ABSTRACT
Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Ebolavirus , Hemorrhagic Fever, Ebola , Animals , Epitopes , Glycoproteins/chemistry , Protein SubunitsABSTRACT
BACKGROUND: Bracts are important for ornamental plants, and their developmental regulation process is complex; however, relatively little research has been conducted on bracts. In this study, physiological, biochemical and morphological changes in Bougainvillea glabra leaves, leaf buds and bracts during seven developmental periods were systematically investigated. Moreover, transcriptomic data of B. glabra bracts were obtained using PacBio and Illumina sequencing technologies, and key genes regulating their development were screened. RESULTS: Scanning electron microscopy revealed that the bracts develop via a process involving regression of hairs and a color change from green to white. Transcriptome sequencing revealed 79,130,973 bp of transcript sequences and 45,788 transcripts. Differential gene expression analysis revealed 50 expression patterns across seven developmental periods, with significant variability in transcription factors such as BgAP1, BgFULL, BgCMB1, BgSPL16, BgSPL8, BgDEFA, BgEIL1, and BgBH305. KEGG and GO analyses of growth and development showed the involvement of chlorophyll metabolism and hormone-related metabolic pathways. The chlorophyll metabolism genes included BgPORA, BgSGR, BgPPH, BgPAO and BgRCCR. The growth hormone and abscisic acid signaling pathways involved 44 and 23 homologous genes, and coexpression network analyses revealed that the screened genes BgAPRR5 and BgEXLA1 are involved in the regulation of bract development. CONCLUSIONS: These findings improve the understanding of the molecular mechanism of plant bract development and provide important guidance for the molecular regulation and genetic improvement of the growth and development of ornamental plants, mainly ornamental bracts.
Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Plant , Gene Regulatory Networks , Nyctaginaceae , Nyctaginaceae/genetics , Nyctaginaceae/metabolism , Transcriptome , Plant Leaves/genetics , Plant Leaves/growth & development , Plant Leaves/metabolism , Genes, Plant , Plant Proteins/genetics , Plant Proteins/metabolism , Flowers/genetics , Flowers/growth & developmentABSTRACT
Zaïre ebolavirus (EBOV) causes Ebola virus disease (EVD), a devastating viral hemorrhagic fever in humans. Nonhuman primate (NHP) models of EVD traditionally use intramuscular infection with higher case fatality rates and reduced mean time-to-death compared to contact transmission typical of human cases of EVD. A cynomolgus macaque model of oral and conjunctival EBOV was used to further characterize the more clinically relevant contact transmission of EVD. NHPs challenged via the oral route had an overall 50% survival rate. NHPs challenged with a target dose of 1 × 102 PFU or 1 × 104 PFU of EBOV via the conjunctival route had 40% and 100% mortality, respectively. Classic signs of lethal EVD-like disease were observed in all NHPs that succumbed to EBOV infection including viremia, hematological abnormalities, clinical chemistries indicative of hepatic and renal disease, and histopathological findings. Evidence of EBOV viral persistence in the eye was observed in NHPs challenged via the conjunctival route. IMPORTANCE This study is the first to examine the Kikwit strain of EBOV, the most commonly used strain, in the gold-standard macaque model of infection. Additionally, this is the first description of the detection of virus in the vitreous fluid, an immune privileged site that has been proposed as a viral reservoir, following conjunctival challenge. The oral and conjunctival macaque challenge model of EVD described here more faithfully recapitulates the prodrome that has been reported for human EVD. This work paves the way for more advanced studies to model contact transmission of EVD, including early events in mucosal infection and immunity, as well as the establishment of persistent viral infection and the emergence from these reservoirs.
Subject(s)
Ebolavirus , Hemorrhagic Fever, Ebola , Animals , Humans , Ebolavirus/physiology , Hemorrhagic Fever, Ebola/transmission , Macaca fascicularis , Disease Models, Animal , Conjunctiva/virology , Disease Transmission, InfectiousABSTRACT
The rise in universal population and accompanying demands have directed toward an exponential surge in the generation of polymeric waste. The estimate predicts that world-wide plastic production will rise to ≈590 million metric tons by 2050, whereas 5000 million more tires will be routinely abandoned by 2030. Handling this waste and its detrimental consequences on the Earth's ecosystem and human health presents a significant challenge. Converting the wastes into carbon-based functional materials viz. activated carbon, graphene, and nanotubes is considered the most scientific and adaptable method. Herein, this world provides an overview of the various sources of polymeric wastes, modes of build-up, impact on the environment, and management approaches. Update on advances and novel modifications made in methodologies for converting diverse types of polymeric wastes into carbon nanomaterials over the last 5 years are given. A remarkable focus is made to comprehend the applications of polymeric waste-derived carbon nanomaterials (PWDCNMs) in the CO2 capture, removal of heavy metal ions, supercapacitor-based energy storage and water splitting with an emphasis on the correlation between PWDCNMs' properties and their performances. This review offers insights into emerging developments in the upcycling of polymeric wastes and their applications in environment and energy.
Subject(s)
Metals, Heavy , Nanostructures , Nanotubes , Humans , Polymers , EcosystemABSTRACT
BACKGROUND: This study examined the trends in diabetes medication taking and its association with the incidence of depression in patients with type 2 diabetes (T2D). METHOD: A retrospective cohort of Medicare enrollees with regular care in 2010 was defined from 100% Texas Medicare claims. The impact of medication taking on incident depression was evaluated from 2010 to 2018. Cox proportional hazards regressions were used to estimate the association between medication taking and depression. RESULTS: A total of 72,461 patients with T2D and with regular care were analyzed. Among 60,216 treated patients, the regular medication taking rate slightly increased from 60.8 to 63.2% during the study period. Patients with regular medication taking at baseline had a 9% lower risk of developing depression (hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.89-0.94), and the magnitude of the association increased after adjustment of the model for time-varied medication taking (HR: 0.82, 95% CI: 0.79-0.85). The presence of nephropathy had the greatest mediating effect (23.2%) on the association of medication taking and depression. CONCLUSION: We demonstrated a steady but modest increase in regular diabetes medication taking over a 9-year period and a significant relationship between medication taking and incident depression in patients with T2D.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Aged , United States/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Retrospective Studies , Depression/epidemiology , Depression/complications , Incidence , Medicare , Risk FactorsABSTRACT
BACKGROUND: Loropetalum chinense var. rubrum (L. chinense var. rubrum) is a precious, coloured-leaf native ornamental plant in the Hunan Province. We found an L. chinense var. rubrum tree with three different leaf colours: GL (green leaf), ML (mosaic leaf), and PL (purple leaf). The mechanism of leaf coloration in this plant is still unclear. Therefore, this study aimed to identify the metabolites and genes involved in determining the colour composition of L. chinense var. rubrum leaves, using phenotypic/anatomic observations, pigment content detection, and comparative metabolomics and transcriptomics. RESULTS: We observed that the mesophyll cells in PL were purple, while those in GL were green and those in ML were a mix of purple-green. The contents of chlorophyll a, b, carotenoids, and total chlorophyll in PL and ML were significantly lower than those in GL. While the anthocyanin content in PL and ML was significantly higher than that in GL. The metabolomics results showed the differences in the content of cyanidin 3-O-glucoside, delphinidin 3-O-glucoside, cyanidin 3,5-O-diglucoside, pelargonidin, and petunidin 3,5-diglucoside in ML, GL, and PL were significant. Considering that the change trend of anthocyanin content change was consistent with the leaf colour difference, we speculated that these compounds might influence the colour of L. chinense var. rubrum leaves. Using transcriptomics, we finally identified nine differentially expressed structural genes (one ANR (ANR1217); four CYP75As (CYP75A1815, CYP75A2846, CYP75A2909, and CYP75A1716); four UFGTs (UFGT1876, UFGT1649, UFGT1839, and UFGT3273) and nine transcription factors (two MYBs (MYB1057 and MYB1211), one MADS-box (MADS1235), two AP2-likes (AP2-like1779 and AP2-like2234), one bZIP (bZIP3720), two WD40s (WD2173 and WD1867) and one bHLH (bHLH1631) that might be related to flavonoid biosynthesis and then impacted the appearance of colour in L. chinense var. rubrum leaves. CONCLUSION: This study revealed potential molecular mechanisms associated with leaf coloration in L. chinense var. rubrum by analyzing differential metabolites and genes related to the anthocyanin biosynthesis pathway. It also provided a reference for research on leaf colour variation in other ornamental plants.
Subject(s)
Anthocyanins , Transcriptome , Chlorophyll A , Metabolome , MetabolomicsABSTRACT
PURPOSE: Despite substantially higher prevalence of depression among people living with HIV/AIDS (PLWHA), few data exist on the incidence and correlates of depression in this population. This study assessed the effect of HIV infection, age, and cohort period on the risk of developing depression by sex among older U.S. Medicare beneficiaries. METHODS: We constructed a retrospective matched cohort using a 5% nationally representative sample of Medicare beneficiaries (1996-2015). People with newly diagnosed (n = 1309) and previously diagnosed (n = 1057) HIV were individually matched with up to three beneficiaries without HIV (n = 6805). Fine-Gray models adjusted for baseline covariates were used to assess the effect of HIV status on developing depression by sex strata. RESULTS: PLWHA, especially females, had higher risk of developing depression within five years. The relative subdistribution hazards (sHR) for depression among three HIV exposure groups differed between males and females and indicated a marginally significant interaction (p = 0.08). The sHR (95% CI) for newly and previously diagnosed HIV (vs. people without HIV) were 1.6 (1.3, 1.9) and 1.9 (1.5, 2.4) for males, and 1.5 (1.2, 1.8) and 1.2 (0.9, 1.7) for females. The risk of depression increased with age [sHR 1.3 (1.1, 1.5), 80 + vs. 65-69] and cohort period [sHR 1.3 (1.1, 1.5), 2011-2015 vs. 1995-2000]. CONCLUSIONS: HIV infection increased the risk of developing depression within 5 years, especially among people with newly diagnosed HIV and females. This risk increased with older age and in recent HIV epidemic periods, suggesting a need for robust mental health treatment in HIV primary care.
Subject(s)
HIV Infections , Aged , Male , Female , Humans , United States/epidemiology , HIV Infections/epidemiology , Retrospective Studies , Risk Factors , Depression/epidemiology , Depression/etiology , MedicareABSTRACT
Ampelopsis grossedentata, commonly known as "Vine Tea" and well-recognized for its rich flavonoid content, is mainly distributed in the southern regions of the Yangtze River basin in China. These regions include Hunan, Hubei, Jiangxi, and Guizhou provinces. Vine Tea is mainly consumed as an herbal tea and has garnered attention for its reported health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective properties. It has been used to alleviate coughs and sore throats (Zhang et al., 2021; Wang et al., 2017; Gao et al., 2009). In the Zhangjiajie region of Hunan province alone, the Vine Tea planting area reached 7,670.5 hectares and produced commercial goods worth 1.417 billion RMB in 2022. In May 2021, leaf margins and veins fading to yellowing mottling, and crumpling of leaf blades in the shape of a boat symptoms were found in ~16% of Vine Tea plants in the Sanjiakuan Township, Yongding District, Zhangjiajie region (29°15'E, 110°30' N) (Figure 1a, b, c). (Figure 1a, b, c). Phytoplasma-like microbial cells (small oval shaped bacterial cells, around 1000 nm in size) were observed in sieve tube cells in the phloem of diseased leaves using transmission electron microscopy. No such cell was observed in the phloem of healthy leaves (Figure 2a, b). To investigate the potential association between phytoplasma and the observed symptoms of the diseased plants, total DNA was isolated from ten diseasedeaves and compared with ten healthy leaves from the same field using SteadyPure Plant Genomic DNA Extraction Kit. The isolated DNAs were analyzed first in a direct PCR using universal phytoplasma primer pair R16mF2/R16mR1 targeting the 16S rRNA gene (Gundersen and Lee 1996) and specific pair rpF1/rpR1 (Lee et al. 1998) targeting the DNA fragment encoding partial ribosomal proteins (rp) L22 (complete) and S3 and S19 (partial). The initial amplified products were used as templates and further amplified by nested PCR respectively with primer pair R16F2n/R16R2 for the 16S rRNA gene (Lee et al. 1998) and the rpF2/rpR2 primer pair for the rp gene (Martini et al. 2007). No amplification was obtained with DNA from healthy leaf samples using any of the four primer pairs. The amplified fragments from diseased leaves by nested PCR were cloned and sequenced (Qingke Biotech, China). The obtained sequences have been deposited in GenBank with accession numbers OR282806 for the 16S rRNA gene and GenBank OR353012 for the rp gene. BLASTn analysis revealed that the partial 16S rRNA gene sequence in our sample shared 99.4% nucleotide sequence identity with 'Candidatus Phytoplasma sp.' (MW364378) and 'Peony yellows phytoplasma' (KY814723) of the 16SrI group. Similarly, our rp gene sequence shared 99.6% nucleotide identity with the rpI group of phytoplasma such as the 'Balsamine virescence phytoplasma' (JN572890) and 'Paulownia witches'-broom phytoplasma' (HM146079). Phylogenetic analysis of the 16S rRNA and rp sequences using MEGA version 7.0 revealed that the phytoplasma strain associated with A. grossedentata yellow leaf syndrome in our study site belonged to the 16SrI (Candidatus Phytoplasma asteris) group of phytoplasma (Figure 3a, b). Using the interactive online phytoplasma classification tool iPhyClassifier (Zhao et al., 2009), virtual restriction fragment length polymorphism (RFLP) analysis of the 16S rRNA gene sequences showed our strain having a distinct RFLP map but was closest to that of the onion yellow phytoplasma 16SrI-B subgroup (GenBank accession number: AP006628), with a similarity coefficient of 0.94 (Figure 4a, b). To confirm phytoplasma transmission, healthy plants were inoculated with three scions of infected plants of A. grossedentata. After 16 days, the new leaves of the inoculated A. grossedentata showed yellow leaf symptoms (Figure 5a, b, c), akin to the symptoms originally observed in the field, and the outer contour of the leaf margin appeared chlorotic. After 26 days, primer pairs R16mF2/R16R1 and R16F2n/R16R2 were used for nested PCR detection of phytoplasma in symptomatic A. grossedentata leaves. Phytoplasma was detected in the first and second leaves of symptomatic branches and leaves while negative control showed no amplification. Sequencing of the amplified fragments showed 100% nucleotide identity to the strain from the grafting source. Our results indicated that the pathogen and the disease can be transmitted by tissue grafting, consistent with the biological characteristics of phytoplasma, and further confirmed that the phytoplasma was the pathogen of yellow leaf syndrome of A. grossedentata. Toour knowledge, this is the first report of phytoplasma of group 16SrI affecting A. grossedentata.
ABSTRACT
OBJECTIVES: To study the virtual reality-pattern visual evoked potential (VR-PVEP) P100 waveform characteristics of monocular visual impairment with different impaired degrees under simultaneous binocular perception and monocular stimulations. METHODS: A total of 55 young volunteers with normal vision (using decimal recording method, far vision ≥0.8 and near vision ≥0.5) were selected to simulate three groups of monocular refractive visual impairment by interpolation method. The sum of near and far vision ≤0.2 was Group A, the severe visual impairment group; the sum of near and far vision <0.8 was Group B, the moderate visual impairment group; and the sum of near and far vision ≥0.8 was Group C, the mild visual impairment group. The volunteers' binocular normal visions were set as the control group. The VR-PVEP P100 peak times measured by simultaneous binocular perception and monocular stimulation were compared at four spatial frequencies 16×16, 24×24, 32×32 and 64×64. RESULTS: In Group A, the differences between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at 24×24, 32×32 and 64×64 spatial frequencies were statistically significant (P<0.05); and the P100 peak time of normal vision eyes at 64×64 spatial frequency was significantly different from the simulant visual impairment eyes (P<0.05). In Group B, the differences between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at 16×16, 24×24 and 64×64 spatial frequencies were statistically significant (P<0.05); and the P100 peak time of normal vision eyes at 64×64 spatial frequency was significantly different from the simulant visual impairment eyes (P<0.05). In Group C, there was no significant difference between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at all spatial frequencies (P>0.05). There was no significant difference in the P100 peak times measured at all spatial frequencies between simulant visual impairment eyes and simultaneous binocular perception in the control group (P>0.05). CONCLUSIONS: VR-PVEP can be used for visual acuity evaluation of patients with severe and moderate monocular visual impairment, which can reflect the visual impairment degree caused by ametropia. VR-PVEP has application value in the objective evaluation of visual function and forensic clinical identification.
Subject(s)
Evoked Potentials, Visual , Virtual Reality , Humans , Vision, Ocular , Vision, Binocular/physiology , Vision Disorders/diagnosisABSTRACT
AIM: Utilization of signal detection methods in longitudinal claims data can improve post-marketing drug surveillance, but to date there has been limited application. The aim of this study is to use 3 approaches, the proportional reporting ratio, Gamma Poisson Shrinker, and tree-based scan statistic in detecting adverse drug events (ADEs) attributed to trastuzumab using an administrative claims dataset. METHODS: Using data from the Texas Cancer Registry and SEER linked to Medicare from 2010 to 2013, we conducted 1:2 propensity score matching. Breast cancer HER2+ patients treated with trastuzumab in addition to standard chemotherapy were matched to HER2- patients treated with standard chemotherapy. Inpatient and outpatient encounters up to 6 months from start of therapy were used to identify adverse events. RESULTS: A total of 4191 patients were included in the study. Across all methods, use of trastuzumab generated signals on 9 distinct body systems. Cardiomyopathy and heart valve disease were the most consistently detected signals. Clinical review determined that most signals represented known ADEs. CONCLUSIONS: We showed that claims data can be used to complement current ADE monitoring using common data mining methods with propensity score matching. Our analysis identified all expected ADEs associated with trastuzumab, and additional signals of valvular heart disorders.
Subject(s)
Breast Neoplasms , Drug-Related Side Effects and Adverse Reactions , Aged , Breast Neoplasms/drug therapy , Cohort Studies , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Medicare , Trastuzumab/adverse effects , United StatesABSTRACT
BACKGROUND: Pilot studies test the feasibility of methods and procedures to be used in larger-scale studies. Although numerous articles describe guidelines for the conduct of pilot studies, few have included specific feasibility indicators or strategies for evaluating multiple aspects of feasibility. In addition, using pilot studies to estimate effect sizes to plan sample sizes for subsequent randomized controlled trials has been challenged; however, there has been little consensus on alternative strategies. METHODS: In Section 1, specific indicators (recruitment, retention, intervention fidelity, acceptability, adherence, and engagement) are presented for feasibility assessment of data collection methods and intervention implementation. Section 1 also highlights the importance of examining feasibility when adapting an intervention tested in mainstream populations to a new more diverse group. In Section 2, statistical and design issues are presented, including sample sizes for pilot studies, estimates of minimally important differences, design effects, confidence intervals (CI) and nonparametric statistics. An in-depth treatment of the limits of effect size estimation as well as process variables is presented. Tables showing CI around parameters are provided. With small samples, effect size, completion and adherence rate estimates will have large CI. CONCLUSION: This commentary offers examples of indicators for evaluating feasibility, and of the limits of effect size estimation in pilot studies. As demonstrated, most pilot studies should not be used to estimate effect sizes, provide power calculations for statistical tests or perform exploratory analyses of efficacy. It is hoped that these guidelines will be useful to those planning pilot/feasibility studies before a larger-scale study.
Subject(s)
Feasibility Studies , Guidelines as Topic/standards , Pilot Projects , Research Design/standards , Humans , Research Design/statistics & numerical dataABSTRACT
BACKGROUND: Breast cancer survivors have a unique risk for negative health outcomes. Engaging in routine physical activity (PA) can reduce these risks. However, PA levels are low among this population. Narrative visualization (NV) is a technique that uses drawings, photographs, and text to contextualize data, which may increase integrated regulation, or motivation related to personal values and identity. A PA intervention targeting breast cancer survivors using an NV strategy may improve PA behavior. The purpose of this study was to determine whether scrapbooking activities could successfully be used as an NV strategy for older (55+) breast cancer survivors. METHODS: Breast cancer survivors were given workbooks, wearable electronic activity monitors, instant cameras, and art supplies including a variety of stickers (e.g., emojis, affirmations). Participants were instructed to use these materials for 7 days. The workbook pages prompted participants to re-draw their daily activity graphs from the wearable's mobile app, then annotate them with text, photographs, stickers, etc. to reflect what the data meant to them. Hybrid thematic analysis was used to analyze the photographs, drawings, and written content to identify emergent themes. Content analysis was also used to investigate use of stickers and photographs. RESULTS: Of the 20 consented women (mean age 67 ± 5 years, 45% non-Hispanic white), 3 participants were lost to follow-up or unable to complete the procedures. The NV procedures were successfully utilized by the remaining 17 participants, who collectively used 945 stickers over 7 days, most of which were emojis. Emojis were both positively and negatively valanced. Participants took a mean of 9 photos over 7 days and completed workbook questions regarding current PA and PA goals. Themes within the photos included family, specific locations, everyday objects, religion, and friends. Themes within the written portions of the workbook included family, chores and obligations, health, personal reflection, hobbies, and shopping. CONCLUSIONS: The materials provided allowed breast cancer survivors to successfully use NV techniques to reflect on their PA data and behavior. These techniques show promise for promoting integrated regulation in activity monitoring interventions. TRIAL REGISTRATION: This study was funded by the National Cancer Institute ( R21CA218543 ) beginning July 1, 2018.
Subject(s)
Breast Neoplasms , Cancer Survivors , Aged , Exercise , Feasibility Studies , Female , Humans , Middle Aged , SurvivorsABSTRACT
Plant growth-promoting rhizobacteria (PGPR) play a crucial role in biological control and pathogenic defense on and within plant tissues, however the mechanisms by which plants associate with PGPR to elicit such beneficial effects need further study. Here, we present time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging of Brachypodium distachyon (Brachypodium) seeds with and without exposure to two model PGPR, i.e., Gram-negative Pseudomonas fluorescens SBW25 (P.) and Gram-positive Arthrobacter chlorophenolicus A6 (A.). Delayed image extraction was used to image PGPR-treated seed sections to reveal morphological changes. ToF-SIMS spectral comparison, principal component analysis (PCA), and two-dimensional (2D) imaging show that the selected PGPR have different effects on the host seed surface, resulting in changes in chemical composition and morphology. Metabolite products and biomarkers, such as flavonoids, phenolic compounds, fatty acids, and indole-3-acetic acid (IAA), were identified on the PGPR-treated seed surfaces. These compounds have different distributions on the Brachypodium seed surface for the two PGPR, indicating that the different bacteria elicit distinct responses from the host. Our results illustrate that ToF-SIMS is an effective tool to study plant-microbe interactions and to provide insightful information with submicrometer lateral resolution of the chemical distributions associated with morphological features, potentially offering a new way to study the mechanisms underlying beneficial roles of PGPR.
Subject(s)
Brachypodium , Micrococcaceae , Molecular Imaging , SeedsABSTRACT
In the past, our lab proposed a two-pore PBPK model for different-size protein therapeutics using de novo derived parameters and the model was validated using plasma PK data of different-size antibody fragments digitized from the literature (Li Z, Shah DK, J Pharmacokinet Pharmacodynam 46(3):305-318, 2009). To further validate the model using tissue distribution data, whole-body biodistribution study of 6 different-size proteins in mice were conducted. Studied molecules covered a wide MW range (13-150 kDa). Plasma PK and tissue distribution profiles is 9 tissues were measured, including heart, lung, liver, spleen, kidney, skin, muscle, small intestine, large intestine. Tumor exposure of different-size proteins were also evaluated. The PBPK model was validated by comparing percentage predictive errors (%PE) between observed and model predicted results for each type of molecule in each tissue. Model validation showed that the two-pore PBPK model was able to predict plasma, tissues and tumor PK of all studied molecules relatively well. This model could serve as a platform for developing a generic PBPK model for protein therapeutics in the future.
Subject(s)
Tissue Distribution/physiology , Trastuzumab/pharmacokinetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Mice, Nude , Models, Biological , Neoplasms/metabolismABSTRACT
Lavandin, as an important cash crop, is cultivated in Kunming, Yun-Gui Plateau of China. For the special growing environment, Lavandin was grown here and used to investigate the changes in the yield and chemical compositions of essential oils extracted from the flowers in different seasons. The essential oils were extracted by hydro-distillation and analysis by gas chromatography-mass spectrometry (GC-MS). Results indicated great changes in chemical composition depending on the season of harvesting. The yields of essential oils ranged from 2.0% to 3.8% among the seasons, and the highest yield was in the summer. Chemical composition data showed that the extracted oils were rich in oxygenated monoterpenes (55.4-81.4%), eucalyptol (38.7-49.8%), camphor (8.41-14.26%), α-bisabolol (6.6-25.5%), and linalool (4.6-12.5%). The contents of eucalyptol and α-bisabolol changed in a contrary trend with seasonal variations. The results provided new insight for Chinese Lavandin germplasm to be used in application and development, and reference to the researcher, the farmer, and investor for sustainable industrialization of the plant grown in the Yun-Gui Plateau of China, but also the similar plateau area of the sustainable developments.
Subject(s)
Oils, Volatile , Seasons , China , FlowersABSTRACT
Direct interspecies electron transfer (DIET) has been considered as a novel and highly efficient strategy in both natural anaerobic environments and artificial microbial fuel cells. A syntrophic model consisting of Geobacter metallireducens and Geobacter sulfurreducens was studied in this work. We conducted in vivo molecular mapping of the outer surface of the syntrophic community as the interface of nutrients and energy exchange. System for Analysis at the Liquid Vacuum Interface combined with time-of-flight secondary ion mass spectrometry was employed to capture the molecular distribution of syntrophic Geobacter communities in the living and hydrated state. Principal component analysis with selected peaks revealed that syntrophic Geobacter aggregates were well differentiated from other control samples, including syntrophic planktonic cells, pure cultured planktonic cells, and single population biofilms. Our in vivo imaging indicated that a unique molecular surface was formed. Specifically, aromatic amino acids, phosphatidylethanolamine components, and large water clusters were identified as key components that favored the DIET of syntrophic Geobacter aggregates. Moreover, the molecular changes in depths of the Geobacter aggregates were captured using dynamic depth profiling. Our findings shed new light on the interface components supporting electron transfer in syntrophic communities based on in vivo molecular imaging.
Subject(s)
Amino Acids, Aromatic/metabolism , Geobacter/physiology , Mass Spectrometry/methods , Molecular Imaging/methods , Phosphatidylethanolamines/metabolism , Amino Acids, Aromatic/chemistry , Biofilms , Electron Transport , Phosphatidylethanolamines/chemistry , Principal Component Analysis , Water/chemistry , Water/metabolismABSTRACT
The rhizosphere is arguably the most complex microbial habitat on Earth, comprising an integrated network of plant roots, soil and a highly diverse microbial community (the rhizosphere microbiome). Understanding, predicting and controlling plant-microbe interactions in the rhizosphere will allow us to harness the plant microbiome as a means to increase or restore plant ecosystem productivity, improve plant responses to a wide range of environmental perturbations, and mitigate the effects of climate change by designing ecosystems for long-term soil carbon storage. To this end, it is imperative to develop new molecular approaches with high spatial resolution to capture interactions at the plant-microbe, microbe-microbe, and plant-plant interfaces. In this work, we designed an imaging sample holder that allows integrated surface imaging tools to map the same locations of a plant root-microbe interface with submicron lateral resolutions, providing novel in vivo analysis of root-microbe interactions. Specifically, confocal fluorescence microscopy, time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM) were used for the first time for the correlative imaging of the Brachypodium distachyon root and its interaction with Pseudomonas SW25, a typical plant growth-promoting soil bacterium. Imaging data suggest that the root surface is inhomogeneous and that the interaction between Pseudomonas and Brachypodium roots was confined to only a few spots along the sampled root segments and that the bacterial attachment spots were enriched in Na- and S-related and high-mass organic species. We conclude that the attachment of the Pseudomonas cells to the root surface is outcompeted by strong root-soil mineral interactions but facilitated by the formation of extracellular polymeric substances (EPS).
Subject(s)
Brachypodium/metabolism , Organic Chemicals/metabolism , Plant Roots/metabolism , Pseudomonas Infections/microbiology , Pseudomonas/metabolism , Brachypodium/microbiology , Mass Spectrometry , Microscopy, Electron, Scanning , Microscopy, Fluorescence , Plant Roots/microbiology , Pseudomonas/isolation & purification , Pseudomonas Infections/metabolism , Soil MicrobiologyABSTRACT
Bilge water from ships is regarded as a major pollutant in the marine environment. Bilge water exists in a stable oil-in-water (O/W) emulsion form. However, little is known about the O/W liquid-liquid (l-l) interface. Traditional bulk characterization approaches are not capable of capturing the chemical changes at the O/W l-l interface. Although surfactants are deemed essential in droplet formation, their roles in bilge water stabilization have not been fully revealed. We have utilized novel in situ chemical imaging tools including in situ scanning electron microscopy (SEM) and in situ time-of-flight secondary ion mass spectrometry (ToF-SIMS) to study the evolving O/W interface using a NAVY bilge model for the first time. The droplet size distribution (DSD) does not change significantly without the addition of X-100 surfactants under static or rocking conditions. Both the oil components and the water clusters are shown to evolve over time at the O/W droplet interface by in situ liquid SIMS imaging. Of particular interest to droplet stabilization, the contribution of surfactants to the aged bilge droplets becomes more significant as the droplet size increases. The higher mass surfactant component does not appear on the droplet surface immediately while many lower mass surfactants are solvated inside the droplet. We have provided the first three-dimensional images of the evolving O/W interface and demonstrated that in situ surface chemical mapping is powerful enough to reveal the complex and dynamic l-l interface in the liquid state. Our observational insights suggest that surfactants are important in mediating droplet growth and facilitating effective separation of bilge water emulsion.
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We present synchrotron-based mass spectrometry to probe products formed in a lithium sulphide electrolyte. In operando analysis was carried out at two different potentials in a vacuum compatible microfluidic electrochemical cell. Mass spectral observations show that the charged electrolyte formed sulphur clusters under dynamic conditions, demonstrating electrolyte electron shuttling.
ABSTRACT
Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF-E2-related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch-like ECH-associated protein 1 (Keap1) reduced the expression of glucose-6-phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia-inducing factor 1α (HIF-1α) in MCF-7 and MDA-MB-231 cells. Overexpression of Nrf2 up-regulated the expression of Notch1 via G6PD/HIF-1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES-1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2-driven breast cancer metastasis.