/metabolismo , Terpenos/química , Terpenos/metabolismo , Nicotiana/metabolismo , Leveduras/metabolismo
9.
Oecologia ; 198(4): 1057-1072, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35380273

RESUMO

Because the diet of many herbivorous insects is restricted to closely related taxa with similar chemistry, intercropping with diverse plant communities may reduce both pest populations and reliance on chemical pesticides in agroecosystems. We tested whether the effectiveness of intercropping against herbivorous insects depends on the phylogenetic relatedness of neighboring crops, using butternut squash (Cucurbita moschata) as a focal crop species in a series of different intercropping combinations. We found that increased phylogenetic divergence of neighboring plants could reduce abundance of herbivorous insects, but the effect was only detectable mid-season. In addition, we tested two hypothesized mechanisms for a negative association between phylogenetic distance of neighboring plants and reduced herbivore populations: one, we tested using Y-tube olfactometer and choice cage trials whether diverse volatile cues impede host-plant location by the dominant pest of butternut squash in our experiment, striped cucumber beetle Acalymma vittatum. Two, we recorded predator and parasitoid abundance relative to crop phylodiversity to test whether diverse crops support larger natural-enemy populations that can better control pest species. Our results, however, did not support either hypothesis. Striped cucumber beetles preferentially oriented toward non-host-plant volatiles, and predator populations more often decreased with phylodiversity than increased. Thus, the mechanisms driving associations in the field between phylogenetic divergence and herbivore populations remain unclear.


Assuntos
Besouros , Cucurbita , Animais , Herbivoria , Filogenia , Plantas
10.
Proc Biol Sci ; 288(1953): 20210785, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34187195

RESUMO

Insecticide use and insufficient forage are two of the leading stressors to pollinators in agroecosystems. While these factors have been well studied individually, the experimental designs do not reflect real-world conditions where insecticide exposure and lack of forage occur simultaneously and could interactively suppress pollinator health. Using outdoor enclosures, we tested the effects of insecticides (imidacloprid + lambda-cyhalothrin) and non-crop forage (clover) in a factorial design, measuring the survival, behaviour and performance of bumblebees (Bombus impatiens), as well as pollination of the focal crop, watermelon. Colony survival was synergistically reduced to 17% in watermelon alone + insecticides (survival was 100% in all other treatments). However, behavioural shifts in foraging were mainly owing to insecticides (e.g. 95% reduced visitation rate to watermelon flowers), while impacts on hive performance were primarily driven by clover presence (e.g. 374% increase in the number of live eggs). Insecticide-mediated reductions in foraging decreased crop pollination (fruit set) by 32%. Altogether, these data indicate that both insecticides and non-crop forage play integral roles in shaping pollinator health in agricultural landscapes, but the relative importance and interaction of these two factors depend on which aspect of 'health' is being considered.


Assuntos
Inseticidas , Agricultura , Animais , Abelhas , Flores , Frutas , Inseticidas/toxicidade , Polinização
11.
Plant Cell ; 30(9): 2214-2229, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30131419

RESUMO

Endogenous peptides regulate plant immunity and growth. Systemin, a peptide specific to the Solanaceae, is known for its functions in plant responses to insect herbivory and pathogen infections. Here, we describe the identification of the tomato (Solanum lycopersicum) PEPR1/2 ORTHOLOG RECEPTOR-LIKE KINASE1 (PORK1) as the TOMATO PROTEIN KINASE1b (TPK1b) interacting protein and demonstrate its biological functions in systemin signaling and tomato immune responses. Tomato PORK1 RNA interference (RNAi) plants with significantly reduced PORK1 expression showed increased susceptibility to tobacco hornworm (Manduca sexta), reduced seedling growth sensitivity to the systemin peptide, and compromised systemin-mediated resistance to Botrytis cinerea. Systemin-induced expression of Proteinase Inhibitor II (PI-II), a classical marker for systemin signaling, was abrogated in PORK1 RNAi plants. Similarly, in response to systemin and wounding, the expression of jasmonate pathway genes was attenuated in PORK1 RNAi plants. TPK1b, a key regulator of tomato defense against B. cinerea and M. sexta, was phosphorylated by PORK1. Interestingly, wounding- and systemin-induced phosphorylation of TPK1b was attenuated when PORK1 expression was suppressed. Our data suggest that resistance to B. cinerea and M. sexta is dependent on PORK1-mediated responses to systemin and subsequent phosphorylation of TPK1b. Altogether, PORK1 regulates tomato systemin, wounding, and immune responses.


Assuntos
Proteínas de Plantas/metabolismo , Solanum lycopersicum/metabolismo , Animais , Botrytis/patogenicidade , Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas , Solanum lycopersicum/microbiologia , Solanum lycopersicum/parasitologia , Manduca/patogenicidade , Oxilipinas/metabolismo , Imunidade Vegetal/fisiologia , Proteínas de Plantas/genética
12.
New Phytol ; 226(2): 595-608, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31863484

RESUMO

Soils and their microbiomes are now recognized as key components of plant health, but how to steer those microbiomes to obtain their beneficial functions is still unknown. Here, we assess whether plant-soil feedbacks can be applied in a crop system to shape soil microbiomes that suppress herbivorous insects in above-ground tissues. We used four grass and four forb species to condition living soil. Then we inoculated those soil microbiomes into sterilized soil and grew chrysanthemum as a focal plant. We evaluated the soil microbiome in the inocula and after chrysanthemum growth, as well as plant and herbivore parameters. We show that inocula and inoculated soil in which a focal plant had grown harbor remarkably different microbiomes, with the focal plant exerting a strong negative effect on fungi, especially arbuscular mycorrhizal fungi. Soil inoculation consistently induced resistance against the thrips Frankliniella occidentalis, but not against the mite Tetranychus urticae, when compared with sterilized soil. Additionally, plant species shaped distinct microbiomes that had different effects on thrips, chlorogenic acid concentrations in leaves and plant growth. This study provides a proof-of-concept that the plant-soil feedback concept can be applied to steer soil microbiomes with the goal of inducing resistance above ground against herbivorous insects.


Assuntos
Microbiota , Solo , Animais , Retroalimentação , Insetos , Plantas
13.
BMC Pregnancy Childbirth ; 20(1): 140, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32138695

RESUMO

BACKGROUND: Afghanistan has one of the world's highest maternal mortality ratios, with more than 60% of women having no access to a skilled birth attendant in some areas. The main challenges for childbearing Afghan women are access to skilled birth attendance, emergency obstetric care and reliable contraception. The NGO-based project Advancing Maternal and Newborn Health in Afghanistan has supported education of midwives since 2002, in accordance with the national plan for midwifery education. The aim of this study is to explore women's experiences of professional midwifery care in four villages in Afghanistan covered by the project, so as to reveal challenges and improve services in rural and conflict-affected areas of the country. METHODS: An exploratory case-study approach was adopted. Fourteen in-depth interviews and four focus-group discussions were conducted. A total of 39 women participated - 25 who had given birth during the last six months, 11 mothers-in-law and three community midwives in the provinces of Kunar and Laghman. Data generated by the interviews and observations was analysed using thematic content analysis. FINDINGS: Many of the women greatly valued the trained midwives' life-saving experience, skills and care, and the latter were important reasons for choosing to give birth in a clinic. Women further appreciated midwives' promotion of immediate skin-to-skin contact and breastfeeding. However, some women experienced rudeness, discrimination and negligence on the part of the midwives. Moreover, relatives' disapproval, shame and problems with transport and security were important obstacles to women giving birth in the clinics. CONCLUSIONS: Local recruitment and professional education of midwives as promoted by Afghan authorities and applied in the project seem successful in promoting utilisation and satisfaction with maternal and neonatal health services in rural Afghanistan. Nevertheless, the quality of the services is still lacking, with some women complaining of disrespectful care. There seems to be a need to focus more on communication issues during the education of midwives. An increased focus on in-service training and factors promoting quality care and respectful communication is necessary and should be prioritised.


Assuntos
Acessibilidade aos Serviços de Saúde , Serviços de Saúde Materna , Tocologia , Aceitação pelo Paciente de Cuidados de Saúde , Qualidade da Assistência à Saúde , Serviços de Saúde Rural , Adolescente , Adulto , Afeganistão , Feminino , Grupos Focais , Humanos , Pesquisa Qualitativa , Adulto Jovem
14.
Lancet Oncol ; 19(3): 347-355, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29395863

RESUMO

BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , District of Columbia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Timoma/imunologia , Timoma/mortalidade , Timoma/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/mortalidade , Neoplasias do Timo/patologia , Fatores de Tempo , Resultado do Tratamento
15.
Plant Cell Environ ; 40(3): 327-329, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27861985

RESUMO

This article comments on: Combined use of herbivore-induced plant volatiles and sex pheromones for mate location in braconid parasitoids.


Assuntos
Atrativos Sexuais , Vespas/efeitos dos fármacos , Animais , Herbivoria/efeitos dos fármacos , Odorantes , Perfumes , Feromônios , Compostos Orgânicos Voláteis
16.
Oecologia ; 185(1): 1-11, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28730345

RESUMO

Non-consumptive effects (NCEs) of predators are ubiquitous in food webs with well-detailed impacts on trophic cascades over multiple levels. However, integrating NCEs with other predator-mediated interactions, like intraguild predation, as well as context-specific habitat factors that shape top-down pressure, remains a challenge. Focusing on two common seed predators, mice (Peromyscus spp.) and carabid beetles (Coleoptera: Carabidae), we quantify trophic and behavioral consequences of predation risk and availability of refuge vegetation on both intraguild predators (mice) and intraguild prey (beetles). In a 2-year field experiment, we manipulated refuge habitat (red clover), small mammal access, and moonlight, which small mammals use as an indirect cue of predation risk. We found that avoidance of predation risk by mice in simulated moonlight reduced carabid activity density in vegetation by up to 50% compared to exposed habitat, but had no cascading effects on seed predation. We linked patterns observed in the field with behavioral mechanisms by observing beetle foraging activity, and found that exposure to both indirect and direct vertebrate predator cues reduced movement by 50%, consistent with predator-mediated activity reductions observed in the field. However, predation risk increased carabid seed consumption by 43%. Thus, weak effects of predation risk on seed removal in the field may be explained by overcompensatory seed feeding by beetles. This work demonstrates that predators elicit responses that cascade over multiple trophic levels, triggering behavioral changes in species lower on the food chain. These behavior-mediated cascades are controlled by their spatiotemporal context and have important downstream impacts on predator-prey dynamics.


Assuntos
Besouros/fisiologia , Medo , Cadeia Alimentar , Animais , Camundongos , Estado Nutricional , Comportamento Predatório/fisiologia , Risco
17.
J Chem Ecol ; 43(6): 573-585, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28600687

RESUMO

Synthetic plant volatile lures attract natural enemies, but may have non-target effects due to the multifunctional nature of volatile signals. For example, methyl salicylate (MeSA) is used to attract predators, yet also serves as a signaling hormone involved in plant pathogen defense. We investigated the consequences of deploying MeSA lures to attract predators for tomato (Solanum lycopersicum) defense against herbivores. To understand the spatial distribution of the lure's effect, we exposed tomatoes in the field to MeSA along a linear distance gradient and induced defenses by simulating feeding by hornworm caterpillars in a fully crossed factorial design (+/- MeSA, +/- herbivory). Subsequently, we analyzed activity of several defensive proteins (protease inhibitors, polyphenol oxidase, peroxidase), development of hornworm larvae (Manduca sexta), growth of fungal pathogens (Cladosporium and Alternaria), and attractiveness to herbivores and predators. Overall, MeSA-exposed plants were more resistant to both insects and pathogens. Secondary pathogen infection was reduced by 25% in MeSA exposed plants, possibly due to elevated polyphenol oxidase activity. Interestingly, we found that lures affected plant pathogen defenses equivalently across all distances (up to 4 m away) indicating that horizontal diffusion of a synthetic volatile may be greater than previously assumed. While thrips avoided colonizing hornworm- damaged tomato plants, this induced resistance was not observed upon pre-exposure to MeSA, suggesting that MeSA suppresses the repellant effect induced by herbivory. Thus, using MeSA lures in biological control may inadvertently protect crops from pathogens, but has mixed effects on plant resistance to insect herbivores.


Assuntos
Herbivoria , Manduca/fisiologia , Salicilatos/química , Salicilatos/farmacologia , Solanum lycopersicum , Alternaria/crescimento & desenvolvimento , Animais , Catecol Oxidase/metabolismo , Cladosporium/crescimento & desenvolvimento , Larva/fisiologia , Solanum lycopersicum/metabolismo , Solanum lycopersicum/microbiologia , Peroxidase/metabolismo , Controle Biológico de Vetores , Folhas de Planta/microbiologia , Inibidores de Proteases/metabolismo , Espectrometria de Massas em Tandem , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/metabolismo
18.
New Phytol ; 210(1): 284-94, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26725245

RESUMO

Herbivore-induced plant volatiles (HIPVs) mediate critical ecological functions, but no studies have quantitatively synthesized data published on HIPVs to evaluate broad patterns. We tested three hypotheses that use eco-evolutionary theory to predict volatile induction: feeding guild (chewing arthropods > sap feeders), diet breadth (specialist herbivores > generalists), and selection history (domesticated plants < wild species). To test these hypotheses, we extracted data from 236 experiments that report volatiles produced by herbivore-damaged and undamaged plants. These data were subjected to meta-analysis, including effects on total volatiles and major biochemical classes. Overall, we found that chewers induced more volatiles than sap feeders, for both total volatiles and most volatile classes (e.g. green leaf volatiles, monoterpenes). Although specialist herbivores induced more total volatiles than generalists, this was inconsistent across chemical classes. Contrary to our expectation, domesticated species induced stronger volatile responses than wild species, even when controlling for plant taxonomy. Surprisingly, this is the first quantitative synthesis of published studies on HIPVs. Our analysis provides support for perceptions in the published literature (chewers > sap feeders), while challenging other commonly held notions (wild > crop). Despite the large number of experiments, we identified several gaps in the existing literature that should guide future investigations.


Assuntos
Evolução Biológica , Ecossistema , Plantas/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Animais , Dieta , Herbivoria/fisiologia
19.
PLoS Biol ; 10(11): e1001437, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23209381

RESUMO

Indirect plant defenses are those facilitating the action of carnivores in ridding plants of their herbivorous consumers, as opposed to directly poisoning or repelling them. Of the numerous and diverse indirect defensive strategies employed by plants, inducible volatile production has garnered the most fascination among plant-insect ecologists. These volatile chemicals are emitted in response to feeding by herbivorous arthropods and serve to guide predators and parasitic wasps to their prey. Implicit in virtually all discussions of plant volatile-carnivore interactions is the premise that plants "call for help" to bodyguards that serve to boost plant fitness by limiting herbivore damage. This, by necessity, assumes a three-trophic level food chain where carnivores benefit plants, a theoretical framework that is conceptually tractable and convenient, but poorly depicts the complexity of food-web dynamics occurring in real communities. Recent work suggests that hyperparasitoids, top consumers acting from the fourth trophic level, exploit the same plant volatile cues used by third trophic level carnivores. Further, hyperparasitoids shift their foraging preferences, specifically cueing in to the odor profile of a plant being damaged by a parasitized herbivore that contains their host compared with damage from an unparasitized herbivore. If this outcome is broadly representative of plant-insect food webs at large, it suggests that damage-induced volatiles may not always be beneficial to plants with major implications for the evolution of anti-herbivore defense and manipulating plant traits to improve biological control in agricultural crops.


Assuntos
Brassica/química , Borboletas/parasitologia , Herbivoria , Compostos Orgânicos Voláteis/química , Vespas/fisiologia , Animais , Feminino , Masculino
20.
Proc Natl Acad Sci U S A ; 109(30): 12075-80, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22778426

RESUMO

Most organisms face the problem of foraging and maintaining growth while avoiding predators. Typical animal responses to predator exposure include reduced feeding, elevated metabolism, and altered development rate, all of which can be beneficial in the presence of predators but detrimental in their absence. How then do animals balance growth and predator avoidance? In a series of field and greenhouse experiments, we document that the tobacco hornworm caterpillar, Manduca sexta, reduced feeding by 30-40% owing to the risk of predation by stink bugs, but developed more rapidly and gained the same mass as unthreatened caterpillars. Assimilation efficiency, extraction of nitrogen from food, and percent body lipid content all increased during the initial phase (1-3 d) of predation risk, indicating that enhanced nutritional physiology allows caterpillars to compensate when threatened. However, we report physiological costs of predation risk, including altered body composition (decreased glycogen) and reductions in assimilation efficiency later in development. Our findings indicate that hornworm caterpillars use temporally dynamic compensatory mechanisms that ameliorate the trade-off between predator avoidance and growth in the short term, deferring costs to a period when they are less vulnerable to predation.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Comportamento Apetitivo/fisiologia , Manduca/crescimento & desenvolvimento , Fenótipo , Comportamento de Redução do Risco , Análise de Variância , Animais , Composição Corporal , Carbono/metabolismo , Nitrogênio/metabolismo , Comportamento Predatório/fisiologia , Proteínas/metabolismo
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