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1.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639201

RESUMO

The arsenic acid-resistant (ArsR) family transcriptional regulators are widely distributed in microorganisms, including in the facultative intracellular pathogen Brucella spp. ArsR proteins are implicated in numerous biological processes. However, the specific roles of ArsR family members in Brucella remain obscure. Here, we show that ArsR6 (BSS2_RS07325) is required for Brucella survival both under heat, oxidative, and osmotic stress and in a murine infection model in vivo. RNA-seq and ChIP-seq reveal that 34 potential target genes for ArsR6 protein were identified, among which eight genes were up-regulated and 26 genes were down-regulated, including outer membrane protein 25D (Omp25D). ArsR6 autoregulates its own expression to maintain bacterial intracellular Cu/Ni homeostasis to benefit bacterial survival in hostile environments. Moreover, ArsR6 also regulates the production of virulence factor Omp25D, which is important for the survival of Brucella under stress conditions. Significantly, Omp25D deletion strain attenuated in a murine infection model in vivo. Altogether, our findings reveal a unique mechanism in which the ArsR family member ArsR6 autoregulates its expression and also modulates Omp25D expression to maintain metal ion homeostasis and virulence in Brucella.

2.
Med Sci Monit ; 27: e935056, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34645777

RESUMO

Retracted, due to breach of publishing guidelines, following the identification of non-original and manipulated figure images. Reference: Hui Zhang, Dong Zhou, Mingang Ying, Minyong Chen, Peng Chen, Zhaoshuo Chen, Fan Zhang: Expression of Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) Exacerbates Hepatocellular Carcinoma Through Suppressing miR-195. Med Sci Monit, 2016; 22: 4820-4829. DOI: 10.12659/MSM.898574.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34617619

RESUMO

Copper-mediated nucleophilic radiofluorination using boronic precursors is a promising, general method to label aromatic compounds with [18 F]fluoride. However, in various reports large amounts of precursor (60 µmol) were needed to achieve high radiochemical conversions (RCCs), which is neither ideal nor practical for the preparation of 18 F radiopharmaceuticals. To investigate this matter, we studied alcohol-enhanced Cu-mediated nucleophilic radiofluorination using a variety of model reactions in which we varied the concentration of [18 F]fluoride (no carrier added or isotope diluted) and the amount of precursor, base and Cu (OTF)2 (Py)4 . We found that lower amounts of precursors (e.g. 15 µmol) could be used, and that the amount of base (e.g., K2 CO3 or KHCO3 ) played a critical and limiting role in the labeling reactions. Greater than one-equivalent of base and sufficient amounts of precursors and Cu (OTf)2 (Py)4 were required to achieve good to high RCCs. The RCCs were also dependent on the overall concentration of the labeling reactions, with low reaction volumes and high concentrations of reagents being preferred. Our findings will help to improve the design of radiolabeling protocols using alcohol-enhanced copper-mediated radiofluorination of boronic precursors for the preparation of 18 F labeled radiopharmaceuticals and other radiohalogen-labeled compounds.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34648706

RESUMO

All-solid-state lithium-metal batteries (ASSLMBs) have received great interest due to their high potential to display both high energy density and safety performance. However, the poor compatibility at the Li/solid electrolyte (SE) interface and penetration of lithium dendrites during cycling strongly impede their successful commercialization. Herein, a thin Ag layer was introduced between Li and Li10GeP2S12 for the in situ formation of a Li-Ag alloy interface, thus tuning the interfacial chemistry and lithium deposition/dissolution behavior. Superior electrochemical properties and improved interfacial stability were achieved by optimizing the Ag thicknesses. The assembled symmetric cell with Li@Ag 1 µm showed a steady voltage evolution up to 1000 h with an areal capacity of 1 mAh cm-2. Moreover, a high reversible capacity of 106.5 mAh g-1 was achieved in an all-solid-state cell after 100 cycles, demonstrating the validity of the Ag layer. This work highlights the importance of the Li/SE interface re-engineering and provides a new strategy for improving the cycle life of ASSLMBs.

5.
Brain Imaging Behav ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34478055

RESUMO

Unilateral temporal lobe epilepsy (TLE) is the most common type of focal epilepsy characterized by foci in the unilateral temporal lobe grey matters of regions such as the hippocampus. However, it remains unclear how the functional features of white matter are altered in TLE. In the current study, resting-state functional magnetic resonance imaging (fMRI) was performed on 71 left TLE (LTLE) patients, 79 right TLE (RTLE) patients and 47 healthy controls (HC). Clustering analysis was used to identify fourteen white matter networks (WMN). The functional connectivity (FC) was calculated among WMNs and between WMNs and grey matter. Furthermore, the FC laterality of hemispheric WMNs was assessed. First, both patient groups showed decreased FCs among WMNs. Specifically, cerebellar white matter illustrated decreased FCs with the cerebral superficial WMNs, implying a dysfunctional interaction between the cerebellum and the cerebral cortex in TLE. Second, the FCs between WMNs and the ipsilateral hippocampus (grey matter foci) were also reduced in patient groups, which may suggest insufficient functional integration in unilateral TLE. Interestingly, RTLE showed more severe abnormalities of white matter FCs, including links to the bilateral hippocampi and temporal white matter, than LTLE. Taken together, these findings provide functional evidence of white matter abnormalities, extending the understanding of the pathological mechanism of white matter impairments in unilateral TLE.

6.
Epilepsia ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510417

RESUMO

OBJECTIVE: China has the largest population of patients with epilepsy worldwide, which imposes a heavy burden on the public and health care systems. Several epidemiological surveys on epilepsy have been performed in China. Although these surveys grossly describe the prevalence and gap in treatment of epilepsy, the status of epilepsy centers is unclear. The number of epilepsy centers has increased substantially in recent decades. Therefore, a nationwide investigation of the scale and distribution, personnel, equipment, and epilepsy care capacity of each epilepsy center is of great value. METHODS: In 2017-2018, a multicenter cross-sectional survey was performed by the Commission on Standardized Development of Epilepsy Centers, China Association Against Epilepsy in 31 provinces, autonomous regions, and municipalities. The survey consisted of 74 questions divided into four sections: (1) overview, (2) personnel, (3) essential equipment and facilities, and (4) epilepsy care service capacity. The questions ranged from January 1, 2016 to December 31, 2016. The data were analyzed using descriptive statistics. RESULTS: There were 358 epilepsy centers for the 1.38 billion national population in 2016. Three quarters were in the eastern and western regions, and >90% were in tertiary hospitals. There were 9688 doctors engaged in epilepsy care, and 4.8% of doctors and electrophysiological physicians/technicians passed the national test for electroencephalography technical accreditation. A total of 9667 patients underwent resective surgeries in 2016. There were 888 vagus nerve stimulation procedures and 275 deep brain stimulation procedures. SIGNIFICANCE: This study is the first unique survey of epilepsy centers in China. Despite their rapid development, epilepsy centers cannot meet patients' needs at this stage. The results provide data-based evidence for the formulation of policies related to epilepsy service planning.

7.
Respiration ; : 1-5, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34515245

RESUMO

Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine-needle aspiration biopsy as initial sampling approaches of mediastinal lymph nodes for lung cancer staging. However, the small sample volume might restrict the diagnostic utility of needle aspiration in certain mediastinal diseases. We have recently shown that transbronchial mediastinal cryobiopsy, which is capable of providing larger amounts of intact tissue, improves diagnostic yield in rare tumors and benign diseases compared to EBUS-TBNA. Here, we present a case of mediastinal nodular lymphocyte predominant Hodgkin lymphoma successfully diagnosed by endoscopic transesophageal cryobiopsy.

8.
J Cell Physiol ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515350

RESUMO

Hypertension is a major cause of chronic kidney disease. However, the pathogenesis of hypertensive kidney disease is not fully understood. Recently, we have shown that CXCL16/phosphoinositide-3 kinase γ (PI3Kγ) plays an important role in the development of renal inflammation and fibrosis in angiotensin II (AngII) induced hypertensive nephropathy. In the present study, we examined the role of phosphatase and tensin homolog (PTEN), a major regulator of PI3K signaling, in the pathogenesis of renal inflammation and fibrosis in an experimental model of hypertension induced by AngII. We generated myeloid PTEN conditional knockout mice by crossing PTENflox/flox mice with LysM-driven Cre mice. Littermate LysM-Cre- / - PTENflox/flox mice were used as a control. Both myeloid PTEN knockout mice and their littermate control mice exhibited similar blood pressure at baseline. AngII treatment resulted in an increase in blood pressure that was comparable between myeloid PTEN knockout mice and littermate control mice. Compared with littermate control mice, myeloid PTEN knockout mice developed more severe kidney dysfunction, proteinuria, and fibrosis following AngII treatment. Furthermore, myeloid PTEN deficiency exacerbated total collagen deposition and extracellular matrix protein production and enhanced myeloid fibroblast accumulation and myofibroblast formation in the kidney following AngII treatment. Finally, myeloid PTEN deficiency markedly augmented infiltration of F4/80+ macrophages and CD3+ T cells into the kidneys of AngII-treated mice. Taken together, these results indicate that PTEN plays a crucial role in the pathogenesis of renal inflammation and fibrosis through the regulation of infiltration of myeloid fibroblasts, macrophages, and T lymphocytes into the kidney.

9.
Cell Cycle ; : 1-11, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470581

RESUMO

Ubiquitin-specific protease 33 (USP33), a deubiquitinating enzyme (DUB), has been identified to serve as a tumor suppressor or an oncogene in different cancers. However, its role in retinoblastoma (RB) remains unknown. Here, we aimed to uncover USP33 expression profile and function in RB, and disclose the underlying mechanism. USP33 levels in RB tissues and cells were determined using RT-qPCR and western blotting assays. USP33 effects on cell growth, cycle, apoptosis and tumorigenesis were studied using MTT, Edu, cycle and western blotting and in vivo assays. The results showed that USP33 expression levels were elevated in RB tissues and cells as compared with normal retinal tissues and cells. Downregulation of USP33 in RB Y79 and WERI-RB1 cells leaded to significant increases in cell apoptosis, G1 phase arrest and tumorigenesis, and reductions in cell growth and G2 and S phase arrest, as well as inhibited the activation of the PI3K/AKT signaling. SP1 overexpression abolished the roles of USP33 downregulation in modulating the activation of PI3K/AKT signaling, cell growth, apoptosis, and cell cycle. This study uncovered that USP33 promoted the progression of RB through regulation of the SP1/PI3K/AKT pathway.

10.
MedComm (Beijing) ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34541573

RESUMO

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor-binding domain (RBD)-specific antibodies from mice through vaccination with a recombinant SARS-CoV-2 RBD. RBD-targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS-CoV-2 neutralization. High-affinity RBD-specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS-CoV-2 viruses and the SARS-CoV-2 pseudovirus particle containing the spike protein S-RBDV367F mutant (SARS-CoV-2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I-IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS-CoV-2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD-specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS-CoV-2 and its isolates.

11.
Front Immunol ; 12: 735014, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512669

RESUMO

A hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effect of a selective STAT6 inhibitor, AS1517499, on myeloid fibroblast activation, macrophage polarization, and development of renal fibrosis in two experimental murine models. To investigate the effect of STAT6 inhibition on myeloid fibroblast activation, macrophage polarization, and kidney fibrosis, wild-type mice were subjected to unilateral ureteral obstruction or folic acid administration and treated with AS1517499. Mice treated with vehicle were used as control. At the end of experiments, kidneys were harvested for analysis of myeloid fibroblast activation, macrophage polarization, and renal fibrosis and function. Unilateral ureteral obstruction or folic acid administration induced STAT6 activation in interstitial cells of the kidney, which was significantly abolished by AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with ureteral obstruction or folic acid nephropathy compared with vehicle-treated mice. Moreover, AS1517499 significantly suppressed M2 macrophage polarization in the injured kidney. Furthermore, AS1517499 markedly reduced the expression levels of extracellular matrix proteins, and development of kidney fibrosis and dysfunction. These findings suggest that AS1517499 inhibits STAT6 activation, suppresses myeloid fibroblast activation, reduces M2 macrophage polarization, attenuates extracellular matrix protein production, and preserves kidney function. Therefore, targeting STAT6 with AS1517499 is a novel therapeutic approach for chronic kidney disease.

12.
J Am Chem Soc ; 143(39): 16206-16216, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34570466

RESUMO

Osmotic energy stored between seawater and freshwater is a clean and renewable energy source. However, developing high-efficiency and durable permselective membranes for harvesting osmotic energy remains a longstanding bottleneck. Herein, we report that a nanocomposite membrane with a biological serosa-mimetic structure can achieve high-performance osmotic energy generation through the coupling of two-dimensional (2D) sulfonated covalent organic framework (COF) nanosheets and anion-grafted aramid nanofibers (ANFs). As verified by theoretical calculations and experimental investigations, the 2D COF nanosheets not only provide abundant one-dimensional (1D)/2D nanofluidic channels to synergistically benefit an ultrafast ion migration but also enable high cation permselectivity via the covalently tethered anions. The grafted ANFs increase the mechanical strength of the membrane and further improve the ion diffusion/rectification. When it was applied in an osmotic power generator, the biomimetic membrane delivered a power density of 9.6 W m-2, far surpassing the commercial benchmark of 5.0 W m-2. This work could boost the viability of osmotic energy conversion toward a sustainable future.

13.
Seizure ; 92: 94-99, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34481323

RESUMO

BACKGROUND: Obesity and overweight have been well established as comorbidities of epilepsy in adults. However, the effects of overweight and obesity on the risk of adult drug-resistant epilepsy (DRE) has not been fully assessed. Thus, the objective of this study was to investigate the relationships between categories of body mass index (BMI) and DRE. METHODS: This was a case-control study. Patients with epilepsy hospitalized for Video electroencephalogram were included in the study from 2015 to 2020. Low/normal weight, overweight, and obesity were defined as BMI<23 and 23-24.9 and ≥25 kg/m2, respectively. The proportions of patients diagnosed with DRE in each category were calculated. RESULTS: A total of 1272 patients with drug-responsive epilepsy and 345 patients with DRE were included in this study. More men than women had DRE (P=0.012). Higher proportions of patients with DRE had a history of status epilepticus (P<0.001), CNS infection (P=0.027), developmental delay (P=0.001), and comorbidity (P<0.001). Obesity (BMI≥25 kg/m2) was associated with an increased risk of DRE (adjusted OR, 2.339; 95% CI, 1.724-3.171). No significant increase in the risk of DRE was found to be associated with overweight. Further stratified analyses by valproic acid (VPA) treatment attenuated the obesity-DRE relationship, but the associations remained statistically significant (adjusted OR, 1.79; 95% CI, 1.15-2.80). CONCLUSION: Obesity, but not overweight, potentially plays a role in DRE, although confounders, such as antiseizure medications (ASMs) use, need to be explored. In the future, well-designed trials are needed to elucidate this issue.

14.
BMC Neurol ; 21(1): 368, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34560837

RESUMO

BACKGROUND: Brain magnetic resonance imaging (MRI) rarely reveals structural changes in patients with suspected anti-Tr/DNER encephalitis and thus provides very limited information. Here, we combined structural MRI, functional MRI, and positron emission tomography-computed tomography (PET-CT) findings to characterize this rare disorder in a patient. CASE PRESENTATION: A 43-year-old woman presented with progressive cerebellar ataxia, memory impairment, anxiety, and depression. Anti-Tr antibodies were detected in both her serum (1:10) and cerebrospinal fluid (1:10). A diagnosis of anti-Tr-positive autoimmune cerebellar ataxia was established. The patient's symptoms were worse, but her brain MRI was normal. Meanwhile, voxel-based morphometry analysis showed bilateral reduced cerebellar volume, especially in the posterior lobe and uvula of the cerebellum and the middle of the left temporal lobe compared with 6 sex- and age-matched healthy subjects (6 females, 43 ± 2 years; p < 0.05). Using seed-based functional connectivity analysis, decreased connectivity between the posterior cingulate cortex/precuneus and left frontal lobe compared to the control group (p < 0.05) was detected. PET-CT revealed bilateral hypometabolism in the cerebellum and relative hypermetabolism in the cerebellar vermis and bilateral frontal lobe, but no malignant changes. CONCLUSIONS: A combination of structural MRI, functional MRI, and brain PET-CT has higher diagnostic and prognostic value than conventional MRI in patients with suspected anti-Tr/DNER encephalitis.

15.
Soft Matter ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570151

RESUMO

Utilizing combined non-covalent interactions and introducing anions as structure-directing factors to build oriented self-assembly and 2D crystalline nanosheet superstructures with precise distance control of surface charges in competitive aqueous solvents still represents a formidable challenge for supramolecular chemists. Here we report a simple, efficient, and general strategy for multiple C-H/N-H⋯anion hydrogen bond enhanced π-π interaction directed 2D oriented self-assembly in water, which is based on the head-to-tail association of perylene monoimide dimers (PMIs) by directing N-H⋯anion interactions to position the anions to the C-H of π systems (PMIs). Interesting, this behavior only occurs for size-matched anions (Cl- to NO3-; <45 Å3), while larger anions could not form 2D crystalline nanosheet superstructures. The results show that crystalline nanosheet superstructures with precise distance control of surface charges can effectively capture DNA, possibly due to their high surface charge density and the distance match between the distance of surface charges and the distance between adjacent base pairs.

16.
J Cancer Res Clin Oncol ; 147(11): 3343-3357, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34472004

RESUMO

PURPOSE: The anti-inflammatory environment of glioma reduces the efficacy of immunotherapies. Therefore, it is vital to transform the immunosuppressive microenvironment of glioma into a pro-inflammatory environment. Sialic acid-binding immunoglobulin-type lectins (Siglecs) can serve as immune checkpoint targets that enhance the anti-tumor immune response. However, the roles of Siglecs in the glioma microenvironment are unknown. This study was conducted to identify targets to inhibit the anti-inflammatory environment to improve therapeutic outcomes in patients with glioma. METHODS: We analyzed the regulatory effect of prognosis-related Siglecs identified from data available in The Cancer Genome Atlas database (TCGA) and China Glioma Genome Atlas Data portal on the immunosuppressive microenvironment of glioma. The effects of prognosis-related Siglecs on the glioma microenvironment were investigated by determining the Pearson correlation coefficients of the Siglecs in transcriptome data from the TCGA database. RESULTS: Siglec-1, -9, -10, and -14 were closely associated with the prognosis of patients with glioma. The expression of these four Siglecs was significantly increased in the high-risk group and positively correlated with anti-inflammatory cytokine levels in the glioma microenvironment. CONCLUSION: Our study provides insights into the effects of prognosis-related Siglecs in glioma immunotherapy, suggesting that targeted prognosis-related Siglecs can modify the microenvironment of glioma and improve the sensitivity of patients with glioma to immunotherapy.

18.
Environ Technol ; : 1-9, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34396930

RESUMO

Sludge-recycling enhanced flocculation (SEF) is an effective method for enhancing flocculation. In the conventional SEF process, the settled sludge is recirculated into the flocculation process without any further treatment. However, studies have shown that the efficacy of the SEF process could be improved by pre-treating the sludge. In this work, the acid activation of sludge was performed using a range of pH values (1.0-6.0) and charge states, with and without long-chain bridging. The resulting residual turbidities, floc fractal dimensions and floc morphologies were then analyzed, to examine the effects of sludge activation on the efficacy of SEF. In the absence of long-chain bridging, it was found that flocculation was enhanced by pH values between 2.0 and 5.0 in the electrostatic patch (EP) and near charge neutrality (NCN) states. In the EP state, the optimal pH for SEF enhancement was pH = 2.0; in the NCN state, the optimal pH was pH = 3.0. In terms of floc morphology, pH values between 2.0 and 5.0 resulted in larger average floc sizes and lower floc fractal dimensions than conventional SEF. However, in the presence of long-chain bridging, sludge activation did not enhance flocculation; residual turbidity increased with decreases in pH, in both the EP and NCN states. Based on these results, it may be surmised that the acid activation of sludge is suitable for cases without long-chain bridging.

19.
BMC Genomics ; 22(1): 621, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404356

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) play an important role in many neurological diseases. This study aimed to investigate differentially expressed lncRNAs and messenger RNAs (mRNAs) in the susceptibility gaining process of primed DBA/1 mice, a sudden unexpected death in epilepsy (SUDEP) model, to illustrate the potential role of lncRNAs in SUDEP. METHODS: The Arraystar mouse lncRNA Microarray V3.0 (Arraystar, Rockville, MD) was applied to identify the aberrantly expressed lncRNAs and mRNAs between primed DBA/1 mice and normal controls. The differences were verified by qRT-PCR. We conducted gene ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and coexpression analyses to explore the possible function of the dysregulated RNAs. RESULTS: A total of 502 lncRNAs (126 upregulated and 376 downregulated lncRNAs) and 263 mRNAs (141 upregulated and 122 downregulated mRNAs) were dysregulated with P < 0.05 and a fold change over 1.5, among which Adora3 and Gstt4 were possibly related to SUDEP. GO analysis revealed that chaperone cofactor-dependent protein refolding and misfolded protein binding were among the top ten downregulated terms, which pointed to Hspa1a, Hspa2a and their related lncRNAs. KEGG analysis identified 28 upregulated and 10 downregulated pathways. Coexpression analysis showed fifteen dysregulated long intergenic noncoding RNAs (lincRNAs) and three aberrantly expressed antisense lncRNAs, of which AK012034 and NR_040757 are potentially related to SUDEP by regulating LMNB2 and ITPR1, respectively. CONCLUSIONS: LncRNAs and their coexpression mRNAs are dysregulated in the priming process of DBA/1 in the brainstem. Some of these mRNAs and lncRNAs may be related to SUDEP, including Adora3, Lmnb2, Hspa1a, Hspa1b, Itrp1, Gstt4 and their related lncRNAs. Further study on the mechanism of lncRNAs in SUDEP is needed.


Assuntos
RNA Longo não Codificante , Morte Súbita Inesperada na Epilepsia , Animais , Tronco Encefálico , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos DBA , RNA Longo não Codificante/genética
20.
Circulation ; 144(14): 1145-1159, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34346740

RESUMO

BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection. Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive, impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMCs) have heterogenous embryonic origins, depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. METHODS: We identified an LDS family with a dominant pathogenic variant in the TGFBR1 gene (TGFBR1A230T) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human induced pluripotent stem cells from a subject with normal aorta to generate human induced pluripotent stem cells carrying TGFBR1A230T, and corrected the mutation in patient-derived human induced pluripotent stem cells using CRISPR-Cas9 gene editing. After their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell lineages, we used conventional molecular techniques and single-cell RNA sequencing to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments using activin A and rapamycin. RESULTS: Our results indicate the TGFBR1A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in neural crest stem cell-SMC. Single-cell RNA sequencing results implicate defective differentiation even in TGFBR1A230T/+ CPC-SMC including disruption of SMC contraction and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1A230T selectively disrupted SMAD3 (SMAD family member 3) and AKT (AKT serine/threonine kinase) activation in CPC-SMC, and led to increased cell proliferation. Consistently, single-cell RNA sequencing revealed molecular similarities between a loss-of-function SMAD3 mutation (SMAD3c.652delA/+) and TGFBR1A230T/+. Last, combination treatment with activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression and function, and rescued the mechanical properties of mutant CPC-SMC tissue constructs. CONCLUSIONS: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with activin A and rapamycin that can rescue the SMC defects caused by the variant.

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