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Front Plant Sci ; 11: 1051, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754188


Light is one of the most important environmental filters for forest understory grass communities. It is predicted that light can select species with the same light requirements, resulting in a decrease in species compositional dissimilarity among grass communities experiencing the same light intensity, and an increase in community dissimilarity under variable light intensities. However, these predictions have been questioned recently in light of modern coexistence theories, and evidence for them in natural communities is often indistinguishable from patterns created by dispersal limitation and biotic interactions. To help fill this gap, we sampled 48 understory grass communities that had regenerated from the same soil seed bank in Southern China. Plots were established under a light intensity gradient. Changes in species composition and neighborhood densities were monitored over a growing season. Our experimental setup controls for bias from dispersal limitation and is useful for detecting the effects of biotic interactions at different intensities of light. As expected, (1) compositional dissimilarity of grass communities increased between communities with different light intensities. The extent to which communities became more dissimilar was positively correlated with the difference in the light intensity. (2) No significant change in compositional dissimilarity was observed among communities experiencing the same light intensity. (3) Finally, relative neighborhood density significantly decreased in communities with moderate to high shading treatments. Our results clearly show that light can drive compositional divergence among communities under different light densities. However, the light may not lead to convergence among communities experiencing the same low light intensity, because intense competition induced by low light might enlarge species compositional differences, as shown with the neighborhood density analysis. Therefore, our study provides more convincing evidence for the importance of light on understory grass communities in subtropical forests and highlights the need to jointly consider biotic interactions when testing for evidence for environmental filtering.

Sci Adv ; 6(6): eaav7504, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32083172


Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r 1 = 30.9 mM-1 s-1, r 2 = 43.2 mM-1 s-1, 1.5 T; r 1 = 23.5 mM-1 s-1, r 2 = 98.6 mM-1 s-1, 7.0 T), strong CXCR4 binding (K d = 1.10 ± 0.18 µM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm3. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

Biomarcadores , Meios de Contraste , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Imagem por Ressonância Magnética , Imagem Molecular , Receptores CXCR4/metabolismo , Animais , Meios de Contraste/química , Modelos Animais de Doenças , Detecção Precoce de Câncer , Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Imagem por Ressonância Magnética/métodos , Camundongos , Modelos Moleculares , Metástase Neoplásica , Ligação Proteica , Curva ROC , Receptores CXCR4/química , Receptores CXCR4/genética , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
Nat Commun ; 10(1): 4777, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664017


Early diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Here we report a collagen type I targeting protein-based contrast agent (ProCA32.collagen1) with strong collagen I affinity. ProCA32.collagen1 possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage (Ishak stage 3 of 6) liver fibrosis and nonalcoholic steatohepatitis (Ishak stage 1 of 6 or 1 A Mild) in animal models via dual contrast modes. ProCA32.collagen1 also demonstrates vasculature changes associated with intrahepatic angiogenesis and portal hypertension during late-stage fibrosis, and heterogeneity via serial molecular imaging. ProCA32.collagen1 mitigates metal toxicity due to lower dosage and strong resistance to transmetallation and unprecedented metal selectivity for Gd3+ over physiological metal ions with strong translational potential in facilitating effective treatment to halt further chronic liver disease progression.

Meios de Contraste/química , Gadolínio/química , Hipertensão Portal/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Doença Crônica , Diagnóstico Precoce , Humanos
Biomaterials ; 224: 119478, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31542517


The Liver is the most common organ for metastasis for various cancers, including uveal melanoma, the most common primary intraocular tumor. Uveal melanoma metastasizes to the liver in ~90% of patients, and results in death in almost all cases due to late detection and lack of effective treatment. There is a pressing unmet medical need to develop MRI contrast agents and imaging methodologies with desired sensitivity and specificity to overcome the high heterogeneous background and in vivo properties as well as reduced toxicity. Herein, we report the development of a collagen targeting protein contrast agent (ProCA32.collagen1), since collagen is a diagnostic biomarker and therapeutic target for many types of primary and metastatic cancers and the tumor microenvironment. In addition to a strong affinity to collagen I, ProCA32.collagen1 possesses high relaxivities (r1 and r2 are 68.0 ±â€¯0.25 and 100.0 ±â€¯0.32 mM-1 s-1 at 1.4 T, respectively, and 42.6 ±â€¯1.0 and 217 ±â€¯2.4 mM-1s-1 at 7.0 T per particle). ProCA32.collagen1 also has strong serum stability against degradation, resistance to transmetallation, and 102 and 1013-fold higher metal selectivity for Gd3+ over Ca2+ and Zn2+, respectively, compared to clinical contrast agents. ProCA32.collagen1 does not exhibit any cell toxicity for various cell lines. Sensitive detection of liver lesions in animal models can be achieved using multiple imaging methodologies, taking advantage of the dual relaxation property of ProCA32.collagen1. ProCA32.collagen1 enables sensitive and early stage detection of hepatic micrometastasis as small as 0.144 mm2 and two different tumor growth patterns. Further development of ProCA32.collagen1 has the potential to greatly facilitate non-invasive, early detection and staging of primary and metastatic liver cancers, and devising effective treatments.

Colágeno/química , Meios de Contraste/química , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Imagem por Ressonância Magnética , Animais , Linhagem Celular , Sobrevivência Celular , Endocitose , Feminino , Humanos , Fígado/patologia , Camundongos Endogâmicos C57BL , Distribuição Tecidual
Med Sci Monit ; 25: 10190-10197, 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31889729


BACKGROUND This study aimed to investigate the molecular mechanisms associated with the effects of propofol in a rat model of pain due to inflammation following subcutaneous injection with complete Freund's adjuvant (CFA). MATERIAL AND METHODS Sprague-Dawley rats were injected subcutaneously in the paw with CFA. Propofol or saline was administered by tail vein injection. After CFA treatment for 0 hours, 4 hours, 1 day, 4 days, 7 days, and 14 days, the behavior of the rats was assessed. An enzyme-linked immunosorbent assay (ELISA) measured serum levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß, and IL-6. Western blot and the quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect levels of p38MAPK and NF-kappaB related mRNA and proteins, including p-p38, p38, p65, p-p65, NOD-like receptor family protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and caspase-1 in rat spinal cord tissues. RESULTS Injection of CFA significantly reduced the mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and frequency responses to cold stimulation. Propofol treatment significantly reduced serum levels of TNF-alpha, IL-1ß, and IL-6. Protein expression levels of p-p38 and p-p65 were upregulated in the rat model, which were inhibited by propofol treatment. CFA injection increased the expression levels of NLRP3, ASC, and caspase-1 in the spinal cord tissues of rats, which were reduced by propofol treatment. CONCLUSIONS In a rat model of pain following subcutanous injection with CFA, propofol reduced CFA-induced pain and inhibited the inflammatory response through the p38MAPK-nuclear factor-kappaB (NF-kappaB) pathway and the NLRP3 inflammasome.

Adjuvante de Freund/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/genética , Dor/tratamento farmacológico , Dor/genética , Propofol/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Inflamassomos/metabolismo , Mediadores da Inflamação/sangue , Injeções Subcutâneas , Masculino , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Propofol/administração & dosagem , Propofol/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
Nanoscale ; 8(25): 12668-82, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26961235


Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd(3+) contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd(3+) binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 ± 0.1 µM for PSMA while the metal binding affinity is maintained at 0.9 ± 0.1 × 10(-22) M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM(-1) s(-1) and r2 of 37.9 mM(-1) s(-1) per Gd (55.2 and 75.8 mM(-1) s(-1) per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM(-1) s(-1) per Gd (188.0 mM(-1) s(-1) per molecule) and r1 of 18.6 mM(-1) s(-1) per Gd (37.2 mM(-1) s(-1) per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.

Antígenos de Superfície/análise , Meios de Contraste , Glutamato Carboxipeptidase II/análise , Imagem por Ressonância Magnética , Imagem Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Gadolínio , Humanos , Masculino , Camundongos , Camundongos Nus