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1.
J Inherit Metab Dis ; 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36680545

RESUMO

Improved second-tier assays are needed to reduce the number of false positives in newborn screening (NBS) for inherited metabolic disorders including those on the Recommended Uniform Screening Panel (RUSP). We developed an expanded metabolite panel for second-tier testing of dried blood spot (DBS) samples from screen-positive cases reported by the California NBS program, consisting of true- and false-positives from four disorders: glutaric acidemia type 1 (GA1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). This panel was assembled from known disease markers and new features discovered by untargeted metabolomics and applied to second-tier analysis of single DBS punches using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a 3-min run. Additionally, we trained a Random Forest (RF) machine learning classifier to improve separation of true- and false positive cases. Targeted metabolomic analysis of 121 analytes from DBS extracts in combination with RF classification at a sensitivity of 100% reduced false positives for GA1 by 83%, MMA by 84%, OTCD by 100%, and VLCADD by 51%. This performance was driven by a combination of known disease markers (3-hydroxyglutaric acid, methylmalonic acid, citrulline, C14:1), other amino acids and acylcarnitines, and novel metabolites identified to be isobaric to several long-chain acylcarnitine and hydroxy-acylcarnitine species. These findings establish the effectiveness of this second-tier test to improve screening for these four conditions and demonstrate the utility of supervised machine learning in reducing false-positives for conditions lacking clearly discriminating markers, with future studies aimed at optimizing and expanding the panel to additional disease targets. This article is protected by copyright. All rights reserved.

2.
J Affect Disord ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36638969

RESUMO

BACKGROUND: Depression is a severe and common mental disorder. The association between depressive symptoms and lung function remains unclear. To determine whether depressive symptoms are associated with lung function in U.S. adults without pulmonary diseases. METHODS: A cross-sectional study of National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2012 were used to estimate the relationship between depressive symptoms and lung function. Depressive symptoms were determined by a participant's score on the Patient Health Questionnaire-9. Forced Expiratory Volume 1st Second (FEV1) Forced Vital Capacity (FVC) were determined by the spirometry. Weighted multivariate linear regression was used to analyze this relationship and subgroup analyses were performed. RESULTS: Of 8027 participants, 576 (7.18 %) participants with depression. Depression group had significant lower FEV1 and FVC than non-depression group. After adjustment for all covariates, there was a significant negative association between depressive symptoms and FVC (ß -4.84, 95 % CI -9.10 to -0.57), especially in non-Hispanic White people (ß -9.03, 95 % CI -14.38 to -3.69). There was no independent association between depressive symptoms and FEV1 in all participants, whereas the association was significant in non-Hispanic White people (ß -4.91, 95 % CI -9.50 to -0.32). CONCLUSIONS: High depressive symptoms were independently associated with decline of FVC among U.S. adults without pulmonary diseases, especially in non-Hispanic White people. In addition, although it was not independently associated with FEV1 in all participants, depressive symptom score was also negatively associated with FEV1 in non-Hispanic White people.

3.
Front Oncol ; 12: 1014859, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457512

RESUMO

Background: Patients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma. Case summary: We report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome. Conclusion: Sarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.

4.
Front Genet ; 13: 1003754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36506303

RESUMO

Lung adenocarcinoma (LUAD) is the one of the most prevalent and fatal form of malignant tumors worldwide. Recently, immunotherapy is widely used in the treatment of patients with LUAD and has proved to be clinically effective in improve the prognosis of patients. But there still has been a tremendous thrust to further improve the efficacy of immunotherapy in individual patients with LUAD. The suppression of T cells and their effector functions in the tumor microenvironment (TME) of LUAD is one of the primary reasons for the low efficacy of immunotherapy in some patients with LUAD. Therefore, identifying positive regulators of T cell proliferation (TPRs) may offer novel avenues for LUAD immunotherapy. In this study, we comprehensively evaluated the infiltration patterns of TPRs in 1,066 patients with LUAD using unsupervised consensus clustering and identified correlations with genomic and clinicopathological characteristics. Three infiltrating TPR clusters were defined, and a TPR-related risk signature composed of nine TPRs was constructed using least absolute shrinkage and selection operator-Cox regression algorithms to classify the individual TPR infiltration patterns. Cluster 1 exhibited high levels of T cell infiltration and activation of immune-related signaling pathways, whereas cluster 2 was characterized by robust T cell immune infiltration and enrichment of pathways associated with carcinogenic gene sets and tumor immunity. Cluster 3 was characterized as an immune-desert phenotype. Moreover, the TPR signature was confirmed as an independent prognostic biomarker for drug sensitivity in patients with LUAD. In conclusion, the TPR signature may serve as a novel tool for effectively characterizing immune characteristics and evaluating the prognosis of patients with LUAD.

5.
Immunol Invest ; : 1-16, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36548483

RESUMO

Ankylosing spondylitis (AS) is an autoimmune disease associated with disturbed gut microbiota. Currently, the treatments and outcomes of AS are not satisfactory. It is reported that resveratrol (RES) is a major phytoalexin with anti-inflammatory, antibacterial and some other pharmacological effects. However, there are no studies on the role of RES in AS. Therefore, this study aimed to explore the effect and mechanism of RES on AS. Proteoglycan and complete freund's adjuvant were used to conduct an AS mouse model, and then the AS mice were gavaged with RES (20 mg/kg and 50 mg/kg) daily for 4 weeks. Subsequently, the effect of RES on AS mice was assessed by detecting disease severity, inflammatory cytokines, NLRP3 inflammasome, TLR4/NF-κB pathway, intestinal mucosal barrier function, intestinal microbial barrier function. The assessment results indicated that RES could significantly relieve progression and severity of AS, inhibit the expression of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, interleukin-17A, interferon-γ), and promote the expression of anti-inflammatory cytokines (interleukin-4). RES intervention caused the inhibition of NLRP3 inflammasome and TLR4/NF-κB pathway. In terms of intestinal barrier function, experimental results found RES increased zonula occludens-1 and occludin expression, and additionally, changed the composition of the gut microbiota by increasing levels of Lactobacillus and Bifidobacterium and reducing levels of Enterococcus faecalis and Escherichia coli. Collectively, RES protects PG-induced AS mice by inhibiting inflammatory responses and TLR4/NF-κB/NLRP3 pathway, restoring intestinal mucosal barrier function, and regulating the composition of the gut microbiota. In other words, RES is a potential candidate for the treatment of AS.

6.
Neuroimage Clin ; 36: 103267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36510412

RESUMO

This study's aim was to investigate functional brain connectivity changes among patients with moyamoya disease (MMD) with limb paresthesia, using functional connectivity analysis based on resting-state functional magnetic resonance imaging (rs-fMRI). A total of 181 patients with MMD were enrolled, including 57 with left limb paresthesia (MLP group), 61 with right limb paresthesia (MRP group), and 63 without paresthesia (MWP group). Encephaloduroarteriosynangiosis (EDAS) was performed in 20 of the 57 patients with left limb paresthesia and 15 of the 61 patients with right limb paresthesia. Twenty-nine age- and sex-matched healthy controls (HC group) were recruited during the same period. All participants underwent rs-fMRI examination, and the patients treated with EDAS were re-examined 3-4 months after the surgery. After data preprocessing, we selected Brodmann area 3 on each side of the brain as the seed region to construct a functional connectivity network of the whole brain, and then we analyzed the differences in functional connectivity between the HC group, MWP group, MLP group, and MRP group. The functional connectivity of Brodmann area 3 (on either side) with the ipsilateral frontal (superior frontal gyrus, middle frontal gyrus, and inferior frontal gyrus) and parietal (supramarginal gyrus, angular gyrus, and superior parietal lobule) cortices was increased among patients with MMD. The functional connectivity enhancement in these brain regions was broader and greater in patients with contralateral limb paresthesia than in patients without paresthesia, and the regions with functional connectivity changes were roughly distributed symmetrically among the MLP group and the MRP group. There were no changes 3-4 months after EDAS in the increased functional connectivity between the frontal and parietal cortices and Brodmann area 3. Limb paresthesia in patients with MMD may be driven by abnormal functional connectivity in the frontal and parietal cortices. Functional changes in associated brain regions may be a target for evaluating the severity of MMD and its response to treatment.


Assuntos
Imageamento por Ressonância Magnética , Doença de Moyamoya , Humanos , Imageamento por Ressonância Magnética/métodos , Doença de Moyamoya/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos
7.
Front Neurosci ; 16: 1029388, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389234

RESUMO

Purpose: To investigate the structural and network topological changes in the white matter (WM) in MMD patients with limb paresthesia by performing diffusion kurtosis imaging (DKI). Materials and methods: A total of 151 MMD patients, including 46 with left-limb paresthesia (MLP), 52 with right-limb paresthesia (MRP), and 53 without paresthesia (MWP), and 28 healthy controls (HCs) underwent whole-brain DKI, while the surgical patients were reexamined 3-4 months after revascularization. The data were preprocessed to calculate the fractional anisotropy (FA) and mean kurtosis (MK) values. Voxel-wise statistics for FA and MK images were obtained by using tract-based spatial statistics (TBSS). Next, the whole-brain network was constructed, and global and local network parameters were analyzed using graph theory. All parameters were compared among the HC, MWP, MLP, and MRP groups, and changes in the MMD patients before and after revascularization were also compared. Results: The TBSS analysis revealed significant reductions in FA and MK in extensive WM regions in the three patient groups. In comparison with the MWP group, the MLP group showed reductions in FA and MK in both right and left WM, mainly in the right WM, while the MRP group mainly showed a reduction in FA in the left WM region and demonstrated no significant change in MK. The graph theoretical analysis showed decreased global network efficiency, increased characteristic path length, and increased sigma in the MWP, MRP, and MLP groups in comparison with the HC group. Among local network parameters, the nodal efficiency decreased in the bilateral MFG and IFGtriang, while the degree decreased in the MFG.L and bilateral IFGtriang. Patients with right-limb paresthesia showed the lowest nodal efficiency and degree in MFG.L and IFGtriang.L, while those with left-limb paresthesia showed the lowest nodal efficiency in MFG.R and IFGtriang.R and the lowest degree in IFGtriang.R. Conclusion: A DKI-based whole-brain structural and network analysis can be used to detect changes in WM damage and network topological changes in MMD patients with limb paresthesia. FA is more sensitive than MK in detecting WM injury, while MFG and IFGtriang are the key nodes related to the development of acroparesthesia.

8.
Autism ; : 13623613221138687, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36419247

RESUMO

LAY ABSTRACT: Some theories suggested that autistic people have better pitch perception skills than non-autistic people. However, in a context where pitch patterns are used to differentiate word meanings (i.e. lexical tones), autistic people may encounter difficulties, especially those with less language experience. We tested this by asking language-delayed autistic children to identify and discriminate two Mandarin lexical tones (/yi/ with Tone 1, meaning 'clothes'; /yi/ with Tone 2, meaning 'aunt'; /yi/: the standard romanization of Mandarin Chinese). On average, these autistic children were 7.35 years old, but their developmental age in language ability was 4.20, lagging behind 7-year-old non-autistic children in terms of language ability. Autistic children's performance in identifying and discriminating lexical tones was compared with two groups of non-autistic children: one group was matched with the autistic group on age, and the other was matched based on language ability. Autistic children performed differently from the non-autistic children matched on age, while autistic and non-autistic children matched on language ability exhibited seemingly similar performance. However, both the non-autistic groups have developed the perceptual ability to process lexical tones as different categories, but this ability was still developing in autistic children. Finally, we found autistic children who performed worse in identifying lexical tones had poorer language ability. The results suggest that language disability might have adverse influence on the development of skills of speech sound processing.

9.
Front Psychol ; 13: 1044362, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36337500

RESUMO

This study uses data from the China Family Panel Studies to analyze the possible impact of non-farming income on household energy choices. We use ordinary least squares and instrumental variable estimation methods to investigate the causal effect of non-farming income on household energy choices. We find that an increase in non-farming income assisted farmers in reducing their use of solid fuels in favor of clean energy. Our heterogeneity analysis, based on the average rural household income and geographical location of the village, shows that the energy upgrade effect of non-farming income is more obvious in high-income areas and suburbs closer to the county seat center. Further, we find that non-farming income has an impact on rural household energy choice mainly through the optimization of household energy-saving appliances and the enhancement of environmental awareness.

10.
Front Med (Lausanne) ; 9: 1008941, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405576

RESUMO

In this study, we investigated the metabolism of white matter by magnetic resonance spectroscopy (MRS) in stroke complicated with diabetes mellitus in combination with glycosylated hemoglobin (HbAlc) detection and clinical neurological deficit score (NIHSS). Fifty-three patients with stroke within 24 h after onset were collected and scanned by MRS. The biochemical, clinical and imaging characteristics of patients were analyzed. Patients were divided into three groups according to HbAlc levels: Good glycemic control (A): < 6.5%; satisfactory glycemic control (B): 6.5-7.5% and poor glycemic control (C): > 7.5%. The results showed that HbA1c levels were positively correlated with NIHSS in patients with acute ischemic stroke (AIS). There is significant difference in NAA/Cr between the infarcted site of the three groups and the mirror site. HbA1C level was negatively correlated with NAA/Cr in patients with AIS, and there was no significant correlation between NIHSS score and NAA/Cr. The data above demonstrated that the MRS imaging can be used to explain the adverse effects of hyperglycated hemoglobin on brain parenchyma from the perspective of imaging. This imaging technique and clinical NIHSS score have a high consistency in evaluating stroke.

11.
Front Mol Neurosci ; 15: 1037835, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36407768

RESUMO

Background: Epigenetic regulation and immunotherapy of tumor microenvironment (TME) is a hot topic in recent years. However, the potential value of tryptophan metabolism genes in regulating TME and immunotherapy is still unclear. Materials and methods: A comprehensive study of glioma patients was carried out based on 40 tryptophan metabolic genes. Subsequently, these prognostic tryptophan metabolic genes are systematically associated with immunological characteristics and immunotherapy. A risk score model was constructed and verified in the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients. Results: We described the changes of tryptophan metabolism genes in 966 glioma samples from genetic and transcriptional fields and evaluated their expression patterns from two independent data sets. We identified two different molecular subtypes and found that two subtypes were associated with clinicopathological features, prognosis, TME cell infiltration, and immune checkpoint blockers (ICBs). Then, four genes (IL4I1, CYP1A1, OGDHL, and ASMT) were screened out by univariate and multivariate cox regression analysis of tryptophan metabolism genes, and a risk score model for predicting the overall survival (OS) of glioma patients was constructed. And its predictive ability is verified using the CGGA database. At the same time, we verified the expression of IL4I1, CYP1A1, OGDHL, and ASMT four genes in glioma specimens and cell lines in GES4260 and GES15824. Therefore, we constructed a nomogram to improve the clinical applicability of the risk assessment model. The high risk score group, characterized by increased TMB and immune cell infiltration, was also sensitive to temozolomide immunotherapy. Our comprehensive analysis of tryptophan metabolic genes in gliomas shows that they play a potential role in tumor immune stromal microenvironment, clinicopathological features, and prognosis. Conclusion: Tryptophan metabolism genes play an indispensable role in the complexity, diversity, and prognosis of TME. This risk score model based on tryptophan metabolism gene is a new predictor of clinical prognosis and immunotherapy response of glioma, and guides a more appropriate immunotherapy strategy for glioma patients.

12.
Artigo em Inglês | MEDLINE | ID: mdl-36410685

RESUMO

PURPOSE/OBJECTIVE(S): Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed prior to treatment. We report a novel application of DNA methylation in peripheral blood before and after radiotherapy to further improve outcomes stratification. MATERIALS/METHODS: Peripheral blood samples from patients with non-metastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiotherapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (post-treatment minus pre-treatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts. RESULTS: Between December 2013 and September 2018, 115 patients participated in this study. HPV negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiotherapy were associated with shorter RFS and OS (P<0.05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (HR 7.1, 95% CI 1.4-35.5, P=0.016) and OS (HR 15.9, 95% CI 1.6-153.6, P=0.017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR 10.2, 95% CI 2.4-43.4, P=0.002) and OS (HR 3.7, 95% CI 1.3-10.4, P=0.015). CONCLUSION: We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiotherapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

13.
ACS Appl Mater Interfaces ; 14(45): 51122-51129, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36331247

RESUMO

Investigating the energy dissipation in micro- and nanoscale is fundamental to improve the performance and reliability of two-dimensional (2D) electronics. Recently, 2D platinum selenide (PtSe2) has drawn extensive attention in developing next-generation functional devices due to its distinctive fusion of versatile properties. Toward practical applications of PtSe2 devices, it is essential to understand the interfacial thermal properties between PtSe2 and its substrate. Among them, the thermal boundary conductance (TBC) has played a critical role for out-of-plane heat dissipation of PtSe2 devices. Here, we identify the energy dissipation behavior of multilayer PtSe2 devices and extract the actual TBC value of the PtSe2/SiO2 interface by Raman thermometry with electrical bias. The obtained TBC value is about 8.6 MW m-2 K-1, and it belongs to the low end of as-known solid-solid interfaces, suggesting possible applications regarding thermoelectric devices or others reliant on a large temperature gradient. Furthermore, the maximum current density of the PtSe2 device determines its threshold power, which is crucial for improving device design and guiding future applications. Therefore, we explore the electrical breakdown profile of the multilayer PtSe2 device, revealing the breakdown current density of 17.7 MA cm-2 and threshold power density of 0.2 MW cm-2, which are larger than typical values for commonly used aluminum and copper. These results provide key insights into the energy dissipation of PtSe2 devices and make PtSe2 an excellent candidate for thermal confinement applications and nanometer-thin interconnects, which will benefit the development of energy-efficient functional 2D devices.

14.
Oral Oncol ; 135: 106218, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36332446

RESUMO

OBJECTIVES: While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. MATERIALS AND METHODS: pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. RESULTS: Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. CONCLUSION: Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.


Assuntos
Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Criança , Feminino , Humanos , Masculino , Antígeno B7-H1/metabolismo , Mutação , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Recidiva Local de Neoplasia , Proteínas de Ligação a RNA/genética
15.
Elife ; 112022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317962

RESUMO

Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.


Cholesterol is present in every cell of the body. While it is best known for its role in heart health, it also plays a major role in hearing, with changes in cholesterol levels negatively affecting this sense. To convert sound waves into electrical brain signals, specialised ear cells rely on hair-like structures which can move with vibrations; cholesterol is present within these hair 'bundles', but its exact role remains unknown. Genetic studies have identified over 120 genes essential for normal hearing. Animal data suggest there may be many more ­ including, potentially, some which control cholesterol. For instance, in mice, loss of the Minar2 gene causes profound deafness. Yet exactly which role the protein that Minar2 codes for plays in the ear remains unknown. This is in part because that protein does not resemble any other related proteins, making it difficult to infer its function. To find out more, Gao et al. investigated loss of minar2 in zebrafish, showing that deleting the gene induced deafness in the animals. Without minar2, the hair bundles in ear cells were longer, thinner, and less able to sense vibrations: cholesterol could not move into these structures, causing them to dysfunction. Exposing the animals to drugs that lower or raise cholesterol levels respectively worsened or improved their hearing abilities. A recent study revealed that mutations in MINAR2 also cause deafness in humans. The findings by Gao et al. highlight the need for further research which explores the role of cholesterol and MINAR2 in hair bundle function, as this may potentially uncover cholesterol-based treatments for hearing problems.


Assuntos
Perda Auditiva , Peixe-Zebra , Animais , Camundongos , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética , Mecanotransdução Celular/fisiologia , Audição/fisiologia , Perda Auditiva/genética , Colesterol
16.
J Funct Biomater ; 13(4)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36278641

RESUMO

This study reports new phenomena of the interstitial fluid (ISF) microflow along perivascular and adventitial clearances (PAC) around neurovascular bundles. The fluorescent tracing was used to observe the ISF flow along the PAC of neurovascular bundles in 8-10 week old BALB/c mice. The new results include: (1) the topologic structure of the PAC around the neurovascular bundles is revealed; (2) the heart-orientated ISF flow along the PAC is observed; (3) the double-belt ISF flow along the venous adventitial clearance of the PAC is recorded; (4) the waterfall-like ISF flow induced by the small branching vessel or torn fascia along the PAC is discovered. Based on the above new phenomena, this paper approached the following objectives: (1) the kinematic laws of the ISF flow along the PAC around neurovascular bundles are set up; (2) the applicability of the hypothesis on the PAC and its subspaces by numerical simulations are examined. The findings of this paper not only enriched the image of the ISF flow through the body but also explained the kernel structure of the ISF flow (i.e., the PAC). It helps to lay the foundation for the kinematics and dynamics of the ISF flow along the PAC around neurovascular bundles.

17.
Mol Genet Metab ; 137(3): 292-300, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36252453

RESUMO

DNA polymorphic markers and self-defined ethnicity groupings are used to group individuals with shared ancient geographic ancestry. Here we studied whether ancestral relationships between individuals could be identified from metabolic screening data reported by the California newborn screening (NBS) program. NBS data includes 41 blood metabolites measured by tandem mass spectrometry from singleton babies in 17 parent-reported ethnicity groupings. Ethnicity-associated differences identified for 71% of NBS metabolites (29 of 41, Cohen's d > 0.5) showed larger differences in blood levels of acylcarnitines than of amino acids (P < 1e-4). A metabolic distance measure, developed to compare ethnic groupings based on metabolic differences, showed low positive correlation with genetic and ancient geographic distances between the groups' ancestral world populations. Several outlier group pairs were identified with larger genetic and smaller metabolic distances (Black versus White) or with smaller genetic and larger metabolic distances (Chinese versus Japanese) indicating the influence of genetic and of environmental factors on metabolism. Using machine learning, comparison of metabolic profiles between all pairs of ethnic groupings distinguished individuals with larger genetic distance (Black versus Chinese, AUC = 0.96), while genetically more similar individuals could not be separated metabolically (Hispanic versus Native American, AUC = 0.51). Additionally, we identified metabolites informative for inferring metabolic ancestry in individuals from genetically similar populations, which included biomarkers for inborn metabolic disorders (C10:1, C12:1, C3, C5OH, Leucine-Isoleucine). This work sheds new light on metabolic differences in healthy newborns in diverse populations, which could have implications for improving genetic disease screening.


Assuntos
Erros Inatos do Metabolismo , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem/métodos , Aminoácidos/genética , Biomarcadores
18.
J Speech Lang Hear Res ; 65(11): 4485-4497, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36194781

RESUMO

PURPOSE: Cochlear implants (CIs) provide significant benefits for profoundly deaf children in their language and cognitive development. However, it remains unclear whether Mandarin-speaking young children with early implantation can develop age-equivalent phonological awareness (PA) skill and working memory (WM) capacity as their normal hearing (NH) peers. The aim of this study was to investigate PA and WM in preschool-aged children with or without hearing loss and to examine the relationship between the two basic skills. METHOD: The data were collected from 16 Mandarin-speaking preschoolers with CIs and 16 age-matched children with NH. All preschool participants were instructed to complete four phonological detection tasks and four digit span tasks. Linear mixed-effects modeling was performed to evaluate PA and WM performances between two groups across different tasks. RESULTS: CI preschoolers showed comparable performances on par with NH controls in phonological detections and visual digit spans. In addition, Pearson correlation analysis revealed a positive relationship between phonological detections and auditory digit spans in preschool-aged children with CIs. CONCLUSION: With early implantation, the congenitally deaf children were capable of developing age-appropriate PA skill and WM capacity, which have practical implications for aural rehabilitation in this special pediatric population.


Assuntos
Implante Coclear , Implantes Cocleares , Correção de Deficiência Auditiva , Surdez , Percepção da Fala , Criança , Pré-Escolar , Humanos , Memória de Curto Prazo , Surdez/psicologia , Correção de Deficiência Auditiva/psicologia
19.
Am J Cancer Res ; 12(8): 3679-3692, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119846

RESUMO

Epigenomic-wide DNA methylation profiling holds the potential to reflect both electronic cigarette exposure-associated risks and individual poor health outcomes. However, a systemic study in animals or humans is still lacking. Using the Infinium Mouse Methylation BeadChip, we examined the DNA methylation status of white blood cells in male ApoE-/- mice after 14 weeks of electronic cigarette exposure with the InExpose system (2 hr/day, 5 days/week, 50% PG and 50% VG) with low (6 mg/ml) and high (36 mg/ml) nicotine concentrations. Our results indicate that electronic cigarette aerosol inhalation induces significant alteration of 8,985 CpGs in a dose-dependent manner (FDR<0.05); 7,389 (82.2%) of the CpG sites are annotated with known genes. Among the top 6 significant CpG sites (P-value<1e-8), 4 CpG sites are located in the known genes, and most (3/5) of these genes have been related to cigarette smoking. The other two CpGs are close to/associated with the Phc2 gene that was recently linked to smoking in a transcriptome-wide associations study. Furthermore, the gene set enrichment analysis highlights the activation of MAPK and 4 cardiomyocyte/cardiomyopathy-related signaling pathways (including adrenergic signaling in cardiomyocytes and arrhythmogenic right ventricular cardiomyopathy) following repeated electronic cigarette use. The MAPK pathway activation correlates well with our finding of increased cytokine mRNA expression after electronic cigarette exposure in the same batch of mice. Interestingly, two pathways related to mitochondrial activities, namely mitochondrial gene expression and mitochondrial translation, are also activated after electronic cigarette exposure. Elucidating the relationship between these pathways and the increased circulating mitochondrial DNA observed here will provide further insight into the cell-damaging effects of prolonged inhalation of e-cigarette aerosols.

20.
Front Psychol ; 13: 918737, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36160566

RESUMO

In the perceptual learning of lexical tones, an automatic and robust attention-to-phonology system enables native tonal listeners to adapt to acoustically non-optimal speech, such as phonetic conflicts in daily communications. Previous tone research reveals that non-native listeners who do not linguistically employ lexical tones in their mother tongue may find it challenging to attend to the tonal dimension or integrate it with the segmental features. However, it is unknown whether the attentional interference initially caused by a maternal attentional system would continue influencing the non-optimal tone perception for simultaneous bilingual teenagers. From an endpoint in the age of language acquisition, we investigate whether the tone-specific attention mechanism developed by the Urdu-Cantonese simultaneous bilinguals is automatic enough to assist them in adapting to a phonetically-conflicting environment. Three groups of teenagers engaged in a four-condition ABX task: Urdu-Cantonese simultaneous bilinguals, Cantonese native listeners, and Urdu-speaking, late learners of Cantonese. The results showed that although the simultaneous bilinguals could phonologically process Cantonese tones in a Cantonese-like way under a conflict-free listening condition, they still failed in adapting to the phonetic conflicts, especially the segment-induced ones. It thus demonstrated that the simultaneous exposure and years of regular education in Hong Kong local schools still could not automatically guarantee simultaneous bilingual processing of Cantonese tones. In interpreting the findings, it hypothesized that, except for simultaneous exposure, the development of a tone-specific attention mechanism is also likely to be L1-inhibitory, tone experience-driven, and language-specific for simultaneous bilinguals.

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