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1.
J Clin Immunol ; 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35040013

RESUMO

PURPOSE: Enterovirus A71 (EV71) causes a broad spectrum of childhood diseases, ranging from asymptomatic infection or self-limited hand-foot-and-mouth disease (HFMD) to life-threatening encephalitis. The molecular mechanisms underlying these different clinical presentations remain unknown. We hypothesized that EV71 encephalitis in children might reflect an intrinsic host single-gene defect of antiviral immunity. We searched for mutations in the toll-like receptor 3 (TLR3) gene. Such mutations have already been identified in children with herpes simplex virus encephalitis (HSE). METHODS: We sequenced TLR3 and assessed the impact of the mutations identified. We tested dermal fibroblasts from a patient with EV71 encephalitis and a TLR3 mutation and other patients with known genetic defects of TLR3 or related genes, assessing the response of these cells to TLR3 agonist poly(I:C) stimulation and EV71 infection. RESULTS: Three children with EV71 encephalitis were heterozygous for rare mutations-TLR3 W769X, E211K, and R867Q-all of which were shown to affect TLR3 function. Furthermore, fibroblasts from the patient heterozygous for the W769X mutation displayed an impaired, but not abolished, response to poly(I:C). We found that TLR3-deficient and TLR3-heterozygous W769X fibroblasts were highly susceptible to EV71 infection. CONCLUSIONS: Autosomal dominant TLR3 deficiency may underlie severe EV71 infection with encephalitis. Human TLR3 immunity is essential to protect the central nervous system against HSV-1 and EV71. Children with severe EV71 infections, such as encephalitis in particular, should be tested for inborn errors of TLR3 immunity.

2.
Mol Neurodegener ; 17(1): 9, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033164

RESUMO

BACKGROUND: Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer's disease (AD). The role of pericyte in early stage of AD pathogenesis remains unclear. METHODS: We investigated the dynamic changes of soluble platelet-derived growth factor receptor ß (sPDGFRß) in cerebrospinal fluid (CSF), a marker of brain pericyte injury, in transition from normal ageing to early AD in a cognitively unimpaired population aged 20 to 90 years. Association between sPDGFRß and ATN biomarkers were analyzed. RESULTS: In lifetime, CSF sPDGFRß continually increased since age of 20 years, followed by the increases of phosphorylated tau-181 (P-tau181) and total tau (T-tau) at the age of 22.2 years and 31.7 years, respectively; CSF Aß42 began to decline since the age of 39.6 years, indicating Aß deposition. The natural trajectories of biomarkers suggest that pericyte injury is an early event during transition from normal status to AD, even earlier than Aß deposition. In AD spectrum, CSF sPDGFRß was elevated in preclinical stage 2 and participants with suspected non-AD pathophysiologies. Additionally, CSF sPDGFRß was positively associated with P-tau181 and T-tau independently of Aß42, and significantly strengthened the effects of Aß42 on P-tau181, suggesting that pericyte injury accelerates Aß-mediated tau hyperphosphorylation. CONCLUSIONS: Our results suggest that pericyte injury contributes to AD progression in the early stage in an Aß-independent pathway. Recovery of pericyte function would be a target for prevention and early intervention of AD.

3.
Anal Chem ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35026109

RESUMO

Here, a label-free perovskite-based photoelectrochemical (PEC) aptasensor was rationally designed for the displacement assay of dibutyl phthalate (DBP), a well-known endocrine disruptor, with the aid of cetyltrimethylammonium bromide (CTAB). In this method, CTAB significantly enhanced the PEC response and humidity resistance of the CH3NH3PbI3 perovskite by forming a protecting layer and passivating the X- and A-sites vacancies of CH3NH3PbI3. In addition, CTAB facilitated the immobilization of an aptamer through van der Waals and hydrophobicity forces, as well as the electrostatic interactions between the phosphate group of the aptamer and the cationic group of CTAB. When exposed to DBP in the affinity solution, the DBP aptamer was released from the electrode because the affinity between DBP and its aptamer competes with the interaction of the aptamer and CTAB. The displacement of the aptamer from the perovskite surface relieves the block effect and thus enhances the photoelectric signal of perovskite. By virtue of the good photoelectrochemical characters of CH3NH3PbI3 and the specific recognition ability of aptamer, the linear range of the PEC sensor was 1.0 × 10-13 to 1.0 × 10-8 M and the detection and quantification limits were down to 2.5 × 10-14 and 8.2 × 10-14 M (S/N = 3), respectively. This work offers a novel strategy for designing aptasensors for the detection of various targets and exhibits the marvelous potential of organic-inorganic perovskite in the field of PEC analysis.

4.
Kaohsiung J Med Sci ; 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34989116

RESUMO

This study is aimed at exploring the biological functions and related mechanism of long noncoding RNA 704 (LINC00704) in the proliferation and cell cycle progression of nasopharyngeal carcinoma (NPC) cells. The expression of LINC00704 in NPC tissues and cells was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). After LINC00704 was overexpressed or knocked down in NPC cell lines, cell counting kit-8 (CCK-8) assay, 5-bromo-2'-deoxyuridine assay, flow cytometry assay, and Transwell assay were adopted to detect the proliferation, cell cycle progression, migration, and invasion of NPC cells. The interaction between LINC00704 and ETS proto-oncogene 1 (ETS1) was verified by bioinformatics analysis, RNA pull-down assay, and RNA immunoprecipitation assay. Dual-luciferase reporter gene assay and chromatin immunoprecipitation followed by qPCR analysis were used to verify the binding status between ETS1 and the promoter region of cyclin-dependent kinase 6 (CDK6). The regulatory effects of LINC00704 and ETS1 on CDK6 expression were detected by Western blot. LINC00704 expression was elevated in NPC tissues and cells, which was significantly correlated with the advanced TNM stage and poor differentiation. LINC00704 overexpression promoted the multiplication, migration, and invasion of NPC cells and blocked the cell cycle progression while knocking down LINC00704 worked oppositely. LINC00704 could bind to ETS1, thus promoting CDK6 transcription. Knocking down LINC00704 inhibited the CDK6 expression in NPC cells. LINC00704 promotes CDK6 transcription by recruiting ETS1 to the promoter region of CDK6, thus promoting the malignant progression of NPC.

5.
Bioengineered ; 13(1): 645-654, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34967278

RESUMO

Paired related homeobox 1 (PRRX1) is a newly identified transcription factor that regulates the expression of various genes. We aimed to investigate the roles of PRRX1 and Matrix metalloproteinases (MMP)13 in dextran sulfate sodium (DSS)-induced inflammation and barrier dysfunction of NCM460 cells. PRRX1 expression in the mucosal tissues of patients with ulcerative colitis was analyzed using the GSE87466 microarray. PRRX1 and MMP13 expression was examined using Western blotting and RT-qPCR following the exposure of the NCM460 cells to DSS. The JASPAR database was used to predict the binding sites of PRRX1 to the MMP13 promoter, which was verified by luciferase reporter and chromatin immunoprecipitation assays. MMP13 expression was then detected following PRRX1 silencing or overexpression. The levels of inflammatory factors were determined using ELISA. Finally, the expression of intestinal barrier function-related proteins was evaluated using Western blotting and cellular permeability was detected by Transepithelial electrical resistance. PRRX1 was upregulated in the mucosal tissue samples of patients with UC. DSS induction upregulated PRRX1 and MMP13 expression. PRRX1 bound to the promoter of MMP13, which was further supported by the decreased expression of MMP13 observed following PRRX1 knockdown and its increased expression following PRRX1 overexpression. Furthermore, PRRX1 deletion decreased TNF-α, IL-1ß and IL-6 levels in the DSS-challenged NCM460 cells, which were subjected to MMP13 overexpression. Moreover, PRRX1 silencing upregulated ZO-1, occludin and claudin-1 expression and elevated the TEER value, whereas MMP13 overexpression attenuated these effects. Collectively, PRRX1 activates MMP13, which in turn promotes the DSS-induced inflammation and barrier dysfunction of NCM460 cells.

6.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34914824

RESUMO

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Assuntos
COVID-19/complicações , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Monócitos/metabolismo , Receptores de IgG/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Células Epiteliais Alveolares/patologia , Linfócitos B/imunologia , Vasos Sanguíneos/patologia , COVID-19/imunologia , COVID-19/patologia , Proliferação de Células , Criança , Estudos de Coortes , Ativação do Complemento , Citocinas/metabolismo , Enterócitos/patologia , Feminino , Humanos , Imunidade Humoral , Inflamação/patologia , Interferon Tipo I/metabolismo , Interleucina-15/metabolismo , Ativação Linfocitária/imunologia , Masculino , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/imunologia , Superantígenos/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia
7.
Math Biosci Eng ; 19(1): 1-33, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34902978

RESUMO

Since the outbreak of COVID-19 in Wuhan, China in December 2019, it has spread quickly and become a global pandemic. While the epidemic has been contained well in China due to unprecedented public health interventions, it is still raging or not yet been restrained in some neighboring countries. Chinese government adopted a strict policy of immigration diversion in major entry ports, and it makes Suifenhe port in Heilongjiang Province undertook more importing population. It is essential to understand how imported cases and other key factors of screening affect the epidemic rebound and its mitigation in Heilongjiang Province. Thus we proposed a time switching dynamical system to explore and mimic the disease transmission in three time stages considering importation and control. Cross validation of parameter estimations was carried out to improve the credibility of estimations by fitting the model with eight time series of cumulative numbers simultaneous. Simulation of the dynamics shows that illegal imported cases and imperfect protection in hospitals are the main reasons for the second epidemic wave, the actual border control intensities in the province are relatively effective in early stage. However, a long-term border closure may cause a paradox phenomenon such that it is much harder to restrain the epidemic. Hence it is essential to design an effective border reopening strategy for long-term border control by balancing the limited resources on hotel rooms for quarantine and hospital beds. Our results can be helpful for public health to design border control strategies to suppress COVID-19 transmission.


Assuntos
COVID-19 , China/epidemiologia , Emigração e Imigração , Humanos , Projetos de Pesquisa , SARS-CoV-2
8.
Front Endocrinol (Lausanne) ; 12: 763021, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867805

RESUMO

Glycosylated hemoglobin A1c (HbA1c) level has strong relevance to microvascular disorders, which are also thought to be the current main aspect of sudden sensorineural hearing loss (SSNHL), so we aim to elucidate the association of the HbA1c level with the severity, types, and prognosis of SSNHL. In this study, comparative analyses based on propensity score matching of the severity, types, and prognosis of SSNHL with the HbA1c level in 116 patients diagnosed as SSNHL were conducted, where they were divided into diabetes mellitus (DM) group and non-DM group. We finally found that, among patients with SSNHL, diabetic patients had a higher HbA1c level, more severe hearing loss, and poorer prognosis than non-diabetic patients. The HbA1c level was found to be significantly correlated with the severity and types of SSNHL, while no strong relevance was found between the higher HbA1c level and the poorer prognosis of SSNHL.

9.
Front Microbiol ; 12: 773829, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867912

RESUMO

Antibiotic resistance (AMR) has always been a hot topic all over the world and its mechanisms are varied and complicated. Previous evidence revealed the metabolic slowdown in resistant bacteria, suggesting the important role of metabolism in antibiotic resistance. However, the molecular mechanism of reduced metabolism remains poorly understood, which inspires us to explore the global proteome change during antibiotic resistance. Here, the sensitive, cotrimoxazole-resistant, amikacin-resistant, and amikacin/cotrimoxazole -both-resistant KPN clinical isolates were collected and subjected to proteome analysis through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). A deep coverage of 2,266 proteins were successfully identified and quantified in total, representing the most comprehensive protein quantification data by now. Further bioinformatic analysis showed down-regulation of tricarboxylic acid cycle (TCA) pathway and up-regulation of alcohol metabolic or glutathione metabolism processes, which may contribute to ROS clearance and cell survival, in drug-resistant isolates. These results indicated that metabolic pathway alteration was directly correlated with antibiotic resistance, which could promote the development of antibacterial drugs from "target" to "network." Moreover, combined with minimum inhibitory concentration (MIC) of cotrimoxazole and amikacin on different KPN isolates, we identified nine proteins, including garK, uxaC, exuT, hpaB, fhuA, KPN_01492, fumA, hisC, and aroE, which might contribute mostly to the survival of KPN under drug pressure. In sum, our findings provided novel, non-antibiotic-based therapeutics against resistant KPN.

11.
Acta Haematol ; : 1-7, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34879367

RESUMO

INTRODUCTION: Circular RNAs (circRNAs) are a novel class of RNAs which occupy gene expression at the transcriptional or post-transcriptional level, involve in many physiological processes, and participate in many diseases, especially in cancer. Our previous study showed 1 altered circRNA named circ-anaphase promoting complex subunit 7 (ANAPC7) that was upregulated in acute myeloid leukemia (AML). To further clear the expression and clinical significance of circ-ANAPC7, we enlarged the sample size and illuminated the diagnostic and monitoring value of circ-ANAPC7 in AML. METHODS: Real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was supposed to confirm the expression of circ-ANAPC7 of AML patients. We assessed the correlation of circ-ANAPC7 and clinical variables using the Spearman correlation test. The receiver operating characteristic (ROC) curve was carried out to evaluate the diagnostic value. RESULTS: Circ-ANAPC7 was first found to be upregulated in AML, and its expression was correlated to white blood cell counts in peripheral blood and blast percentage in bone marrow. ROC curve analysis revealed that circ-ANAPC7 has a significant value of auxiliary AML diagnosis (area under the curve = 0.915, p < 0.001). Furthermore, the expression level of circ-ANAPC7 was changed accompanied with disease condition transformation. CONCLUSION: Circ-ANAPC7 was upregulated in newly diagnosed and relapsed AML. It may serve as potential biomarkers for AML patient's diagnosis and monitoring.

12.
Front Immunol ; 12: 768189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912340

RESUMO

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+ -specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16 + monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

14.
Front Microbiol ; 12: 763022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950117

RESUMO

Ex situ (captivity in zoos) is regarded as an important form of conservation for endangered animals. Many studies have compared differences in the gut microbiome between captive and wild animals, but few have explained those differences at the functional level due to the limited amount of 16S rRNA data. Here, we compared the gut microbiome of captive and wild Rhinopithecus roxellana, whose high degree of dietary specificity makes it a good subject to observe the effects of the captive environment on their gut microbiome, by performing a metagenome-wide association study (MWAS). The Chao1 index was significantly higher in the captive R. roxellana cohort than in the wild cohort, and the Shannon index of captive R. roxellana was higher than that of the wild cohort but the difference was not significant. A significantly increased ratio of Prevotella/Bacteroides, which revealed an increased ability to digest simple carbohydrates, was found in the captive cohort. A significant decrease in the abundance of Firmicutes and enrichment of genes related to the pentose phosphate pathway were noted in the captive cohort, indicating a decreased ability of captive monkeys to digest fiber. Additionally, genes required for glutamate biosynthesis were also significantly more abundant in the captive cohort than in the wild cohort. These changes in the gut microbiome correspond to changes in the composition of the diet in captive animals, which has more simple carbohydrates and less crude fiber and protein than the diet of the wild animals. In addition, more unique bacteria in captive R. roxellana were involved in antibiotic resistance (Acinetobacter) and diarrhea (Desulfovibrio piger), and in the prevention of diarrhea (Phascolarctobacterium succinatutens) caused by Clostridioides difficile. Accordingly, our data reveal the cause-and-effect relationships between changes in the exact dietary composition and changes in the gut microbiome on both the structural and functional levels by comparing of captive and wild R. roxellana.

15.
Cell J ; 23(5): 552-561, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34837683

RESUMO

Objective: There is growing evidence showing that circular RNAs (circRNAs) are crucial regulators in modulating the biological behavior of tumors. This work is aimed to probe the role of circ_0000517 in non-small cell lung cancer (NSCLC) and to elucidate its mechanism of action. Materials and Methods: In this experimental study, the differentially expressed circRNAs in NSCLC were screened using the GEO database (GSE158695). Circ_0000517, miR-326, miR-330-5p, and MMP2 expression levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis and Western blot. The proliferation, apoptosis, migration, and invasion of NSCLC cells were detected by CCK-8, flow cytometry, and transwell assays. RNA immunoprecipitation (RIP), RNA pull-down, and dual-luciferase reporter gene assays were performed to clarify the association between the circ_0000517 and miR-326/miR-330-5p. Results: Circ_0000517 was shown to be up-regulated in NSCLC tissues and cell lines. The up-regulation of circ_0000517 is closely associated with advanced clinical stage of cancer, lymph node metastasis, and poor prognosis in NSCLC patients. Circ_0000517 knockdown impeded the proliferation, migration, and invasion of NSCLC cells and enhanced their apoptosis. Mechanistically, circ_0000517 was demonstrated to up-regulate MMP2 expression via decoying miR-326 and miR-330-5p to facilitate the malignant biological behaviors of NSCLC cells. Conclusion: This work reveals that circ_0000517 is implicated in NSCLC cell growth and metastasis through the modulation of miR-326/miR-330-5p/MMP2, providing novel insights into the role of circRNAs in NSCLC progression.

16.
Small ; : e2104168, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34821034

RESUMO

A multifunctional ion-sensitive floating gate Fin field-effect transistor (ISFGFinFET) for hydrogen and sodium detection is demonstrated. The ISFGFinFET comprises a FGFET and a sensing film, both of which are used to detect and improve sensitivity. The sensitivity of the ISFGFinFET can be adjusted by modulating the coupling effect of the FG. A nanoseaweed structure is fabricated via glancing angle deposition (GLAD) technology to obtain a large sensing area to enhance the sensitivity for hydrogen ion detection. A sensitivity of 266 mV per pH can be obtained using a surface area of 3.28 mm2 . In terms of sodium ion detection, a calix[4]arene sensing film to monitor sodium ions, obtaining a Na+ sensitivity of 432.7 mV per pNa, is used. In addition, the ISFGFinFET demonstrates the functionality of multiple ions detection simultaneously. The sensor arrays composed of 3 × 3 pixels are demonstrated, each of which comprise of an FGFET sensor and a transistor. Furthermore, 16 × 16 arrays with a decoder and other peripheral circuits are constructed and simulated. The performance of the proposed ISFGFinFET is competitive with that of other state-of-the-art ion sensors.

17.
Front Neurol ; 12: 753270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777223

RESUMO

Objectives: Sudden sensorineural hearing loss (SSNHL) is a common otological emergency, causing a measure of hearing loss and affecting the quality of life. This study aims to investigate the association of thyroid-related hormone levels with moderately severe-to-profound SSNHL. Methods: The study included 70 patients with moderately severe-to-profound SSNHL and 100 age- and sex-matched healthy controls. Peripheral venous blood samples were taken from the participants, and their thyroid-related hormone levels were measured at admission and 1 week after treatment. Results: In moderately severe-to-profound SSNaHL patients, the concentrations of total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) (all P < 0.05) were significantly lower than in the control group. The TT3, TT4, FT3, and TSH levels were significantly higher in the effective group than in the ineffective group (all P < 0.05). Linear correlation analysis revealed that TSH level (R = 0.707, P < 0.05) elevation after treatment successfully predicted a favorable outcome of hearing recovery. Logistic regression analyses suggested low FT3 and TSH levels to be independent occurrence predictors, while the increase of TSH level may be an independent favorable outcome predictor. Conclusions: The results suggest that low FT3 and TSH levels are risk factors for moderately severe-to-profound SSNHL. By discovering the positive association between TSH elevation and hearing recovery, along with the potential novel predictors of FT3 and TSH, our study may contribute valuable insights to the research and treatment of moderately severe-to-profound SSNHL.

18.
Neural Plast ; 2021: 8966584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721571

RESUMO

Noninvasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can induce long-term potentiation-like facilitation, but whether the combination of TMS and tDCS has additive effects is unclear. To address this issue, in this randomized crossover study, we investigated the effect of preconditioning with cathodal high-definition (HD) tDCS on intermittent theta burst stimulation- (iTBS-) induced plasticity in the left motor cortex. A total of 24 healthy volunteers received preconditioning with cathodal HD-tDCS or sham intervention prior to iTBS in a random order with a washout period of 1 week. The amplitude of motor evoked potentials (MEPs) was measured at baseline and at several time points (5, 10, 15, and 30 min) after iTBS to determine the effects of the intervention on cortical plasticity. Preconditioning with cathodal HD-tDCS followed by iTBS showed a greater increase in MEP amplitude than sham cathodal HD-tDCS preconditioning and iTBS at each time postintervention point, with longer-lasting after-effects on cortical excitability. These results demonstrate that preintervention with cathodal HD-tDCS primes the motor cortex for long-term potentiation induced by iTBS and is a potential strategy for improving the clinical outcome to guide therapeutic decisions.

19.
Hum Reprod ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34791246

RESUMO

STUDY QUESTION: Can whole-exome sequencing (WES) and in vitro validation studies identify new causative genes associated with teratozoospermia, particularly for sperm head defect? SUMMARY ANSWER: We investigated a core group of infertile patients, including 82 cases with unexplained abnormal sperm head and 67 individuals with multiple morphological abnormalities of the sperm flagella (MMAF), and revealed rare and novel deleterious gene variants correlated with morphological abnormalities of the sperm head or tail defects. WHAT IS KNOWN ALREADY: Teratozoospermia is one of the most common factors causing male infertility. Owing to high phenotypic variability, currently known genetic causes of teratozoospermia can only explain a rather minor component for patients with anomalous sperm-head shapes, and the agents responsible for atypical sperm head shapes remain largely unknown. STUDY DESIGN, SIZE, DURATION: We executed WES analysis of a Chinese cohort of patients (N = 149) with teratozoospermia to identify novel genetic causes particularly for defective sperm head. We also sought to reveal the influence of different abnormalities of sperm morphology on ICSI outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, a cohort of 149 infertile men (82 with abnormal sperm head and 67 with MMAF) were recruited. We implemented WES on infertile patients and analyzed the negative effects of the mutations of candidate genes on their protein conformations and/or expression. We also investigated the candidate genes' spatiotemporal expression/localization during spermatogenesis in both humans and mice, and explored their interactions with proteins that are known to be involved in sperm development. We also compared the ICSI outcomes of the affected individuals with various aberrations in sperm morphology. MAIN RESULTS AND THE ROLE OF CHANCE: We identified rare and deleterious variants of piwi like RNA-mediated gene silencing 4 (PIWIL4: 1/82 patients, 1.21%), coiled-coil and C2 domain containing 1B (CC2D1B: 1/82 patients, 1.21%), cyclin B3 (CCNB3: 1/82 patients, 1.21%), KIAA1210 (KIAA1210: 2/82 patients, 2.43%) and choline phosphotransferase 1 (CHPT1: 1/82 patients, 1.21%), which are novel correlates of morphological abnormalities of the sperm head; functional evidence supports roles for all of these genes in sperm head formation. The mutations of septin 12 (SEPTIN12: 2/82 patients, 2.43%) are suggested to be associated with acrosome defects. We additionally observed novel causative mutations of dynein axonemal heavy chain 2 (DNAH2: 1/67 patients, 1.49%), dynein axonemal heavy chain 10 (DNAH10: 1/67 patients, 1.49%) and dynein axonemal heavy chain 12 (DNAH12: 1/67 patients, 1.49%) in patients with MMAF, and revealed a significantly lower fertilization rate of the abnormal sperm-head group compared to the MMAF group following ICSI. Consequently, our study also suggests that the mutations of PIWIL4 and CC2D1B might be circumvented by ICSI to a degree, and that CHPT1 and KIAA1210 loss-of-function variants might be associated with failed ICSI treatment. LIMITATIONS, REASONS FOR CAUTION: In this study, we discovered the relationship between the genotype and phenotype of the novel causative genes of sperm head deformities in humans. However, the molecular mechanism of the relevant genes involved in sperm head development needs to be further illuminated in future research. Furthermore, evidence should be provided using knockout/knock-in mouse models for additional confirmation of the roles of these novel genes in spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: This cohort study of 149 Chinese infertile men documents novel genetic factors involved in teratozoospermia, particularly in anomalous sperm head formation. For the first time, we suggest that SEPTIN12 is related to human acrosomal hypoplasia, and that CCNB3 is a novel causative gene for globozoospermia in humans. We also uncovered variants in two genes-KIAA1210 and CHPT1associated with acrosomal biogenesis in patients with small or absent acrosomes. Additionally, it is postulated that loss-of-function mutations of PIWIL4 and CC2D1B have a contribution to the abnormal sperm-head formation. Furthermore, we are first to demonstrate the influence of different sperm morphologies on ICSI outcomes and indicates that the abnormal sperm head may play a significant role in fertilization failure. Our findings therefore provide valuable information for the diagnosis of teratozoospermia, particularly with respect to abnormalities of the sperm head. This will allow clinicians to adopt the optimal treatment strategy and to develop personalized medicine directly targeting these effects. STUDY FUNDING/COMPETING INTEREST(S): This work was financed by the West China Second University Hospital of Sichuan University (KS369 and KL042). The authors declare that they do not have any conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.

20.
Magn Reson Imaging ; 86: 20-27, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34808303

RESUMO

BACKGROUND: To investigate the performance of synthetic relaxometry, three-dimensional pseudo-continuous arterial spin labelling (pCASL) and diffusion-weighted imaging (DWI) in differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs) and to compare with the conventional MRI. METHODS: Seventy-two patients with gliomas (including 27 LGGs and 45 HGGs) were studied using synthetic magnetic resonance imaging (sy-MRI), pCASL, and DWI with a 3.0 T MR scanner. T1 relaxometry (T1), T2 relaxometry (T2), as well as proton density (PD) from sy-MRI, cerebral blood flow (CBF) from pCASL, apparent diffusion coefficient (ADC) from DWI and enhancement quality (EQ), proportion enhancing (PE) from conventional contrast enhanced image based Visually-Accessible-Rembrandt-Images (VASARI) scoring system, were all analyzed by two radiologists. The Student's t-test, Mann-Whitney U test or Fisher's exact test was used to compare the parameters between LGGs and HGGs. The diagnostic performance of each parameter and their combination for glioma grading were analyzed. RESULTS: Significant statistical differences in T1, PD, CBF, ADC, EQ and PE are observed between LGGs and HGGs (all P < 0.001). The ADC values have higher discrimination abilities compared with other univariable parameters, with the AUC of 0.905. AUC values for conventional contrast-enhanced method, EQ and PE from VASARI, and conventional contrast-free method, CBF + ADC, are 0.873 and 0.912 respectively. The combined T1, PD, CBF and ADC model had the best performance for differentiating LGGs and HGGs with AUC, sensitivity and specificity of 0.993, 95.5%, 100%, respectively. CONCLUSIONS: Relaxometry parameters derived from synthetic MRI contributed to the discrimination of low-grade gliomas from high-grade gliomas. Proposed contrast-free approach combining T1, PD, CBF and ADC showed a strong discriminative power, and outperformed conventional approaches.

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