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Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. Whereas many studies have investigated the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. In this study, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries, hypothesizing that the high prevalence of infection in patients with PTL may result in specific changes in the T cell and B cell repertoires. We analyzed TCR ß-chain (TCR-ß) and IgH diversity, CDR3 lengths, clonal sharing, and preferential usage of variable and joining gene segments. Both TCR-ß and IgH repertoires had shorter CDR3s compared with those in maternal blood. In cord blood samples, we found that CDR3 lengths correlated with gestational age, with shorter CDR3s in preterm neonates suggesting a less developed repertoire. Preterm cord blood displayed preferential usage of a number of genes. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features and convergence with maternal TCR-ß clones compared with that of term infants. The higher clonal convergence in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients and contribute to a better understanding of neonate immune repertoire development and potential changes associated with PTL.
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Cadeias Pesadas de Imunoglobulinas/imunologia , Recém-Nascido/imunologia , Trabalho de Parto Prematuro/imunologia , Nascimento Prematuro/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Regiões Determinantes de Complementaridade/imunologia , Feminino , Humanos , Recém-Nascido Prematuro/imunologia , GravidezRESUMO
Membrane proteins involved in transport processes are key targets for pharmaceutical research and industry. Despite continuous improvements and new developments in the field of electrical readouts for the analysis of transport kinetics, a well-suited methodology for high-throughput characterization of single transporters with nonionic substrates and slow turnover rates is still lacking. Here, we report on a novel architecture of silicon chips with embedded nanopore microcavities, based on a silicon-on-insulator technology for high-throughput optical readouts. Arrays containing more than 14â¯000 inverted-pyramidal cavities of 50 femtoliter volumes and 80 nm circular pore openings were constructed via high-resolution electron-beam lithography in combination with reactive ion etching and anisotropic wet etching. These cavities feature both, an optically transparent bottom and top cap. Atomic force microscopy analysis reveals an overall extremely smooth chip surface, particularly in the vicinity of the nanopores, which exhibits well-defined edges. Our unprecedented transparent chip design provides parallel and independent fluorescent readout of both cavities and buffer reservoir for unbiased single-transporter recordings. Spreading of large unilamellar vesicles with efficiencies up to 96% created nanopore-supported lipid bilayers, which are stable for more than 1 day. A high lipid mobility in the supported membrane was determined by fluorescent recovery after photobleaching. Flux kinetics of α-hemolysin were characterized at single-pore resolution with a rate constant of 0.96 ± 0.06 × 10-3 s-1. Here, we deliver an ideal chip platform for pharmaceutical research, which features high parallelism and throughput, synergistically combined with single-transporter resolution.
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Proteínas de Membrana/análise , Nanoporos/ultraestrutura , Análise Serial de Proteínas/instrumentação , Desenho de Equipamento , Proteínas Hemolisinas/análise , Cinética , Bicamadas Lipídicas/química , Modelos Moleculares , Imagem Óptica/instrumentação , Silício/químicaRESUMO
The transport rate of molecules through polymeric membranes is normally limited because of their micrometer-scale thickness which restricts their suitability for more practical application. To study the effect of effective pore length on the transport behavior, polymer membranes containing cylindrical and asymmetric-shaped nanopores were prepared through a two-step ion track-etching technique. Permeation experiments were performed separately to investigate the transport properties (molecular flux and selectivity) of these track-etched membranes. The permeation data shows that the molecular flux across membranes containing asymmetric nanopores is higher compared to those having cylindrical pores. On the other hand, the cylindrical pore membranes exhibit higher selectivity than asymmetric pores for the permeation of charged molecules across the membrane. Current-voltage (I-V) measurements of single-pore membranes further verify that asymmetric pores exhibit lower resistance for the flow of ions and therefore show higher currents than cylindrical pores. Moreover, unmodified and polyethyleneimine (PEI) modified asymmetric-shaped pore membranes were successfully used for the separation of cationic and anionic analyte molecules from their mixture, respectively. In this study, two distinct effects (pore geometry and pore density, i.e. number of pores cm(-2)), which mainly influence membrane selectivity and molecular transport rates, were thoroughly investigated in order to optimize the membrane performance. In this context, we believe that membranes with high molecular transport rates could readily find their application in molecular separation and controlled drug delivery processes.
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Asthma with fixed airway obstruction (FAO) is associated with significant morbidity and rapid decline in lung function, making its treatment challenging. Quantitative computed tomography (QCT) along with data postprocessing is a useful tool to obtain detailed information on airway structure, parenchymal function, and computational flow features. In this study, we aim to identify the structural and functional differences between asthma with and without FAO. The FAO group was defined by a ratio of forced expiratory volume in 1 s (FEV1 ) to forced vital capacity (FVC), FEV1 /FVC <0.7. Accordingly, we obtained two sets of QCT images at inspiration and expiration of asthma subjects without (N = 24) and with FAO (N = 12). Structural and functional QCT-derived airway variables were extracted, including normalized hydraulic diameter, normalized airway wall thickness, functional small airway disease, and emphysema percentage. A one-dimensional (1D) computational fluid dynamics (CFD) model considering airway deformation was used to compare the pressure distribution between the two groups. The computational pressures showed strong correlations with the pulmonary function test (PFT)-based metrics. In conclusion, asthma participants with FAO had worse lung functions and higher-pressure drops than those without FAO.
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Obstrução das Vias Respiratórias , Asma , Humanos , Estudos de Viabilidade , Hidrodinâmica , Asma/complicações , Asma/diagnóstico por imagem , Obstrução das Vias Respiratórias/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
In this study, we investigate the impact of zenith angle variations on cosmic-ray induced background in High-Purity Germanium (HPGe) gamma spectrometers using a coincidence technique based on plastic scintillator-Germanium detectors. We utilize an HPGe detector (Model GC2018 Mirion Ge Detector) enclosed within a low-activity cylindrical lead shield (Model 747E Mirion Lead Shield). For cosmic ray detection, a coincidence detection system with plastic scintillator detectors was positioned on top of the lead shielding. The zenith angle at the Germanium detector is computed using the dimensions of the square plastic scintillator and its distance from the Germanium detector center. We carried out measurements of cosmic-ray induced background in an HPGe gamma spectrometer with a square plastic configuration (80cm x 80cm), equivalent to a 45° zenith angle. The experimental measurements were compared with GEANT4 simulation data. The results demonstrate a good agreement between the measured energy spectrum and the simulated data across the energy range of 0.05 to 47 MeV. Further investigations into the effects of varying zenith angles provide valuable insights for optimizing HPGe spectrometer setups with minimized background interference.
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Plastic food packaging is an essential element for customer convenience and the preservation of food quality. Nonetheless, heavy metals in the packaging materials, either intentionally or nonintentionally added, can be transferred to the food. Therefore, determining heavy metal contents in these packaging materials is essential. In this study, heavy metals, including Co, Ge, As, Cd, Sb, Pb, Al, and Zn from different intrinsic plastic food packaging materials were analyzed using the inductively coupled plasma-mass spectrometry (ICP-MS) method. Moreover, the migration of these elements into the environment was also investigated. This method is validated following the new technique's requirements, which include linearity range, accuracy, precision, the limit of detection (LOD), and the limit of quantitation (LOQ). The method has been suitably validated with the regression equation from the standards prepared in HNO3 1% v/v. The linear range was found to be ~1-20 ng mL-1 for Co, Ge, As, Cd, Sb, and Pb and 5-80 ng mL-1 for Al and Zn elements. The LODs are ~0.10, 0.25, 0.12, 0.13, 0.11, 0.12, 0.61, and 0.85 ng mL-1, and the LOQs are 0.33, 0.83, 0.40, 0.43, 0.36, 0.40, 2.01, and 2.81 ng mL-1 obtained for Co, Ge, As, Cd, Sb, Pb, Al, and Zn, respectively. In addition, the recovery percentages received ranged 85.4%-94.1% for Co, 82.6%-95.1% for Ge, 86.3%-97.9% for As, 87.3%-96.3% for Cd, 88.0%-104.4% for Sb, 96.3%-106.0% for Pb, 88.4%-104.0% for Al, and 95.1%-99.7% for Zn. Finally, the migration of these heavy metals from polypropylene (PP) and polystyrene (PS) into foodstuffs was also simulated according to EU legislation, showing that the most leached element was Zn, followed by Al and Pd, with the migration of ~8.38% and ~0.41%, and ~0.19%, respectively.
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Optimization and validation for simultaneous quantitation of four aflatoxins B1, B2, G1, and G2 in peanuts and raisins were performed on ultra-performance liquid chromatography in a combination of fluorescence detector, without derivatization. The advantages were short analysis time, simple sample handling, and reduced solvent consumption. Instrument detection limits of AFB1, AFB2, AFG1, and AFG2 were 0.07, 0.01, 0.1, and 0.008 µg/kg, respectively, lower than those obtained by LCMSMS and HPLC-FLD with derivatization. Two solvent mixtures were chosen for two different matrices whose matrix effect was not negligible (2.81%-8.04% for peanuts and 5.63%-11.43% for raisins). The linear ranges were from 0.2 to 20 µg/L for AFB1 and AFG1 and from 0.05 to 5 µg/L for AFB2 and AFG2. The limits of detection and quantification were 0.025-0.1 and 0.075-0.3 µg/kg for peanuts and raisins, respectively. Recoveries at three other concentrations from 0.75 to 125 µg/kg of total aflatoxins were obtained between 76.5% and 99.8% (with RSD < 6%) following the SANTE 11312/2021. Validation parameters complied with the requirements of ISO/IEC 17025:2017. The extracts and the sample could be stabilized at 4°C and 20°C for 24 h and at -20°C for up to 21 days, respectively. Thus, the study can be used as a standard method for the analysis of Aflatoxins (AFs) in peanut and raisin matrices. Investigation of 350 peanut samples collected at Markets in the central districts of HCM city showed that 28.6% were contaminated with AFB1 from 0.31 up to 554 µg/kg; 13.4% contained AFB2, and 5.7% of AFG1 in the range of 0.4-53 µg/kg and 0.4-9.57 µg/kg, respectively; AFG2 (about 0.6%) was detected from 0.45 to 0.75 µg/kg. Meanwhile, 12.8% exceeded the total aflatoxins limit, and 13.4% exceeded the AFB1 limit. AFs were almost not found in the 350 raisin samples.
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Single-use plastic waste is gradually considered a potential material for circular economy. Ion exchange resin obtained from polystyrene waste by sulfonating with H2SO4 was used for heavy metal removal from electroplating wastewater. Batch mode experiments of Cu2+, Zn2+, and Cd2+ were carried out to determine effect of pH, initial concentration, equilibrium time, and the isotherm and kinetic parameters; the stability of the resin in continuous operation was then evaluated. Finally, the longevity of the resin after being exhausted was explored. The results indicated that at pH 6, a pseudo-second-order kinetic model was applicable to describe adsorption of studied heavy metals by sulfonated polystyrene with adsorption capacities of 7.48 mg Cu2+/g, 7.23 mg Zn2+/g, and 6.50 mg Cd2+/g, respectively. Moreover, the ion exchange process between sulfonated polystyrene resin and Cu2+, Zn2+, Cd2+ ions followed the Langmuir isotherm adsorption model with R2 higher than 96%. The continuous fixed-bed column in conditions of a sulfonated polystyrene mass of 500 g, and a flow rate of 2.2 L/h was investigated for an influent solution with known initial concentration of 20 mg/L. Thomas and Yoon-Nelson models were tested with regression analysis. When being exhausted, the sulfonated polystyrene was regenerated by NaCl in 10 min with ratio 5 mL of NaCl 2 M per 1 g saturated resins. After 4 times regeneration, the heavy metal removal efficiency of sulfonated polystyrene was reduced to 50%. These aforementioned results can figure out that by sulfonating polystyrene waste to synthesize ion exchanging materials, this method is technically efficient and environmentally friendly to achieve sustainability.
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Metais Pesados , Poluentes Químicos da Água , Adsorção , Cádmio/análise , Concentração de Íons de Hidrogênio , Cinética , Metais Pesados/análise , Plásticos , Poliestirenos/análise , Cloreto de Sódio , Águas Residuárias/análise , Poluentes Químicos da Água/análiseRESUMO
In this study, the phytochemical composition and antibacterial activity of the essential oils isolated from the rhizomes and the aerial parts of Homalomena cochinchinensis were analysed for the first time using gas chromatography-mass spectrometry (GC-MS) and disk diffusion method. Consequently, 36 constituents were reported from H. cochinchinensis rhizomes, including linalool (57.4%), terpinen-4-ol (10.6%), α-sabinene (4.2%) as major compounds. Meanwhile, 30 compounds have been identified in the essential oil of the aerial parts of H. cochinchinensis, which myrcene (41.1%), sabinene (8.2%), D-limonene (9.1%) were the main constituents. Furthermore, the antibacterial activity of the essential oil from the rhizomes of the studied species could inhibit the growth of all six tested bacterial strains, including Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Salmonella typhimurium whereas the essential oil from the aerial parts was proved to be able to inhibit the growth of five bacterial strains except S. enteritidis.
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Araceae , Óleos Voláteis , Antibacterianos/química , Antibacterianos/farmacologia , Escherichia coli , Testes de Sensibilidade Microbiana , Óleos Voláteis/química , Óleos de Plantas/química , Rizoma , Staphylococcus aureusRESUMO
Here we demonstrate a novel biosensing platform for the detection of lactoferrin (LFN) via metal-organic frameworks, in which the metal ions have accessible free coordination sites for binding, inside the single conical nanopores fabricated in polymeric membrane. First, monolayer of amine-terminated terpyridine (metal-chelating ligand) is covalently immobilized on the inner walls of the nanopore via carbodiimide coupling chemistry. Second, iron-terpyridine (iron-terPy) complexes are obtained by treating the terpyridine modified-nanopores with ferrous sulfate solution. The immobilized iron-terPy complexes can be used as recognition elements to fabricate biosensing nanodevice. The working principle of the proposed biosensor is based on specific noncovalent interactions between LFN and chelated metal ions in the immobilized terpyridine monolayer, leading to the selective detection of analyte protein. In addition, control experiments proved that the designed biosensor exhibits excellent biospecificity and nonfouling properties. Furthermore, complementary experiments are conducted with multipore membranes containing an array of cylindrical nanopores. We demonstrate that in the presence of LFN in the feed solution, permeation of methyl viologen (MV(2+)) and 1,5-naphthalenedisulphate (NDS(2-)) is drastically suppressed across the iron-terPy modified membranes. On the basis of these findings, we envision that apart from conventional ligand-receptor interactions, the designing and immobilization of alternative functional ligands inside the synthetic nanopores would extend this method for the construction of new metal ion affinity-based biomimetic systems for the specific binding and recognition of other biomolecules.
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Técnicas Biossensoriais , Ferro/química , Lactoferrina/análise , Nanoporos , Polímeros/química , Piridinas/química , Polímeros/síntese química , Propriedades de SuperfícieRESUMO
Sulfur is a prospective material for next-generation batteries with high theoretical capacity, but its drawbacks hinder its commercialization. To overcome the low conductivity of natural sulfur and the shuttle effect of lithium polysulfide, the study proposes a novel sulfur film coated with three-dimensional nitrogen and cobalt-codoped polyhedral carbon wrapped on a multiwalled carbon nanotube sponge (3D-S@NCoCPC sponge) composite as a high-performance cathode material for rechargeable lithium-sulfur batteries. The interconnected conductive carbon network with abundant pores provides more room for the homogeneous distribution of sulfur within the composite and creates a favorable pathway for electrolyte permeability and lithium-ion diffusion. Moreover, the strong interaction between cobalt and lithium polysulfides leads to efficient suppression of the shuttle effect. In addition, the homogeneous distribution of sulfur and cobalt within the composite enhances electronic transfer for the conversion reaction of sulfur. As expected, the cathode with a high sulfur content of 77.5 wt % in the composite achieved a high initial discharge capacity of 1192 mA h g-1 and high Coulombic efficiency of 99.98% after 100 cycles at 100 mA g-1 current density. Stable performance was achieved with 92.9% capacity retention after 200 cycles at 1000 mA/g current density.
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Synthetic nanopores made from DNA replicate the key biological processes of transporting molecular cargo across lipid bilayers. Understanding transport across the confined lumen of the nanopores is of fundamental interest and of relevance to their rational design for biotechnological applications. Here we reveal the transport principles of organic molecules through DNA nanopores by synergistically combining experiments and computer simulations. Using a highly parallel nanostructured platform, we synchronously measure the kinetic flux across hundreds of individual pores to obtain rate constants. The single-channel transport kinetics are close to the theoretical maximum, while selectivity is determined by the interplay of cargo charge and size, the pores' sterics and electrostatics, and the composition of the surrounding lipid bilayer. The narrow distribution of transport rates implies a high structural homogeneity of DNA nanopores. The molecular passageway through the nanopore is elucidated via coarse-grained constant-velocity steered molecular dynamics simulations. The ensemble simulations pinpoint with high resolution and statistical validity the selectivity filter within the channel lumen and determine the energetic factors governing transport. Our findings on these synthetic pores' structure-function relationship will serve to guide their rational engineering to tailor transport selectivity for cell biological research, sensing, and drug delivery.
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Nanoporos , Transporte Biológico , DNA/metabolismo , Bicamadas Lipídicas , Simulação de Dinâmica MolecularRESUMO
In aquatic environments, assessment of microplastic concentrations is increasing worldwide but environments from developing countries remain under-evaluated. Due to disparities of facilities, financial resources and human resources between countries, protocols of sampling, analysis and observations used in developed countries cannot be fully adapted in developing ones, and required specific adaptations. In Viet Nam, an adapted methodology was developed and commonly adopted by local researchers to implement a microplastic monitoring in sediments and surface waters of 21 environments (rivers, lakes, bays, beaches) of eight cities or provinces. Microplastic concentrations in surface waters varied from 0.35 to 2522 items m-3, with the lowest concentrations recorded in the bays and the highest in the rivers. Fibers dominated over fragments in most environments (from 47% to 97%). The microplastic concentrations were related to the anthropogenic pressure on the environment, pointing out the necessity in a near future to identify the local sources of microplastics.
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Microplásticos , Poluentes Químicos da Água , Cidades , Monitoramento Ambiental , Sedimentos Geológicos , Humanos , Plásticos , Rios , Vietnã , Poluentes Químicos da Água/análiseRESUMO
We present an experimental demonstration of a synthetic nanoporous membrane suitable for charge-selective transport of ionic species. The surfaces and walls of synthetic nanochannels, fabricated in heavy ion-tracked polyethylene terephthalate membranes are negatively charged due to the presence of carboxylate moieties. These nanofilters discriminate and gate the transport of cations while inhibiting the passage of anions. The permselectivity of these membranes is reversed by converting the carboxylic moieties into terminated amino groups. The positively charged (aminated) membranes facilitate the transport of anions. Based on the same principle, charged biomolecules (bovine serum albumin and lysozyme) are successfully filtered through these membranes. These membranes also exhibit the phenomenon of ion concentration polarization.
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Membranas Artificiais , Nanoestruturas/química , Proteínas/química , Aminoácidos/química , Difusão , Interações Hidrofóbicas e Hidrofílicas , Transporte de Íons , Íons/química , Muramidase/química , Nanoestruturas/ultraestrutura , Compostos Orgânicos/química , Tamanho da Partícula , Porosidade , Soroalbumina Bovina/químicaRESUMO
All-solid-state batteries have gained significant attention as promising candidates to replace liquid electrolytes in lithium-ion batteries for high safety, energy storage performance, and stability under elevated temperature conditions. However, the low ionic conductivity and unsuitability of lithium metal in solid polymer electrolytes is a critical problem. To resolve this, we used a cubic garnet oxide electrolyte (Li7La3Zr2O12 - LLZO) and ionic liquid in combination with a polymer electrolyte to produce a composite electrolyte membrane. By applying a solid polymer electrolyte on symmetric stainless steel, the composite electrolyte membrane shows high ionic conductivity at elevated temperatures. The effect of LLZO in suppressing lithium dendrite growth within the composite electrolyte was confirmed through symmetric lithium stripping/plating tests under various current densities showing small polarization voltages. The full cell with lithium iron phosphate as the cathode active material achieved a highest specific capacity of 137.4 mAh g-1 and a high capacity retention of 98.47% after 100 cycles at a current density of 50 mA g-1 and a temperature of 60°C. Moreover, the specific discharge capacities were 137 and 100.8 mAh g-1 at current densities of 100 and 200 mA g-1, respectively. This research highlights the capability of solid polymer electrolytes to suppress the evolution of lithium dendrites and enhance the performance of all-solid-state batteries.
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BACKGROUND: Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms. OBJECTIVE: The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis. STUDY DESIGN: Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28-41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma. RESULTS: Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma. CONCLUSION: This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications.
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Ácidos Nucleicos Livres/sangue , Corioamnionite/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Cordão Umbilical/microbiologia , Adulto , Corioamnionite/microbiologia , Estudos de Coortes , Feminino , Sangue Fetal/química , Sangue Fetal/metabolismo , Sangue Fetal/microbiologia , Idade Gestacional , Humanos , Recém-Nascido , Mycoplasma/genética , Mycoplasma/patogenicidade , Sepse Neonatal/sangue , Sepse Neonatal/diagnóstico , Sepse Neonatal/microbiologia , Gravidez , Streptococcus mitis/genética , Streptococcus mitis/patogenicidade , Cordão Umbilical/patologia , Ureaplasma/genética , Ureaplasma/patogenicidade , Adulto JovemRESUMO
Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the ß-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1-green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.
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Terapias Fetais , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose VII , Animais , Feminino , Tolerância Imunológica , Camundongos , Microglia , Mucopolissacaridose VII/terapia , GravidezRESUMO
In this work, we show an effective ultrasonication-assisted self-assembly method under surfactant solution for a high-rate capable rGO-wrapped LiNi0.6Co0.2Mn0.2O2 (Ni-rich cathode material) composite. Ultrasonication indicates the pulverization of the aggregated bulk material into primary nanoparticles, which is effectively beneficial for synthesizing a homogeneous wrapped composite with rGO. The cathode composite demonstrates a high initial capacity of 196.5 mAh/g and a stable capacity retention of 83% after 100 cycles at a current density of 20 mA/g. The high-rate capability shows 195 and 140 mAh/g at a current density of 50 and 500 mA/g, respectively. The high-rate capable performance is attributed to the rapid lithium ion diffusivity, which is confirmed by calculating the transformation kinetics of the lithium ion by galvanostatic intermittent titration technique (GITT) measurement. The lithium ion diffusion rate (D Li) of the rGO-wrapped LiNi0.6Co0.2Mn0.2O2 composite is ca. 20 times higher than that of lithium metal plating on anode during the charge procedure, and this is demonstrated by the high interconnection of LiNi0.6Co0.2Mn0.2O2 and conductive rGO sheets in the composite. The unique transformation kinetics of the cathode composite presented in this study is an unprecedented verification example of a high-rate capable Ni-rich cathode material wrapped by highly conductive rGO sheets.
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Blocking of a charged pore by an oppositely charged nanoparticle can support rectifying properties in a cylindrical nanopore, as opposed to the usual case of a fixed asymmetry in the pore geometry and charge distribution. We present here experimental data and model calculations to confirm this fundamental effect. The nanostructure imaging and the effects of nanoparticle concentration, pore radius, and salt concentration on the electrical conductance-voltage (G-V) curves are discussed. Logic responses based on chemical and electrical inputs/outputs could also be implemented with a single pore acting as an effective nanofluidic diode. To better show the generality of the results, different charge states and relative sizes of the nanopore and the nanoparticle are considered, emphasizing those physical concepts that are also found in the ionic drug blocking of protein ion channels.