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1.
Opt Express ; 28(19): 27268-27276, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32988023

RESUMO

In this work, we proposed and experimentally demonstrated a compact and low polarization-dependent silicon waveguide crossing based on subwavelength grating multimode interference couplers. The subwavelength grating structure decreases the effective refractive index difference and shrinks the device footprint. Our designed device is fabricated on the 220-nm SOI platform and performs well. The measured crossing is characterized with low insertion loss (< 1 dB), low polarization-dependence loss (< 0.6 dB), and low crosstalk (< -35 dB) for both TE and TM polarizations with a compact footprint of 12.5 µm × 12.5 µm.

2.
Opt Express ; 27(13): 18731-18739, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31252810

RESUMO

We demonstrate highly efficient lithium niobate thin film Michelson interferometer modulators with half-wave voltage length product of 1.4 V∙cm. Amorphous silicon grating couplers have been incorporated to achieve a 3.8-dB/port waveguide-fiber coupling loss. Devices with 1-mm phase shifter arms have a footprint of 2.5 mm × 1.7 mm. The demonstrated modulation data rates is up to 35 Gb/s.

3.
Opt Express ; 27(13): 19002-19018, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31252834

RESUMO

The fluorescence enhancement in an over-etched gold zero-mode waveguide (ZMW) was investigated through both numerical simulation and experiments. Using Cy3 and Cy5 as the fluorescent probes, the simulation showed that the undercut not only enhances the fluorescence signals of both fluorophores, but also greatly improves the radial uniformity of the excitation fields in the ZMW. Furthermore, using a focused-ion-beam tool, we fabricated Au-ZMW arrays with different radius and undercut. The fluorescence enhancement per molecule and the effective excitation volume of the Au-ZMW were then measured as functions of its radial size and over-etching depth by using fluorescence correlation spectroscopy. It was found that the undercut can significantly enhance the fluorescence signal per molecule in the ZMW, but it also slightly increased the excitation volume. Decreasing the radial size of the ZMW can efficiently reduce the excitation volume and also further enhance the fluorescence per molecule. These results together indicate that combining the undercut and reduction of radius of the ZMW can serve as a simple and effective way to essentially improve the performance of an Au-ZMW for single molecule fluorescence detection.

4.
Nano Lett ; 18(7): 4460-4466, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29940122

RESUMO

Subwavelength imaging requires the use of high numerical aperture (NA) lenses together with immersion liquids in order to achieve the highest possible resolution. Following exciting recent developments in metasurfaces that have achieved efficient focusing and novel beam-shaping, the race is on to demonstrate ultrahigh-NA metalenses. The highest NA that has been demonstrated so far is NA = 1.1, achieved with a TiO2 metalens and back-immersion. Here, we introduce and demonstrate a metalens with a high NA and high transmission in the visible range, based on crystalline silicon (c-Si). The higher refractive index of silicon compared to TiO2 allows us to push the NA further. The design uses the geometric phase approach also known as the Pancharatnam-Berry (P-B) phase, and we determine the arrangement of nanobricks using a hybrid optimization algorithm (HOA). We demonstrate a metalens with NA = 0.98 in air, a bandwidth (full width at half-maximum, fwhm) of 274 nm, and a focusing efficiency of 67% at 532 nm wavelength, which is close to the transmission performance of a TiO2 metalens. Moreover, and uniquely so, our metalens can be front-immersed into immersion oil and achieve an ultrahigh NA of 1.48 experimentally and 1.73 theoretically, thereby demonstrating the highest NA of any metalens in the visible regime reported to the best of our knowledge. The fabricating process is fully compatible with microelectronic technology and therefore scalable. We envision the front-immersion design to be beneficial for achieving ultrahigh-NA metalenses as well as immersion metalens doublets, thereby pushing metasurfaces into practical applications such as high resolution, low-cost confocal microscopy and achromatic lenses.

5.
Opt Express ; 26(23): 29651-29658, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30469926

RESUMO

We demonstrate hybrid amorphous silicon uniform grating couplers for efficient coupling between the standard single-mode fiber and sub-micron lithium niobate waveguides. The grating couplers exhibit coupling efficiency of -3.06 dB and 1-dB bandwidth of 55 nm. The amorphous silicon grating couplers can also provide a universal building block applicable to other photonic platforms such as silicon nitride waveguides, whose moderate refractive index values prevent high efficiency grating couplers to be fabricated in the native waveguide.

6.
Opt Lett ; 43(3): 474-477, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29400818

RESUMO

We design and fabricate a low-loss silicon photonic two-dimensional grating coupler that serves to couple light between standard single-mode fibers and single-mode waveguides in the silicon-on-insulator platform and to split both orthogonal polarization states. The efficiency of the fabricated device is enhanced by a backside metal mirror and reaches a record value of -1.8 dB with a 1 dB bandwidth of 32 nm around 1550 nm. The demonstrated coupling efficiency is 2.2 dB better than the conventional two-dimensional grating coupler without a metal mirror.

7.
Opt Lett ; 43(6): 1319-1322, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29543281

RESUMO

Photonic integrated devices that emit vortex beam carrying orbital angular momentum are becoming key components for multiple applications. Here we propose and demonstrate a high-efficiency vortex beam emitter based on a silicon micro-ring resonator integrated with a metal mirror. Such a compact emitter is capable of generating vortex beams with a high efficiency and small divergence angle. Vector vortex beams of various topological charges are selectively generated by the emitter at different wavelengths with an emission efficiency of up to 37%.

8.
Opt Lett ; 42(17): 3391-3394, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28957045

RESUMO

The chip-fiber grating coupler is a fundamental building block in integrated photonics, providing convenient on-wafer testing and packaging. Couplers based on a silicon nitride (SiNx) material platform can achieve wider bandwidths than silicon-based couplers, but suffer from lower efficiency due to the relative low material refractive index. The efficiency of the SiNx grating coupler can be improved by using high-reflectivity silicon grating reflectors underneath. However, such a silicon grating reflector requires several fabrication steps, including lithography, etching, high precision alignment (HPA), and chemical mechanical polishing (CMP). In this Letter, we demonstrate an easy-to-fabricate SiNx-on-SOI transverse-electric mode grating coupler requiring only one patterning step (grating alone), and without the need for HPA and CMP. A coupling coefficient of -2.5 dB and 1-dB-bandwidth of 65 nm has been experimentally measured.

9.
Opt Express ; 24(3): 1865-72, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26906765

RESUMO

High-quality SiNx films with controllable low stress and low optical loss are deposited at ultra-low temperature (75 °C) using inductively coupled plasma chemical vapor deposition (ICP-CVD). Two kinds of integrated photonic structures have been demonstrated that exemplify its viability as a photonic integration platform. A microcavity consists of two distributed Bragg reflectors (DBR) formed by alternating a total of 49 layers of SiNx and SiO2 with a total thickness of about 11.5 µm is grown without any cracks, confirming the excellent stress control in the process. Microring resonators are also fabricated in as-deposited planar SiNx waveguide layer using electron-beam lithography (EBL) and plasma etching. Average waveguide loss of 0.79 ± 0.22 dB/cm has been achieved in the range of 1550-1600 nm for ring radii larger than 40 µm. The ultra-low temperature grown SiNx with properties of low loss and low stress is therefore a promising photonic integration platform for various photonic integration applications.

10.
Front Cell Dev Biol ; 12: 1397954, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915448

RESUMO

This comprehensive review inspects the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) across multiple organ systems. Examining their impact on the integumentary, respiratory, cardiovascular, urinary, and skeletal systems, the study highlights the versatility of MSC-EVs in addressing diverse medical conditions. Key pathways, such as Nrf2/HO-1, consistently emerge as central mediators of their antioxidative and anti-inflammatory effects. From expediting diabetic wound healing to mitigating oxidative stress-induced skin injuries, alleviating acute lung injuries, and even offering solutions for conditions like myocardial infarction and renal ischemia-reperfusion injury, MSC-EVs demonstrate promising therapeutic efficacy. Their adaptability to different administration routes and identifying specific factors opens avenues for innovative regenerative strategies. This review positions MSC-EVs as promising candidates for future clinical applications, providing a comprehensive overview of their potential impact on regenerative medicine.

11.
J Inflamm Res ; 17: 1671-1683, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38504696

RESUMO

Background: Research has indicated that VRK1 is essential for the tumor cell cycle. However, its prognostic and immunotherapeutic predictive significance has not been documented in hepatocellular carcinoma (HCC). Methods: The TCGA, ICGC, and GSE14520 datasets were used to investigate VRK1 expression and its predictive significance of survival outcomes. The qRT-PCR and immunohistochemistry (IHC) were used to confirm the findings. The immunotherapeutic response of VRK1 was anticipated by the IMvigor210 cohort. Lastly, the association between immune infiltration, m6A modification, and functional enrichment of differentially expressed genes (DEGs) was investigated in connection to VRK1 expression. Results: VRK1 expression was markedly elevated on both the mRNA and protein levels in HCC. In HCC patients, a high expression of VRK1 was linked to a poor prognosis. Furthermore, there was a substantial positive correlation seen between increased VRK1 expression and the response rate to anti-PD-L1 immunotherapy. Relationships between VRK1 and m6A-related genes as well as different immune cells were shown by correlation studies. Lastly, enrichment analysis revealed a tight relationship between VRK1 and important biological functions, including DNA replication, cell cycle control, and fatty acid metabolism. Conclusion: Our research reveals the potential of VRK1 as a novel biomarker for prognosis and immunotherapy response in HCC patients.

12.
JMIR Public Health Surveill ; 10: e51883, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39045874

RESUMO

Background: The relation between climate change and human health has become one of the major worldwide public health issues. However, the evidence for low-latitude plateau regions is limited, where the climate is unique and diverse with a complex geography and topography. objectives: This study aimed to evaluate the effect of ambient temperature on the mortality burden of nonaccidental deaths in Yunnan Province and to further explore its spatial heterogeneity among different regions. Methods: We collected mortality and meteorological data from all 129 counties in Yunnan Province from 2014 to 2020, and 16 prefecture-level cities were analyzed as units. A distributed lagged nonlinear model was used to estimate the effect of temperature exposure on years of life lost (YLL) for nonaccidental deaths in each prefecture-level city. The attributable fraction of YLL due to ambient temperature was calculated. A multivariate meta-analysis was used to obtain an overall aggregated estimate of effects, and spatial heterogeneity among 16 prefecture-level cities was evaluated by adjusting the city-specific geographical characteristics, demographic characteristics, economic factors, and health resources factors. Results: The temperature-YLL association was nonlinear and followed slide-shaped curves in all regions. The cumulative cold and heat effect estimates along lag 0-21 days on YLL for nonaccidental deaths were 403.16 (95% empirical confidence interval [eCI] 148.14-615.18) and 247.83 (95% eCI 45.73-418.85), respectively. The attributable fraction for nonaccidental mortality due to daily mean temperature was 7.45% (95% eCI 3.73%-10.38%). Cold temperature was responsible for most of the mortality burden (4.61%, 95% eCI 1.70-7.04), whereas the burden due to heat was 2.84% (95% eCI 0.58-4.83). The vulnerable subpopulations include male individuals, people aged <75 years, people with education below junior college level, farmers, nonmarried individuals, and ethnic minorities. In the cause-specific subgroup analysis, the total attributable fraction (%) for mean temperature was 13.97% (95% eCI 6.70-14.02) for heart disease, 11.12% (95% eCI 2.52-16.82) for respiratory disease, 10.85% (95% eCI 6.70-14.02) for cardiovascular disease, and 10.13% (95% eCI 6.03-13.18) for stroke. The attributable risk of cold effect for cardiovascular disease was higher than that for respiratory disease cause of death (9.71% vs 4.54%). Furthermore, we found 48.2% heterogeneity in the effect of mean temperature on YLL after considering the inherent characteristics of the 16 prefecture-level cities, with urbanization rate accounting for the highest proportion of heterogeneity (15.7%) among urban characteristics. Conclusions: This study suggests that the cold effect dominated the total effect of temperature on mortality burden in Yunnan Province, and its effect was heterogeneous among different regions, which provides a basis for spatial planning and health policy formulation for disease prevention.


Assuntos
Cidades , Mortalidade , Humanos , China/epidemiologia , Cidades/epidemiologia , Cidades/estatística & dados numéricos , Mortalidade/tendências , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Temperatura , Mudança Climática , Adulto , Idoso de 80 Anos ou mais , Efeitos Psicossociais da Doença
13.
Opt Express ; 21(25): 30481-91, 2013 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-24514625

RESUMO

A laser-induced damage array composed of numerous pinpoints is generated in a large-aperture KDP crystal to suppress the transverse stimulated Raman scattering (TSRS). The 36 cm × 8.5 mm × 7 mm damage array is used to block the propagation of the TSRS photons within the crystal and decrease the TSRS gain length. Then several series of experiments were conducted on a large-aperture laser system to test this method and experimental results show that the amplification of TSRS is significantly suppressed by the laser-induced damage array.

14.
J Cosmet Dermatol ; 22(4): 1369-1376, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36575892

RESUMO

BACKGROUND: Sensitive skin (SS) is a clinical syndrome defined by the occurrence of unpleasant sensations (such as stinging, burning, pain, pruritus, and tingling) in response to stimuli that normally should not provoke them. According to growing evidence, transient receptor potential vanilloid subtype 1 (TRPV1) has elevated expression in individuals with SS and is linked with the severity of SS symptoms. However, its pathogenesis is still unknown. OBJECTIVE: Herein, Citrus reticulata (Tangerine) fruit extract (CR) was obtained and examined for its effect on SS with a focus on TRPV1 stimulation and expression. METHODS: A recombinant hTRPV1 over-expression cell line (HaCaT-TRPV1-OE cell) was constructed to screen substances and extracts from several plants. Intracellular calcium mobilization was monitored by Flexstation 3 and a fluorescence microscope using Fluo 8 AM fluorophore. Next, immunofluorescence was used to detect the TRPV1 expression under different stimulants treated for 24 h. To investigate the relief and increased tolerance of CR to lactic acid-induced skin discomfort, clinical tests were carried out on the nasolabial folds or cheek areas. RESULTS: According to the obtained results, compared to HaCaT cells, HaCaT-TRPV1-OE cells showed a higher expression of TRPV1. Neuronal hyperresponsiveness in SS triggered by capsaicin (CAP), lactic acid, phenoxyethanol or nicotinamide may be through activation of TRPV1 and increased TRPV1 expression. CAP activates TRPV1 in HaCaT-TRPV1-OE cells, and more than 100 plants or chemicals were tested for their inhibitory effects before being screened for CR. CR (1%-4%) inhibited TRPV1 activation induced by CAP or phenoxyethanol or nicotinamide. Meanwhile, CR (0.25%) suppressed TRPV1 protein expression induced by phenoxyethanol or lactic acid. In vivo results showed that CR not only instantly relieved lactic acid-induced skin discomfort under 5 min but also enhanced skin tolerance to lactic acid after 7 days of continuous use. CONCLUSIONS: Topical application of CR showed an instant and long-lasting improvement in SS by modulating the activation and expression of TRPV1. Moreover, it has been suggested that CR might act as a TRPV1 inhibitor to reduce skin irritation or sensitivity.


Assuntos
Citrus , Extratos Vegetais , Dermatopatias , Canais de Cátion TRPV , Capsaicina/farmacologia , Citrus/química , Frutas/química , Ácido Láctico , Dor , Extratos Vegetais/farmacologia , Dermatopatias/tratamento farmacológico , Canais de Cátion TRPV/efeitos dos fármacos , Humanos
15.
J Cosmet Dermatol ; 22(2): 651-660, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36221990

RESUMO

BACKGROUND: Small molecular natural products, such as betaine, have unique moisturizing advantages. Capparis spinosa L. fruit is rich in quaternary ammonium alkaloids such as betaine and stachydrine. However, few studies investigated its efficacy and mechanism on human skin. OBJECTIVE: Polysaccharides-free C. spinosa fruit extract (CS) was obtained to study its moisturizing effect and mechanisms focusing on filaggrin (FLG) synthesis and degradation. METHODS: The clinical moisturizing test was carried out on human arms, calves, and faces after CS treatment for 0.5-6 h. The change in the level of FLG, caspase 14, loricrin, and transglutaminase 5 (TGM 5) was measured by immunofluorescence after CS treatment for 4 and 24 h in a reconstructed epidermis model. Also, the content of pyrrolidone carboxylic acid (PCA) in the stratum corneum was tested by high-performance liquid chromatography (HPLC) both in the epidermis model and human calves. RESULTS: Compared with glycerin (positive control), 5% CS showed a strong skin hydration effect on arms and calves when applied for 0.5-6 h. Also, the face hydration increased at 0.5 and 4 h. In addition, 3% CS applied to the recombinant epidermis model under low humidity promoted the immunodetected levels of caspase 14 and PCA content but reduced the levels of FLG at 4 h, however, the levels of FLG, loricrin, and TGM 5 were promoted at 24 h. Meanwhile, CS treatment for 4 h in human calves increased the PCA content in the stratum corneum by 29.9%. CONCLUSIONS: Topical application of CS on human skin showed an instant and long-lasting increase in skin hydration by regulating the FLG network. It promoted FLG degradation to form PCA at 4 h both in vivo and in vitro, increasing FLG synthesis after 24 h, potentially reforming the FLG monomer reservoir to alleviate the skin's dry condition.


Assuntos
Capparis , Humanos , Animais , Bovinos , Capparis/metabolismo , Proteínas Filagrinas , Caspase 14/metabolismo , Betaína , Frutas , Proteínas de Filamentos Intermediários/metabolismo
16.
Light Sci Appl ; 12(1): 151, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37331984

RESUMO

With the distinct advantages of high resolution, small pixel size, and multi-level pure phase modulation, liquid crystal on silicon (LCoS) devices afford precise and reconfigurable spatial light modulation that enables versatile applications ranging from micro-displays to optical communications. However, LCoS devices suffer from a long-standing problem of polarization-dependent response in that they only perform phase modulation on one linear polarization of light, and polarization-independent phase modulation-essential for most applications-have had to use complicated polarization-diversity optics. We propose and demonstrate, for the first time, an LCoS device that directly achieves high-performance polarization-independent phase modulation at telecommunication wavelengths with 4K resolution and beyond by embedding a polarization-rotating metasurface between the LCoS backplane and the liquid crystal phase-modulating layer. We verify the device with a number of typical polarization-independent application functions including beam steering, holographical display, and in a key optical switching element - wavelength selective switch (WSS), demonstrating the significant benefits in terms of both configuration simplification and performance improvement.

17.
Appl Opt ; 51(19): 4285-90, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22772099

RESUMO

The dark spot effect downstream from the nonlinear hot image is accounted for in this paper. The conditions for the formation of dark spot are carefully discussed. The explanation is based on analytical analysis, and the results are verified by numerical simulations. The dependence of the location of the dark spot on the nonlinear phase delay seems to suggest a probable method for measuring the nonlinear refractive coefficient of materials.

18.
Appl Opt ; 51(25): 6089-94, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22945155

RESUMO

The analysis of Bespalov and Talanov concerning small scale self-focusing or filamentation effects for plane waves is generalized to a tapered beam case in this paper. A model of nonlinear phase and amplitude perturbations different from Siegman's is suggested. The previous conclusion that self-focusing is very ineffectual for strongly tapered, both divergent and convergent, beams in optical Kerr media as compared to small-scale self-focusing in plane waves is found to be inappropriate. Moreover, the different conditions of phase matching in cases of cylindrical and spherical waves are explicated, which could throw some light on the issue.

19.
Research (Wash D C) ; 2022: 9850316, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36258844

RESUMO

Driven by the ever-increasing demand for fingerprint-resistant techniques in modern society, numerous researches have proposed to develop innovative antifingerprint coatings based on superhydrophobic/superoleophobic surface design. However, whether superhydrophobic/superoleophobic surfaces have favorable repellency to the microscopic fingerprint is in fact an open question. Here, we establish a reliable method that enables evaluating the antifingerprint capability of various surfaces in a quantitative way. We show that superhydrophobicity is irrelevant with fingerprint repellency. Regarding superoleophobic surfaces, two distinct wetting states of microscopic fingerprint residues, i.e., the "repellent" and the "collapsed" states, are revealed. Only in the "repellent" state, in which the fingerprint residues remain atop surface textures upon being pressed, superoleophobic surfaces can bring about favorable antifingerprint repellency, which correlates positively with their receding contact angles. A finger-deformation-dependent intrusion mechanism is proposed to account for the formation of different fingerprint wetting states. Our findings offer important insights into the mechanism of fingerprint repellency and will help the design of high-performance antifingerprint surfaces for diverse applications.

20.
Fish Shellfish Immunol ; 31(6): 1088-96, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21959037

RESUMO

B-cell activating factor (BAFF), a member of the TNF family, is critical to the survival, proliferation, maturation, and differentiation of B-cells. In the present study, a CpBAFF was amplified from the white-spotted catshark (Chiloscyllium plagiosum) using RT-PCR and RACE (rapid amplification of cDNA end) techniques. To our knowledge, this is the first report of any BAFF gene being cloned from a cartilaginous fish. The open reading frame (ORF) of CpBAFF cDNA consists of 819 bases encoding a protein of 272 amino acids. This protein was found to contain a predicted transmembrane domain, a putative furin protease cleavage site, and a typical TNF homology domain corresponding to other identified BAFF homologues. Sequence alignment showed that CpBAFF shares 37-57% identity with BAFF amino acid sequences reported in other vertebrates. Three-dimensional structure modeling analysis revealed a soluble mature portion of CpBAFF (CpsBAFF) with a long D-E loop specific to the BAFF gene, which has not been found in other reported TNF proteins. Phylogenetic reconstruction showed that CpBAFF is most closely related to other fish BAFFs and clusters with BAFF genes from higher vertebrates (reptiles, birds, and mammals). Real-time quantitative RT-PCR demonstrated that CpBAFF mRNA expression was high in the spleen but moderate in the kidney and branchia. Recombinant CpsBAFF fused to NusA-His(6)-tag was efficiently expressed in Escherichia coli BL21 (DE3), and a molecular weight of approximately 83 kDa was determined using SDS-PAGE and Western blotting. In vitro MTT assay indicated that the purified pET43.1a (+)-CpsBAFF protein can co-stimulate the proliferation of mammalian B-cells with anti-IgM in a dose-dependent manner. The present findings not only present novel information that may be relevant to shark immunity but also provide some new insights into the origins and evolution of immunity in all vertebrates.


Assuntos
Fator Ativador de Células B/genética , Modelos Moleculares , Tubarões/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Análise por Conglomerados , Primers do DNA/genética , DNA Complementar/genética , Eletroforese em Gel de Poliacrilamida , Escherichia coli , Dados de Sequência Molecular , Técnicas de Amplificação de Ácido Nucleico , Fases de Leitura Aberta/genética , Filogenia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Especificidade da Espécie , Baço/metabolismo , Sais de Tetrazólio , Tiazóis
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