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1.
Emerg Microbes Infect ; 9(1): 32-41, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31859609

RESUMO

To better evaluate HIV-1 vaccines and therapeutics, the National Institutes for Food and Drug Control of China developed a panel of HIV-1 pseudoviruses including 462 viral strains derived from China, covering the majority of contemporaneous subtypes and circulating recombinant forms. Compared with the standard pseudovirus panels derived from other countries/regions, the Chinese isolates are more susceptible to neutralization by the sera obtained in China, revealing the strain/subtype specificity. Some of these pseudoviruses have already been used for the evaluation of HIV vaccines and drug candidates in Chinese clinical trials. The pseudoviruses panel is widely shared with interested scientists involved in the research and development of vaccines and antiviral drugs against HIV-1 strains prevalent in China.

2.
Cancer Lett ; 469: 162-172, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31634527

RESUMO

Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 has proved successful in patients with relapsed/refractory B cell malignancies. However, long-term follow-up indicates that remission in a substantial proportion of patients is not sustainable. Most patients that experience recurrence have tumors and lost the CAR-T cells. To maintain the activity of CAR-T cells, Raji-B-NDG mice were treated sequentially with CAR-T-19 cells and homologous cells expressing human CD19 to promote expansion of CAR-T cells. Sequential treatment of mice with CAR-T-19 cells followed by Raji tumor cells led to marked prolongation of survival. The best case scenario after sequential treatment was a survival time of more than 200 days; the average survival time of mice in the non-sequential treatment group was 80 days. We treated mice with autologous CD19-modified T cells after initial treatment with CAR-T-19 cells. The overall survival and recurrence-free survival times of mice receiving sequential treatment were significantly longer. The percentages of CAR+ T cells in peripheral blood increased. Sequential therapy with autologous CAR-T-19 and aT19 cells provides a new strategy for generating memory CAR-T cells, which may lead ultimately to increased clinical efficacy.

3.
Methods Mol Biol ; 2081: 177-190, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31721125

RESUMO

Pseudoviruses are useful tools because of their safety and versatility compared to wild type viruses. Optical imaging of reporter gene labeled pseudoviruses in small animal models can allow for real-time analysis of the infection process without sacrificing the host, which has proven invaluable in the longitudinal study of disease events and testing the antiviral efficiencies of vaccine candidates, monoclonal antibodies and small molecule compounds. Here, we describe the generation of Marburg pseudovirus (pMARV) and establishment of imaging mouse model by using a deep-cooled CCD camera imager. We also describe the widespread organ distribution of pMARV during infection by ex vivo imaging of necropsied tissues. This system can significantly facilitate Marburg virus studies and enable the evaluation of treatments against MARV in BSL-2 containments.

5.
Emerg Microbes Infect ; 8(1): 1584-1592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31682199

RESUMO

The genetic and/or antigenic differences between street rabies virus (RABV) and vaccine strains could potentially affect effectiveness of rabies vaccines. As such, it is important to continue monitoring the glycoprotein (G) of the street isolates. All RABVG sequences in public database were retrieved and analysed. Using a pseudovirus system, we investigated 99 naturally occurring mutants for their reactivities to well-characterized neutralizing monoclonal antibodies (mAbs) and vaccine-induced antisera. A divergence in G sequences was found between vaccine strains and recent street isolates, with mutants demonstrating resistance to neutralizing mAbs and vaccine-induced antibodies. Moreover, antigenic variants were observed in a wide range of animal hosts and geographic locations, with most of them emerging since 2010. As the number of antigenic variants has increased in recent years, close monitoring on street isolates should be strengthened.

6.
Adv Sci (Weinh) ; 6(14): 1900399, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31380210

RESUMO

Pressure-induced electronic structure transition from insulating phase to metal state is a potential new paradigm for halide perovskites. The metallization based on these materials may afford a novel motif toward realizing new electronic properties even superconductivity phenomenon. Herein, how static compression modulates the crystal and electronic structure of typical perovskite semiconductors cesium lead iodine (CsPbI3) by both experimental and theoretical studies is reported. The comprehensive studies discover the insulator-metal transition of CsPbI3 at 39.3 GPa, and reveal the key information behind the electronic transition. The perovskite's precise structural evolution is tracked upon compression, from orthorhombic Pnma phase to monoclinic C2/m structure before the metallic transition. More interestingly, the C2/m phase has the most distorted octahedra and the shortest Pb-I bond length relative to the average bond length that is ever reported in a halide perovskite structure. The electronic transition stems from the structural changes accompanied by the anomalously self-distorted octahedra. These studies show that pressure can significantly alter the structural and electronic properties of these technologically important perovskites.

7.
J Med Virol ; 91(11): 2016-2024, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31294846

RESUMO

The development of therapies for human smallpox is needed due to the increasing concern over the potential use of smallpox virus as a biological weapon. Here, we report a high-throughput screening for anti-smallpox virus drugs from a 767-small-molecule library, employing two vaccinia virus (VACV) strains containing firefly luciferase (VTT-Fluc and VG9-Fluc) as surrogate viruses. Using an eight-point dose response format assay, 26 compounds of different pharmacological classes were identified with in vitro anti-VACV activities. Mycophenolate mofetil (MMF) and tranilast (TRA) were detected to possess the highest anti-VACV potency (selectivity index values of >334 and >74, respectively); they could inhibit VTT-Fluc replication in nude mice at 5 days post-infection by 99% (10 mg/kg, P < .01) and 59% (45 mg/kg, P = .01), respectively, as indicated by bioluminescent intensity. In conclusion, MMF and TRA are promising anti-smallpox virus candidates for further optimization and repurposing for use in clinical practice.

8.
Hum Vaccin Immunother ; 15(10): 2286-2294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170027

RESUMO

Rift Valley fever virus (RVFV), a recognized category A priority pathogen, causes large outbreaks of Rift Valley fever with some fatalities in humans in humans and huge economic losses in livestock. As wild-type RVFV must be handled in BSL-3 or BSL-4 laboratories, we constructed a high-titer vesicular stomatitis virus (VSV) pseudotype bearing RVFV envelope glycoproteins to detect neutralizing antibodies in vitro under BSL-2 conditions. The neutralizing properties of 39 amino acid mutant sites that have occurred naturally over time in the RVFV envelope glycoproteins were analyzed with their corresponding pseudoviral mutants separately. Compared with the results in the primary strain, the variants showed no statistically significant differences. We next established a Balb/c mouse pseudovirus infection model for detecting neutralizing antibodies against pseudovirus. Five immunizations with pseudoviral DNA protected the mice from infection with the pseudovirus. Bioluminescence imaging, which we used to evaluate viral dissemination and distribution in the mice, showed a good relationship between the neutralizing antibodies titers in vitro. These pseudovirus methods will allow for the safe determination of neutralizing antibodies in vivo and in vitro, and will assist with studies on vaccines and drugs against RVFV with the long term objective of Rift Valley fever prevention.

10.
Exp Ther Med ; 17(5): 3423-3428, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30988721

RESUMO

Immune regulation mechanism of vitamin D level and interleukin (IL)-17/IL-17 receptor (IL-17R) pathway in Crohn's disease was studied. Of 40 clean mature healthy rats, 10 rats were used as control group based on random number table, the remaining 30 rats to establish Crohn's disease rat models. After successful modeling, 30 rats were divided into model group, low-dose group and high-dose group with random number table. On the 1st day after modeling, rats in low-dose group were given a single dose of 1,750 IU of vitamin D, and rats in high-dose group a single dose of 7,500 IU of vitamin D. Changes in the condition of rats after modeling were observed and scored. Enzyme-linked immunosorbent assay was used for detecting IL-12, IL-17 and CXCL11 levels, western blotting for detecting IL-17R level, and flow cytometry for detecting Th1 cell and Th17 cell levels in the lamina propria of colon mucosa. Disease activity index scores were significantly lower in low-dose group and high-dose group of rats than those in model group (P<0.05). Those were significantly lower in high-dose group of rats than those in low-dose group (P<0.05). IL-17 and IL-17R levels were significantly lower in high-dose group of rats than those in low-dose group (P<0.05). Th1 cell level was significantly higher in high-dose group of rats than that in low-dose group (P<0.05), but Th17 cell level was lower than that in low-dose group (P<0.05). IL-12 levels were significantly higher in model group, low-dose group and highdose group of rats than those in control group (P<0.05). CXCL11 levels were significantly lower in model group, low-dose group and high-dose group of rats than those in control group (P<0.05). Vitamin D can effectively treat Crohn's disease, which may improve the chemotaxis and differentiation of Th1 cells by inhibiting IL-17/IL-17R pathway, thereby improving immune function and reducing the severity of disease.

11.
Emerg Microbes Infect ; 8(1): 272-281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866781

RESUMO

Because of its high infectivity in humans and the lack of effective vaccines, Nipah virus is classified as a category C agent and handling has to be performed under biosafety level 4 conditions in non-endemic countries, which has hindered the development of vaccines. Based on a highly efficient pseudovirus production system using a modified HIV backbone vector, a pseudovirus-based mouse model has been developed for evaluating the efficacy of Nipah vaccines in biosafety level 2 facilities. For the first time, the correlates of protection have been identified in a mouse model. The limited levels of neutralizing antibodies against immunogens fusion protein (F), glycoprotein (G), and combination of F and G (FG) were found to be 148, 275, and 115, respectively, in passive immunization. Relatively lower limited levels of protection of 52, and 170 were observed for immunogens F, and G, respectively, in an active immunization model. Although the minimal levels for protection of neutralizing antibody in passive immunization were slightly higher than those in active immunization, neutralizing antibody played a key role in protection against Nipah virus infection. The immunogens F and G provided similar protection, and the combination of these immunogens did not provide better outcomes. Either immunogen F or G would provide sufficient protection for Nipah vaccine. The Nipah pseudovirus mouse model, which does not involve highly pathogenic virus, has the potential to greatly facilitate the standardization and implementation of an assay to propel the development of NiV vaccines.


Assuntos
Infecções por Henipavirus/prevenção & controle , Vírus Nipah/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Animais , Anticorpos Neutralizantes/metabolismo , Contenção de Riscos Biológicos , Cães , Infecções por Henipavirus/imunologia , Humanos , Células Madin Darby de Rim Canino , Camundongos , Vacinas Virais/imunologia
12.
J Phys Condens Matter ; 31(24): 245404, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-30794997

RESUMO

Binary hydrogen-rich compounds with H clathrate structures can serve as high-temperature superconductors under high pressures. Here, a novel ternary clathrate structure YCaH12 with space group Pm-3m is uncovered at high pressure using ab initio methods. It is predicted that YCaH12 can be stable above 180 GPa and decomposes into YH6 and CaH6 above 257 GPa. Our calculations show that YCaH12 is a potential high-temperature superconductor with T c of 230 K at 180 GPa owing to the strong electron-phonon coupling related to the optical phonon softening of H-cages. The pre-eminent pressure-induced superconductive behavior under attainable pressure is encouraging in the ternary hydrides.

13.
Foodborne Pathog Dis ; 16(5): 325-330, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30807231

RESUMO

Hepatitis E virus (HEV) is an important human pathogen with pigs serving as the main natural animal reservoir. In China, pork is the most popular meat, while pig viscera are also widely consumed. The aim of this study was to evaluate the prevalence of HEV among pigs at slaughter, and assess the presence of HEV in raw pork and pig viscera as food. Samples of pig blood, raw pork, liver, kidney, and blood curd were collected from slaughterhouse or (and) retail market. Anti-HEV antibody in serum samples was detected using enzyme-linked immunosorbent assay based on an ORF2 antigen sandwich kit. HEV RNA was tested by reverse transcription nested polymerase chain reaction (RT-nested PCR) and the viral load was further assessed using quantitative real-time PCR. The final amplicons of RT-nested PCR were sequenced and undergone phylogenetic analysis. Prevalence of antibodies to HEV was 90.4% (104/115) in pigs at slaughtered level, and one serum sample was HEV RNA positive (0.9%, 1/115). HEV RNA was detected in liver, kidney, and blood samples with positivity of 6.1% (7/114), 3.1% (4/129), and 1.2% (2/170) respectively with viral loads ranged 102.4-104.4 (2.4Log-4.4Log) genome equivalents per gram, but not in pork. The HEV RNA prevalence in both liver and kidney were statistically higher than in pork. Phylogenetic analysis showed that all obtained sequences belonged to HEV genotype 4, which were divided into subtypes 4a, 4b, 4d, and 4i, highly identical to the known human and swine HEV sequences in China. The results indicate that raw pig viscera are more likely to harbor HEV than pork, suggesting a higher transmission risk related to consuming pig organs.

14.
Transbound Emerg Dis ; 66(2): 1085-1089, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661292

RESUMO

Hepatitis E virus (HEV) was first detected in rabbits in the year 2009. Rabbit HEV is now known to be widely prevalent in rabbits and tentatively assigned into genotype 3 (HEV-3) as subgenotype-3ra (HEV-3ra). However, its role in human infection remains undetermined. This study was conducted to investigate the prevalence of HEV infection among rabbit slaughterhouse workers and to identify whether the workers exposed to rabbits are at a higher risk of HEV infection. Seventy-five workers at rabbit slaughterhouses and a control group of 421 general adults in the same area in Hebei province, China, were serologically examined for anti-HEV antibodies. HEV seroprevalences between the slaughterhouse workers and the general adults were compared. Age-adjusted prevalence of anti-HEV immunoglobulin G (IgG) in the rabbit slaughterhouse workers and control group was 46.1% and 10.8% respectively. The slaughterhouse workers had significantly higher seroprevalence and an approximately 6.9-fold increased risk for being seropositive for anti-HEV IgG as compared to the general population (odds ratio, 6.9; 95% CI: 4.3, 10.9). In slaughterhouse workers, anti-HEV IgG positive rate was positively associated with working years; in general adults, this rate was positively associated with age. The prevalence of anti-HEV immunoglobulin M (IgM) among exposed workers (6.7%) was significantly higher than that of control groups (1.2%). In conclusion, the seroprevalence of HEV is significantly higher in slaughterhouse workers than in general adults indicating that occupational exposure to rabbits is a potential risk factor for HEV infection.


Assuntos
Matadouros , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/imunologia , Hepatite E/epidemiologia , Exposição Ocupacional , Animais , Anticorpos , China/epidemiologia , Feminino , Hepatite E/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Razão de Chances , Prevalência , Coelhos , Fatores de Risco , Estudos Soroepidemiológicos
15.
Int J Food Microbiol ; 291: 5-9, 2019 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-30419475

RESUMO

Hepatitis E virus (HEV) is an important human pathogen, with pigs and other species serving as natural animal reservoirs. Recently, the report of detection of genotype 4 HEV in dairy milk with high positive rate in Yunnan province of China has attracted extensive attention. To assess the zoonotic risk of cows as HEV reservoir and transmission of HEV through dairy milk, 467 fecal samples of cows, 276 fresh milk samples, and 140 retail milk samples were collected across Hebei Province, China, from March 2017 to May 2018, and detected for HEV RNA. Fecal samples of rabbit or pig were also collected for HEV detection from farms of mixed farming with cows or farms neighboring cow farms. HEV RNA was not detected in any cow feces or in any milk samples, but 9.3% feces of pigs and 18.9% feces of rabbits were positive for HEV RNA. In addition, all of the dairy milk samples undergone HEV antigen and anti-HEV antibody detections, but none was positive. Phylogenetic analysis showed that all of the HEV isolates from pigs belonged to genotype 4 and those from rabbits were genotype 3-rabbit HEV. The results indicate that, currently in Hebei province of China, HEV is not apparently prevalent in cows and hence there is no zoonotic transmission risk through dairy milk towards humans, albeit the genotype 4 and 3 (rabbit) HEV are prevalent in pigs and rabbits respectively.


Assuntos
Vírus da Hepatite E/fisiologia , Hepatite E/veterinária , Animais , Bovinos , China/epidemiologia , Fazendas/normas , Fezes/virologia , Feminino , Genótipo , Hepatite E/epidemiologia , Hepatite E/transmissão , Vírus da Hepatite E/genética , Humanos , Leite/virologia , Prevalência , RNA Viral/genética , Coelhos , Suínos , Zoonoses/epidemiologia , Zoonoses/virologia
16.
J Infect Dis ; 219(1): 19-25, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982588

RESUMO

Background: Since the emergence of influenza A(H7N9) virus in 2013, there have been 5 waves of influenza A(H7N9) epidemics in China. However, evolution of the hemagglutinin (HA) protein antigenicity has not been systematically investigated. Methods: To better understand how antigenic drift in HA proteins of influenza (A)H7N9 virus occurs, 902 influenza A(H7N9) virus HA protein sequences from a public database were retrieved and analyzed. Fifty-three mutants with single amino acid substitutions in HA protein were introduced into pseudoviruses, and their antigenic characteristics were analyzed using pseudovirus-based assays. Results: The frequencies of 9 mutations incrementally increased over the past 5 years, with mutations identified at multiple sites. While mean neutralization titers of most variants remained unchanged, 3 mutations, A143V, A143T, and R148K, displayed a median 4-fold lower susceptibility to neutralization by antisera against influenza A/Anhui/1/2013(H7N9) virus. Notably, A143V and A143T were located outside the previously reported antigenic sites. The most dominant variant (A143V/R148K) in the most recent season constituted 74.11% of all mutations and demonstrated a 10-fold reduction in its reactivity to influenza A/Anhui/1/2013(H7N9) virus antisera. Importantly, compared with the DNA construct without the corresponding HA protein mutation, DNA vaccine encoding the A143V/R148K mutant induced a 5-fold increase in the neutralizing activity against this circulating virus. Conclusions: An appropriate vaccine strain should be considered in response to increasing antigenic drift in influenza A(H7N9) virus HA protein.


Assuntos
Substituição de Aminoácidos/imunologia , Antígenos Virais/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Substituição de Aminoácidos/genética , Animais , China/epidemiologia , Modelos Animais de Doenças , Cães , Feminino , Cobaias , Células HEK293 , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Imunização , Subtipo H7N9 do Vírus da Influenza A/genética , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Células Madin Darby de Rim Canino , Mutagênese Sítio-Dirigida , Mutação , Neuraminidase/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Vacinas de DNA/imunologia
17.
J Cancer ; 9(20): 3812-3823, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405853

RESUMO

Background: Liquid biopsies based on next-generation sequencing (NGS) assays are confronted with more opportunities and challenges. Widespread clinical implementation of NGS-based cancer in vitro diagnostic tests (IVDs) highlighted the urgency to establish reference materials (RMs) which could provide full control of the process from nucleic acid extraction to test report generation. Quality control based on cell-free DNA (cfDNA) RMs is especially important for liquid biopsies. Methods: Here, we used genomic DNA from thirteen cell lines to establish four negative cfDNA RMs (N1-N4) and four multiplex cfDNA RMs (L1-L4) at serial allelic frequencies ranging from approximately 2% to 0.1%. All the cfDNA RMs were quantified and validated via both droplet digital polymerase chain reaction (ddPCR) and NGS. These RMs were distributed to eight domestic manufacturers to collaboratively evaluate the performance of several domestic NGS-based cancer IVDs covering four major NGS platforms (NextSeq, HiSeq, Ion Proton, and BGISEQ). Results: Each multiplex RM has eleven colorectal cancer-related mutations, including six KRAS mutations (G12S, G12C, G12D, G12A, G12V, and G13D), three NRAS mutations (G12D, Q61R, and Q61K), one PIK3CA mutation (H1047R), and one BRAF mutation (V600E). Each mutation in the cfDNA RMs was quantified and validated via both ddPCR and NGS, showing the good relevance of mutant allelic frequency. These RMs were distributed to eight domestic manufacturers for collaborative evaluation. All eight manufacturers provided similar results by domestic NGS-based cancer IVDs, except for manufacturer #5. The coefficient of variation (CV) was increased with decreasing mutant allelic frequency, and poor repetition occurred when the allelic frequency was lower than 0.5%. Conclusions: These results indicated that these cfDNA RMs would be pivotal for NGS-based cancer IVDs, especially for liquid biopsies of colorectal cancer-related mutations and would guide the further development of RMs covering more onco-related mutations.

19.
Acta Pharm Sin B ; 8(4): 629-638, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30109186

RESUMO

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure-activity relationship analysis indicated: (i) 12N-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 µmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of 7d identified its high effectiveness, and in vivo anti-MARV assay of 7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.

20.
Viruses ; 10(9)2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30142928

RESUMO

Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.


Assuntos
Infecções por Coronavirus/imunologia , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Técnicas de Introdução de Genes , Coronavírus da Síndrome Respiratória do Oriente Médio/crescimento & desenvolvimento , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Proteínas de Bactérias/metabolismo , Proteína 9 Associada à CRISPR , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/genética , Endonucleases/metabolismo , Humanos , Camundongos , Recombinação Genética
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