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1.
Philos Trans A Math Phys Eng Sci ; 380(2214): 20210126, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34802265

RESUMO

Men who have sex with men (MSM) make up the majority of new human immunodeficiency virus (HIV) diagnoses among young people in China. Understanding HIV transmission dynamics among the MSM population is, therefore, crucial for the control and prevention of HIV infections, especially for some newly reported genotypes of HIV. This study presents a metapopulation model considering the impact of pre-exposure prophylaxis (PrEP) to investigate the geographical spread of a hypothetically new genotype of HIV among MSM in Guangdong, China. We use multiple data sources to construct this model to characterize the behavioural dynamics underlying the spread of HIV within and between 21 prefecture-level cities (i.e. Guangzhou, Shenzhen, Foshan, etc.) in Guangdong province: the online social network via a gay social networking app, the offline human mobility network via the Baidu mobility website, and self-reported sexual behaviours among MSM. Results show that PrEP initiation exponentially delays the occurrence of the virus for the rest of the cities transmitted from the initial outbreak city; hubs on the movement network, such as Guangzhou, Shenzhen, and Foshan are at a higher risk of 'earliest' exposure to the new HIV genotype; most cities acquire the virus directly from the initial outbreak city while others acquire the virus from cities that are not initial outbreak locations and have relatively high betweenness centralities, such as Guangzhou, Shenzhen and Shantou. This study provides insights in predicting the geographical spread of a new genotype of HIV among an MSM population from different regions and assessing the importance of prefecture-level cities in the control and prevention of HIV in Guangdong province. This article is part of the theme issue 'Data science approach to infectious disease surveillance'.


Assuntos
Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Adolescente , China/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Humanos , Masculino
2.
Food Chem ; 372: 131259, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34627087

RESUMO

A robust data fusion strategy integrating Tri-step infrared spectroscopy (IR) with electronic nose (E-nose) was established for rapid qualitative authentication and quantitative evaluation of red wines using Cabernet Sauvignon as an example. The chemical fingerprints of four types of wines were thoroughly interpreted by Tri-step IR, and the defined spectral fingerprint region of alcohol and sugar was 1200-950 cm-1. The wine types were authenticated by IR-based principal component analysis (PCA). Furthermore, ten quantitative models by partial least squares (PLS) were built to evaluate alcohol and total sugar contents. In particular, the model based on the fusion datasets of spectral fingerprint region and E-nose was superior to the others, in which RMSEP reduced by 47.95% (alcohol) and 79.90% (total sugar), rp increased by 11.95% and 43.47%, and RPD >3.0. The developed methodology would be applicable for mass screening and rapid multi-chemical-component quantification of wines in a more comprehensive and efficient manner.

3.
Protein Expr Purif ; 190: 106005, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34695570

RESUMO

Disulfide bond formed between the cysteine pairs plays a key role in maintaining the integrity of the protein structure and function. The ubiquitin-associated (UBA) domain of human HOIP contains three cysteine residues, Cys504, Cys551, and Cys572. Disulfide bonds formed by Cys504 and Cys551 residues are highly conserved, but the effect of disulfide bonds on the biochemical characteristics of UBA has not been elucidated. In addition, due to the presence of isolated Cys572, inactive inclusion bodies may be formed during protein expression or trigger protein aggregation during protein purification. In this study, the co-expression of SUMO fusion protein combined with SUMO protease (ULP enzyme) in Escherichia coli was successfully applied to improve the soluble expression of UBA domain. Introduced three mutants (UBAC551A, UBAC572A and UBAC551,572A) determined the effects of disulfide bonds on the biochemical characteristics of UBA. Circular dichroism and analytical size exclusion chromatography results showed that the target proteins obtained by co-expression could be folded correctly and had biological activity. Both thermal-induced and urea-induced results demonstrated that the elimination of disulfide bonds would significantly reduce the stability of UBA. Fluorescence spectroscopy result showed that the elimination of disulfide bonds slightly increases the binding affinity of UBA to ligands. In summary, soluble, stable and active UBA domain and its mutants were prepared by co-expression system, which will further contribute to the structural and functional research of UBA.

4.
Front Pharmacol ; 12: 748658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776966

RESUMO

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS-SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

5.
Front Surg ; 8: 736680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778358

RESUMO

Background: Anterior cervical discectomy and fusion (ACDF) has been widely performed to treat cervical generative diseases. Cage subsidence is a complication after ACDF. Although it is known that segmental kyphosis, acceleration of adjacent segmental disease, and restenosis may occur due to cages subsidence; however detailed research comparing zero-profile cages (ROI-C) and conventional plate and cage construct (CPC) on cage subsidence has been lacking. Objective: The objectives of this study was to compare the rate of postoperative cage subsidence between zero profile anchored spacer (ROI-C) and conventional cage and plate construct (CPC) and investigate the risk factors associated with cage subsidence following ACDF. Methods: Seventy-four patients with ACDF who received either ROI-C or CPC treatment from October 2013 to August 2018 were included in this retrospective cohort study. Clinical and radiological outcomes and the incidence of cage subsidence at final follow up-were compared between groups. All patients were further categorized into the cage subsidence (CS) and non-cage subsidence (NCS) groups for subgroup analysis. Results: The overall subsidence rate was higher in the ROI-C group than in the CPC group (66.67 vs. 38.46%, P = 0.006). The incidence of cage subsidence was significantly different between groups for multiple-segment surgeries (75 vs. 34.6%, P = 0.003), but not for single-segment surgeries (54.55 vs. 42.30%, P = 0.563). Male sex, operation in multiple segments, using an ROI-C, and over-distraction increased the risk of subsidence. Clinical outcomes and fusion rates were not affected by cage subsidence. Conclusion: ROI-C use resulted in a higher subsidence rate than CPC use in multi-segment ACDF procedures. The male sex, the use of ROI-C, operation in multiple segments, and over-distraction were the most significant factors associated with an increase in the risk of cage subsidence.

7.
BMC Plant Biol ; 21(1): 557, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814838

RESUMO

BACKGROUND: Arabidopsis protein disulfide isomerase 1 (AtPDI1) has been demonstrated to have disulfide isomerase activity and to be involved in the stress response. However, whether the anti-stress function is directly related to the activities of thiol-disulfide exchange remains to be elucidated. RESULTS: In the present study, encoding sequences of AtPDI1 of wild-type (WT) and double-cysteine-mutants were transformed into an AtPDI1 knockdown Arabidopsis line (pdi), and homozygous transgenic plants named pdi-AtPDI1, pdi-AtPDI1m1 and pdi-AtPDI1m2 were obtained. Compared with the WT and pdi-AtPDI1, the respective germination ratios of pdi-AtPDI1m1 and pdi-AtPDI1m2 were significantly lower under abiotic stresses and exogenous ABA treatment, whereas the highest germination rate was obtained with AtPDI1 overexpression in the WT (WT- AtPDI1). The root length among different lines was consistent with the germination rate; a higher germination rate was observed with a longer root length. When seedlings were treated with salt, drought, cold and high temperature stresses, pdi-AtPDI1m1, pdi-AtPDI1m2 and pdi displayed lower survival rates than WT and AtPDI1 overexpression plants. The transcriptional levels of ABA-responsive genes and genes encoding ROS-quenching enzymes were lower in pdi-AtPDI1m1 and pdi-AtPDI1m2 than in pdi-AtPDI1. CONCLUSION: Taken together, these results clearly suggest that the anti-stress function of AtPDI1 is directly related to the activity of disulfide isomerase.

8.
BMC Oral Health ; 21(1): 599, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814909

RESUMO

BACKGROUND: Periapical periodontitis is a common oral inflammatory disease that affects periapical tissues and is caused by bacteria in the root canal system. The relationship among the local metabolome, the inflammatory grade, and the type and abundance of microorganisms associated with periapical periodontitis is discussed in this study. METHODS: The inflammatory grades of periapical samples from 47 patients with chronic periapical periodontitis in permanent anterior teeth were determined based on the immune cell densities in tissues subjected to haematoxylin and eosin staining. The metabolome was evaluated using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by principal component analysis and orthogonal partial least squares discriminant analysis. The microbiome was accessed using 16 S rRNA high-throughput sequencing. The differences in the metabolomes and microbiomes of the periapical periodontitis samples were assessed using Spearman's correlation analysis. RESULT: N-acetyl-D-glucosamine, L-tryptophan, L-phenylalanine, and 15 other metabolites were identified by the comparison between samples with severe inflammation and mild or moderate inflammation. Four amino acid metabolism pathways and one sugar metabolism pathway were associated with the inflammatory grade of periapical periodontitis. The abundance of Actinomycetes was negatively correlated with the abundance of glucosamine (GlcN), while the abundance of Tannerella was positively correlated with the abundance of L-methionine. CONCLUSIONS: The local metabolome of periapical periodontitis is correlated with the inflammatory grade. The abundance of the local metabolites GlcN and L-methionine is correlated with the abundance of the major microorganisms Actinomycetes and Tannerella, respectively.

9.
Int J Bioprint ; 7(4): 414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805595

RESUMO

Bolus is a kind of auxiliary device used in radiotherapy for the treatment of superficial lesions such as skin cancer. It is commonly used to increase skin dose and overcome the skin-sparing effect. Despite the availability of various commercial boluses, there is currently no bolus that can form full contact with irregular surface of patients' skin, and incomplete contact would result in air gaps. The resulting air gaps can reduce the surface radiation dose, leading to a discrepancy between the delivered dose and planned dose. To avoid this limitation, the customized bolus processed by three-dimensional (3D) printing holds tremendous potential for making radiotherapy more efficient than ever before. This review mainly summarized the recent development of polymers used for processing bolus, 3D printing technologies suitable for polymers, and customization of 3D printing bolus. An ideal material for customizing bolus should not only have the feature of 3D printability for customization, but also possess radiotherapy adjuvant performance as well as other multiple compound properties, including tissue equivalence, biocompatibility, antibacterial activity, and antiphlogosis.

10.
Am J Cardiol ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34736721

RESUMO

Saphenous vein grafts (SVGs) have high rates of in-stent restenosis (ISR). We compared the baseline clinical and angiographic characteristics of patients and lesions that did develop ISR with those who did not develop ISR during a median follow-up of 2.7 years in the DIVA study (NCT01121224). We also examined the ISR types using the Mehran classification. ISR developed in 119 out of the 575 DIVA patients (21%), with similar incidence among patients with drug-eluting stents and bare-metal stents (BMS) (21% vs 21%, p = 0.957). Patients in the ISR group were younger (67 ± 7 vs 69 ± 8 years, p = 0.04) and less likely to have heart failure (27% vs 38%, p = 0.03) and SVG lesions with Thrombolysis In Myocardial Infarction 3 flow before the intervention (77% vs 83%, p <0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p <0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p <0.01), and longer total stent length (31.37 ± 22.11 vs 25.64 ± 17.42 mm, p = 0.01). The incidence of diffuse ISR was similar in patients who received drug-eluting-stents and BMS (57% vs 54%, p = 0.94), but BMS patients were more likely to develop occlusive restenosis (17% vs 33%, p = 0.05).

11.
J Vis Exp ; (176)2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34747411

RESUMO

Type 1 diabetes mellitus (T1DM) is caused by autoimmune destruction of pancreatic ß cells, which results in little or no insulin production. Islet transplantation plays an important role in the treatment of T1DM, with the improved glycometabolic control, the reduced progression of complications, the reduction of hypoglycemic episodes when compared with traditional insulin therapy. The results of phase III clinical trial also demonstrated the safety and efficacy of islet allotransplantation in T1DM. However, the shortage of pancreas donors limits its widespread use. Animals as a source of islets such as the pig offer an alternative choice. Because the architecture of the pig pancreas is different from the islets of mice or humans, the pig islet isolation procedure is still challenging. Since the translation of alternative porcine islet sources (xenogeneic) to the clinical setting for treating T1DM through cellular transplantation is of great importance, a cost-effective, standardized, and reproducible protocol for isolating porcine islets is urgently needed. This manuscript describes a simplified and cost-effective method to isolate and purify adult porcine islets based on the previous protocols that have successfully transplanted porcine islets to non-human primates. This will be a beginners guide without the use of specialized equipment such as a COBE 2991 Cell Processor.

12.
Water Res ; 207: 117825, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34763279

RESUMO

Still ∼10% of world's population has no sustainable access to centralized water supply system, causing millions of deaths annually by waterborne diseases. Here, we develop polypyrrole nanowire arrays (PPyNWs)-modified electrodes by polymerization of pyrrole on graphite felt for point-of-use water disinfection via low-voltage electroporation. A flow-through mode is specially applied to alleviate diffusion barrier of pyrrole in the porous graphite felt for uniform PPyNWs growth. The flow-through disinfection device using the optimized PPyNWs electrode achieves above 4-log removal for model virus (MS2) and gram-positive/negative bacteria (E. faecalis and E. coli) at applied voltage of 1.0 V and fluxes below 1000 and 2500 L/m2/h. Electroporation is recognized as the dominant disinfection mechanism by using square-wave alternating voltage of ±1.0 V to eliminate the electrochemical reactions. In-situ sampling experiments reveal that anode acts as the main disinfection function due to its electric field attraction with negatively charged E. coli cells. The live/dead baclight staining experiments indicate an adsorption-desorption process of E. coli cells on anode, and the adsorption-desorption balance determines the disinfection abilities of PPyNWs anode. Under 1.0 V and 2000 L/m2/h, the disinfection device enables above 4-log E. coli removal in tap water within 7-day operation with energy consumption below 20 mJ/L, suggesting its sound application potential for point-of-use water disinfection.

13.
Artigo em Inglês | MEDLINE | ID: mdl-34782265

RESUMO

variable selection is critical to select characteristic variables of critical quality attributes to improve model performance and interpret the identified variables in multivariate calibration. However, classical variable selection methods were developed and optimized by the prediction error. It is rare for the robustness evaluation of variable selection methods. In this study, the robustness of four different variable selection methods was investigated by adding different types of simulate noises to validation set and calibration and validation sets, respectively. The reproducibility as well as root mean squared error of prediction (RMSEP) were used together as common measure in assessing the robustness of different variable selection methods. The robustness of four variable selection methods method was investigated using two near infrared (NIR) datasets including open-source dataset of corn and Chinese herbal medicine (CHM) dataset. The result illustrated that variable importance in projection (VIP) was substantially more robust to additive noise, with smaller RMSEP value and high reproducibility. This provides a novel strategy for the reliability evaluation of variable selection methods in NIR model of critical quality attributes.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34773240

RESUMO

The antagonistic effect of selenium (Se) against cadmium (Cd)-induced breast carcinogenesis was reported, but underlying mechanisms were unclear. The aim of this study was to identify the epigenetically regulated genes and biological pathways mediating the antagonistic effect. We exposed MCF-7 cells to Cd and Se alone or simultaneously. Cell proliferation was assessed by MTT assay, and differential epigenome (DNA methylation, microRNA, and long non-coding RNA) was obtained by microarrays. We cross-verified the epigenetic markers with differential transcriptome, and the ones modulated by Cd and Se in opposite directions were regarded to mediate the antagonistic effect. The epigenetically regulated genes were validated by using gene expression data in human breast tissues. We further assessed the biological functions of these validated genes. Our results showed that Se alleviated the proliferative effect of Cd on MCF-7 cell. A total of 10 epigenetically regulated genes were regarded to mediate the antagonistic effect, including APBA2, KIAA0895, DHX35, CPEB3, SVIL, MYLK, ZFYVE28, ABLIM2, GRB10, and PCDH9. Biological function analyses suggested that these epigenetically regulated genes were involved in multiple cancer-related pathways, such as focal adhesion and PI3K/Akt pathway. In conclusion, we provided evidence that Se antagonized the Cd-induced breast carcinogenesis via epigenetic modification and revealed the critical pathways.

16.
Res Vet Sci ; 141: 138-144, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34740045

RESUMO

Enterocytozoon bieneusi is a common gastrointestinal parasite that has a broad range of hosts, including birds, mammals, and even humans. The changes of gut bacterial communities have been demonstrated during the course of E. bieneusi. This study aimed to examine the infection status, and assess the zoonotic potential and influence of E. bieneusi on gut bacterial communities of captive foxes in Xinxiang, central China. Fecal samples were collected from 216 captive foxes, and amplification of the internal transcribed spacer (ITS) gene of each sample was performed by nested polymerase chain reaction. E. bieneusi was detected in 48 (22.2%) samples, and five previously reported genotypes CHN-F1 (n = 25), D (n = 18), BEB6 (n = 3), NCF2 (n = 1), and CHN-DC1 (n = 1) were identified, with CHN-F1 being the dominant genotype (25/48, 52.1%). Phylogenetic analysis further revealed that CHN-F1, D, NCF2, and CHN-DC1 genotypes belonged to the zoonotic group 1 of E. bieneusi, whereas BEB6 belonged to group 2. Moreover, sequencing and bioinformatics analysis of the V3-V4 region of 16S rRNA gene in five E. bieneusi-positive and five negative samples showed that gut microbial diversity was higher in the infected animals. In both groups, Firmicutes and Bacteroidetes were the two most abundant phyla, but the Firmicutes/Bacteroidetes ratio was lower in E. bieneusi-positive foxes (7.9:1) as compared with E. bieneusi-negative foxes (5:1). More importantly, at the phylum level, "beneficial bacteria" such as Firmicutes (1.6%) and Bacteroides (5.8%) increased, whereas "opportunistic pathogens" such as Fusobacteria (8.2%) decreased. Similarly, at the genus level, the pathogenic Clostridiaceae_Clostridium (10.0%) decreased, whereas the "beneficial bacteria" Lactococcus (6.6%) increased. These interesting phenomena warrant further investigation.

17.
NeuroRehabilitation ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34776422

RESUMO

BACKGROUND: Swallowing disorders represent one of the most common complications after cerebral infarction. OBJECTIVE: To study the effects of different frequencies of repetitive transcranial magnetic stimulation (rTMS) on swallowing disorders after cerebral infarction. METHODS: Ninety patients with swallowing disorder after cerebral infarction were enrolled and randomly assigned to three groups: the 10 Hz frequency rTMS group (30 patients), the 5 Hz frequency rTMS group (30 patients), and the 1 Hz frequency rTMS group (30 patients); another 90 healthy persons without swallowing disorders were included as the control group. The Kubota's water-swallow test, the video fluoroscopic swallow study (VFSS), and the Electroencephalograph (EEG) were analyzed before and after treatment; the EEG of the control group was detected as the baseline. RESULTS: The Kubota's water-swallow test scores were significantly decreased while the scores of pharynx period and the aspiration degree of VFSS significantly increased in 10 Hz frequency rTMS group than before treatment (P≤0.05); the amplitudes of C3 of the EEG significantly increased in three frequency groups than before treatment (P≤0.05). CONCLUSIONS: 10 Hz frequency of rTMS is effective for the treatment of swallowing disorder after cerebral infarction, the excitement of C3 area maybe the therapeutic target of rTMS on swallowing disorder after cerebral infarction.

18.
BMC Nephrol ; 22(1): 342, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34656084

RESUMO

BACKGROUND: Peritoneal dialysis (PD) can be associated with abnormal cardiac structure and function and increased mortality risk. Therefore, in this study, we analyzed the cardiac structure and function dynamic changes using echocardiography during the first 2 years of PD therapy. We also assessed its associations with all-cause mortality risk after 2 years of follow-up. METHODS: End-stage renal disease (ESRD) patients that have started PD from 2011 to 2017, and had echocardiography at baseline and years 1 and 2, were included in this study. Echocardiographic parameters were compared between baseline and year 2. Multivariable Cox models were used to estimate the association between echocardiographic parameters changes and all-cause mortality risk. RESULTS: We finally enrolled 72 PD patients in this study. The mean right ventricular diameter (RVD) increased from baseline (18.31 mm) to year 1 (18.75 mm) and year 2 (19.65 mm). We also observed a significant decrease in cardiac output (CO) between baseline and year 2. Additionally, a slight decrease trend in ejection fraction (EF) was observed. Finally, every 1 % increase in RVD was associated with a 68.2 % higher mortality risk after dialysis (HR, 1.682; 95 % CI, 1.017-2.783). CONCLUSIONS: Our results demonstrated a susceptibility for deteriorated right cardiac structure and function during the first 2 years of PD treatment. Also, higher all-cause mortality risk was observed after 2 years of PD. Altogether, these results highlighted the need for additional focus on regular echocardiographic examinations during long-term PD management. TRIAL REGISTRATION: The PD-CRISC cohort, registered with the Chinese Clinical Trial Registry ( ChiCTR1900023565 ).

19.
Front Oncol ; 11: 752725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707994

RESUMO

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.

20.
Sci Rep ; 11(1): 20983, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697379

RESUMO

Recessive variants of the SLC26A4 gene are an important cause of hereditary hearing impairment. Several transgenic mice with different Slc26a4 variants have been generated. However, none have recapitulated the auditory phenotypes in humans. Of the SLC26A4 variants identified thus far, the p.T721M variant is of interest, as it appears to confer a more severe pathogenicity than most of the other missense variants, but milder pathogenicity than non-sense and frameshift variants. Using a genotype-driven approach, we established a knock-in mouse model homozygous for p.T721M. To verify the pathogenicity of p.T721M, we generated mice with compound heterozygous variants by intercrossing Slc26a4+/T721M mice with Slc26a4919-2A>G/919-2A>G mice, which segregated the c.919-2A > G variant with abolished Slc26a4 function. We then performed serial audiological assessments, vestibular evaluations, and inner ear morphological studies. Surprisingly, both Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M showed normal audiovestibular functions and inner ear morphology, indicating that p.T721M is non-pathogenic in mice and a single p.T721M allele is sufficient to maintain normal inner ear physiology. The evidence together with previous reports on mouse models with Slc26a4 p.C565Y and p.H723R variants, support our speculation that the absence of audiovestibular phenotypes in these mouse models could be attributed to different protein structures at the C-terminus of human and mouse pendrin.

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