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1.
Artigo em Inglês | MEDLINE | ID: mdl-34606979

RESUMO

Isogenic cells growing in identical environments show cell-to-cell variations because of the stochasticity in gene expression. High levels of variation or noise can disrupt robust gene expression and result in tremendous consequences for cell behaviors. In this work, we showed evidence from single-cell RNA-sequencing data analysis that microRNAs (miRNAs) can reduce gene expression noise at the mRNA level in mouse cells. We identified that the miRNA expression level, number of targets, target pool abundance, and strength of miRNA interactions with its targets are the key features contributing to noise repression. miRNAs tend to work together in cooperative subnetworks to repress target noise synergistically in a cell-type-specific manner. By building a physical model of posttranscriptional regulation and observing in synthetic gene circuits, we demonstrated that accelerated degradation with elevated transcriptional activation of the miRNA target provides resistance to extrinsic fluctuations. Together, through the integrated analysis of single-cell RNA and miRNA expression profiles, we demonstrated that miRNAs are important posttranscriptional regulators for reducing gene expression noise and conferring robustness to biological processes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34674136

RESUMO

PURPOSE: Artery contrasted computed tomography (CT) enables accurate observations of the arteries and surrounding structures, thus being widely used for the diagnosis of diseases such as aneurysm. To avoid the complications caused by contrast agent, this paper proposes an aorta-aware deep learning method to synthesize artery contrasted CT volume form non-contrast CT volume. METHODS: By introducing auxiliary multi-resolution segmentation tasks in the generator, we force the proposed network to focus on the regions of aorta and the other vascular structures. Then, the segmentation results produced by the auxiliary tasks were used to extract aorta. The detection of abnormal CT images containing aneurysm was implemented by estimating the maximum axial radius of aorta. RESULTS: In comparison with the baseline models, the proposed network with auxiliary tasks achieved better performances with higher peak signal-noise ratio value. In aorta regions which are supposed to be the main region of interest in many clinic scenarios, the average improvement can be up to 0.33dB. Using the synthesized artery contrasted CT, the F score of aneurysm detection achieved 0.58 at slice level and 0.85 at case level. CONCLUSION: This study tries to address the problem of non-contrast to artery contrasted CT modality translation by employing a deep learning model with aorta awareness. The auxiliary tasks help the proposed model focus on aorta regions and synthesize results with clearer boundaries. Additionally, the synthesized artery contrasted CT shows potential in identifying slices with abdominal aortic aneurysm, and may provide an option for patients with contrast agent allergy.

3.
Aging (Albany NY) ; 13(19): 23393-23406, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34644263

RESUMO

Cosmc mutations may cause abnormal O-glycosylation and result in Tn antigen expression. In the current study, it was discovered that proliferation and migration of Tn+ cells (Jurkat T and LS174T-Tn+ cells) with mutant Cosmc decreased after transfected Cosmc, and their sensitivity to apoptosis induced by Apo2L/TRAIL increased. Core 1-, 2-, and 3-derived O-glycans were absent in Tn+ cells. After Cosmc transfection, normal extended core 1-derived O-glycans appeared and were accompanied by increased T-synthase activity. Core 2-derived O-glycans appeared in transfected LS174T-Tn+ cells, and their structural types and levels were lower than those in LS174T-Tn- cells. Core 3-derived O-glycans were present only in LS174T-Tn- cells. The activity of C3GnT in LS174T-Tn+ cells was lower than that in LS174T-Tn- cells, and it was absent in Jurkat T cells. Cosmc transfection did not alter C3GnT activity or core 3-derived O-glycans in Jurkat T and LS174T-Tn+ cells. The results demonstrated that the composition and structure of O-glycans were different among various Tn+ cells, which not only affected cell malignant behavior but also modulated sensitivity to apoptotic stimuli. Thus, Cosmc transfection may effectively decrease the malignant behavior of Tn+ tumor cells and enhance their sensitivity to apoptosis when induced by Apo2L/TRAIL through modification of O-glycans.

4.
Phys Chem Chem Phys ; 23(40): 23173-23183, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34618881

RESUMO

MXenes represent an emerging family of two-dimensional materials of transition metal carbides/carbonitrides terminated with functional groups like -O, -OH, and -F on the chemically active surface of MX slabs. As a member of the family, Nb2CTx exhibits superior lithium storage capacity over most of the other MXenes as anode materials in lithium-ion batteries (LIBs). However, an in-depth understanding of the charge storage mechanism is still lacking so far. Here, through combining complementary experiments and density functional theory calculations, we provide insights into the (de)lithiation process. Specifically, Nb2CTx with dominant -O functional groups stores charge as a result of changes in the oxidation states of both transition metals Nb and O, which is supported by Bader charge analysis showing a significant change in the oxidation states of Nb and O upon lithiation. As monitored by ex situ X-ray diffraction, the interlayer spacing of Nb2CTx changes slightly upon lithium ion (de)intercalation, corresponding to a volume change of only 2.3% with a near zero-strain feature. By coupling with a LiFePO4/C cathode, the full cell presents superior rate capability and cycling stability as well. The insights into the charge storage mechanism of Nb2CTx in this work provide useful guidance for the rational design of MXene-based anode materials for high-performance LIBs.

5.
Int J Biol Macromol ; 190: 713-721, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474053

RESUMO

Zika virus (ZIKV) induces neurological and autoimmune complications such as microcephaly and Guillain-Barre syndrome. Effective vaccines are necessary to prevent the ZIKV infection. E protein of ZIKV is responsible for virus attachment, entry, and fusion. The domain III of E protein (EDIII) contains the neutralizing epitopes and is ideal to act as an antigen for ZIKV vaccine. However, EDIII is poorly immunogenic. CRM197 is a carrier protein and can activate T helper cells for EDIII. Mannan is a ligand of TLR-4 or TLR-2. Eight-arm PEG can link multiple EDIII molecules in one entity. In the present study, EDIII was covalently conjugated with CRM197, 8-arm PEG and mannan to improve the immunogenicity of EDIII. The conjugate (CRM-EDIII-PM) elicited high EDIII-specific antibody titers in the BALB/c mice. Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-5 and IL-10) were secreted at a marked level. Thus, CRM-EDIII-PM could stimulate potent humoral and cellular immune response to EDIII. The serum exposure of CRM-EDIII-PM to the immune system was prolonged. Moreover, CRM-EDIII-PM did not lead to apparent toxicity to the organs. Therefore, CRM-EDIII-PM was expected as a promising vaccine candidate for its ability to induce strong immune responses.

6.
Chem Commun (Camb) ; 57(74): 9394-9397, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528982

RESUMO

An efficient kinetic resolution of N-aryl ß-amino alcohols has been developed via asymmetric para-aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. Broad substrate scope and high kinetic resolution performances were afforded with this method. Control experiments supported the critical roles of the NH and OH group in these reactions.

7.
J Med Chem ; 64(18): 13752-13765, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34477367

RESUMO

Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.

8.
J Med Chem ; 64(18): 13830-13840, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34492176

RESUMO

Class F G protein-coupled receptors are characterized by a large extracellular domain (ECD) in addition to the common transmembrane domain (TMD) with seven α-helixes. For smoothened receptor (SMO), structural studies revealed dissected ECD and TMD, and their integrated assemblies. However, distinct assemblies were reported under different circumstances. Using an unbiased approach based on four series of cross-conjugated bitopic ligands, we explore the relationship between the active status and receptor assembly. Different activity dependency on the linker length for these bitopic ligands corroborates the various occurrences of SMO assembly. These results reveal a rigid "near" assembly for active SMO, which is in contrast to previous results. Conversely, inactive SMO adopts a free ECD, which would be remotely captured at "far" assembly by cholesterol. Altogether, we propose a mechanism of cholesterol flow-caused SMO activation involving an erection of ECD from far to near assembly.

9.
ACS Appl Mater Interfaces ; 13(37): 44254-44265, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34519196

RESUMO

Combining the advantages of dual-ion batteries (DIBs) and sodium-ion batteries (SIBs), we herein develop a superior sodium-based dual-ion battery (Na-DIB) based on the PTCDA organic anode and ionic liquid (IL) electrolyte. The system shows the highest specific discharge capacity of 177 mAh g-1 at 0.5C and excellent capacity retention over 100% at 2C after 200 cycles. Notably, even at an ultrahigh rate of 20C, the battery still maintains a considerable capacity of 60 mAh g-1 with a coulombic efficiency (CE) close to 100 and 94% capacity retention after 1000 cycles. Moreover, the self-discharge of the system has been investigated and shown to have an extremely low value of 0.18% h-1. Consequently, this work presents an excellent Na-DIB system, which could be a promising candidate for large-scale applications.

10.
J Med Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

11.
BMC Oral Health ; 21(1): 457, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544417

RESUMO

BACKGROUND: A nomogram is a tool that transforms complex regression equations into simple and visual graphs and enables clinicians and patients to conveniently compute output probabilities without needing medical knowledge and complex formulas. The aim of this study was to develop and validate a predictive nomogram to screen for severe caries among 12-year-old children based on risk factors in Sichuan Province, China. METHODS: A cross-sectional study of 4573 12-year-olds was conducted up to May 2016 in middle schools from three districts and three counties in Sichuan Province, China. All the children underwent oral examinations and completed questionnaires to assess general information, oral impacts on daily performance, dietary habits, subjective health conditions, history of dental trauma, frequency of toothache, dental visits, and knowledge, attitudes, and behaviours toward oral hygiene. Univariate analysis and multivariate logistic regression analysis were used to determine which variables were significantly associated with severe caries (operationalized as DMFT ≥ 3). A nomogram was developed and validated by using the 'rms' package and two cross-validation methods. RESULTS: Severe caries was found in 537 of the 4573 children (11.74%). Multivariate logistic regression analysis revealed that the following variables predicted a higher risk of severe caries: 'female' [odds ratio (OR) = 1.985, 95% confidence interval (95% CI): 1.63-2.411], 'urban' (OR = 2.389, 95% CI: 1.96-2.91), 'non-only child' (OR = 1.317, 95% CI: 1.07-1.625), 'very poor self-assessment of oral health status' (OR = 2.157, 95% CI: 1.34-3.467) and 'visited a dentist less than 6 months' (OR = 1.861, 95% CI: 1.38-2.505). Multivariate logistic regression analysis also indicated that the following variables predicted a lower risk of severe caries: 'middle level of urbanization' (OR = 0.395, 95% CI: 0.32-0.495) and 'high level of urbanization' (OR = 0.466, 95% CI: 0.37-0.596). Both the fivefold and leave-one-out cross-validation methods indicated that the nomogram model built by these 6 variables displayed good disease recognition ability. CONCLUSIONS: The nomogram was a simple-to-use model to screen children for severe caries. This model was found to facilitate non-dental professionals in assessing risk values without oral examinations and making referrals to dental professionals.


Assuntos
Suscetibilidade à Cárie Dentária , Cárie Dentária , Criança , Estudos Transversais , Índice CPO , Cárie Dentária/diagnóstico , Cárie Dentária/epidemiologia , Feminino , Humanos , Nomogramas , Saúde Bucal , Prevalência , Instituições Acadêmicas
12.
Artigo em Inglês | MEDLINE | ID: mdl-34492510

RESUMO

Iridin, one of the main bioactive components isolated from Belamcanda chinensis (L.) DC, exerts various pharmacological activities, such as anti-inflammation, antioxidant, and antitumor. However, the metabolism and pharmacokinetics of iridin are still unknown. After 100 mg/kg administration of iridin orally, the plasma, urine, and fecal bio-samples from Sprague-Dawley (SD) rats were collected and detected by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The pharmacokinetics of the major metabolite irigenin (aglycon of iridin) and a total of thirteen metabolites of iridin were identified, including five metabolites in plasma, ten metabolites in urine, and six metabolites in feces. The most principal metabolic pathway of iridin was glucuronidation after demethylation and was mediated by UDP-glucuronosyltransferases (UGTs) 1A7, 1A8, 1A9 and 1A10. This study highlights the first-time investigation of the metabolism of iridin in vivo, and the pharmacokinetics of irigenin (the major metabolite of iridin) in rats. These results provide robust evidence for further research and clinical application of iridin.

13.
Stat Med ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34474502

RESUMO

Current status data arise when each subject is observed only once and the failure time of interest is only known to be either smaller or larger than the observation time rather than observed exactly. For the situation, due to the use of imperfect diagnostic tests, the failure status could often suffer misclassification or one observes misclassified data, which may result in severely biased estimation if not taken into account. In this article, we discuss regression analysis of such misclassified current status data arising from the additive hazards model, and a simulation-extrapolation (SIMEX) approach is developed for the estimation. Furthermore, the asymptotic properties of the proposed estimators are established, and a simulation study is conducted to assess the empirical performance of the method, which indicates that the proposed procedure performs well. In particular, it can correct the estimation bias given by the naive method that ignores the existence of misclassification. An application to a medical study on gonorrhea is also provided.

14.
J Med Internet Res ; 23(9): e30854, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34346888

RESUMO

BACKGROUND: The COVID-19 pandemic has imposed a large, initially uncontrollable, public health crisis both in the United States and across the world, with experts looking to vaccines as the ultimate mechanism of defense. The development and deployment of COVID-19 vaccines have been rapidly advancing via global efforts. Hence, it is crucial for governments, public health officials, and policy makers to understand public attitudes and opinions towards vaccines, such that effective interventions and educational campaigns can be designed to promote vaccine acceptance. OBJECTIVE: The aim of this study was to investigate public opinion and perception on COVID-19 vaccines in the United States. We investigated the spatiotemporal trends of public sentiment and emotion towards COVID-19 vaccines and analyzed how such trends relate to popular topics found on Twitter. METHODS: We collected over 300,000 geotagged tweets in the United States from March 1, 2020 to February 28, 2021. We examined the spatiotemporal patterns of public sentiment and emotion over time at both national and state scales and identified 3 phases along the pandemic timeline with sharp changes in public sentiment and emotion. Using sentiment analysis, emotion analysis (with cloud mapping of keywords), and topic modeling, we further identified 11 key events and major topics as the potential drivers to such changes. RESULTS: An increasing trend in positive sentiment in conjunction with a decrease in negative sentiment were generally observed in most states, reflecting the rising confidence and anticipation of the public towards vaccines. The overall tendency of the 8 types of emotion implies that the public trusts and anticipates the vaccine. This is accompanied by a mixture of fear, sadness, and anger. Critical social or international events or announcements by political leaders and authorities may have potential impacts on public opinion towards vaccines. These factors help identify underlying themes and validate insights from the analysis. CONCLUSIONS: The analyses of near real-time social media big data benefit public health authorities by enabling them to monitor public attitudes and opinions towards vaccine-related information in a geo-aware manner, address the concerns of vaccine skeptics, and promote the confidence that individuals within a certain region or community have towards vaccines.


Assuntos
COVID-19 , Mídias Sociais , Vacinas contra COVID-19 , Humanos , Pandemias , Opinião Pública , SARS-CoV-2 , Estados Unidos
16.
Artigo em Inglês | MEDLINE | ID: mdl-34410028

RESUMO

Left main coronary artery atresia (LMCAA) is a rare congenital anomaly of the coronary artery that may have an unfavorable prognosis if left untreated. Surgical revascularization by either coronary artery bypass grafting or coronary reconstruction osteoplasty is unanimously recognized as the treatment of choice for this condition. Here, we first report a case of LMCAA treated with revascularization by percutaneous coronary intervention (PCI) through a retrograde approach. Intravascular ultrasound revealed an unusual coronary structure for the left main artery. PCI appears to be a feasible and effective alternative to surgery for the treatment of LMCAA, particularly if a minimally invasive method is desired.

17.
PLoS One ; 16(8): e0255259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34351973

RESUMO

In response to the soaring needs of human mobility data, especially during disaster events such as the COVID-19 pandemic, and the associated big data challenges, we develop a scalable online platform for extracting, analyzing, and sharing multi-source multi-scale human mobility flows. Within the platform, an origin-destination-time (ODT) data model is proposed to work with scalable query engines to handle heterogenous mobility data in large volumes with extensive spatial coverage, which allows for efficient extraction, query, and aggregation of billion-level origin-destination (OD) flows in parallel at the server-side. An interactive spatial web portal, ODT Flow Explorer, is developed to allow users to explore multi-source mobility datasets with user-defined spatiotemporal scales. To promote reproducibility and replicability, we further develop ODT Flow REST APIs that provide researchers with the flexibility to access the data programmatically via workflows, codes, and programs. Demonstrations are provided to illustrate the potential of the APIs integrating with scientific workflows and with the Jupyter Notebook environment. We believe the platform coupled with the derived multi-scale mobility data can assist human mobility monitoring and analysis during disaster events such as the ongoing COVID-19 pandemic and benefit both scientific communities and the general public in understanding human mobility dynamics.


Assuntos
Disseminação de Informação/métodos , Dinâmica Populacional/tendências , Big Data , COVID-19/epidemiologia , Humanos , Modelos Estatísticos , Análise Numérica Assistida por Computador , Pandemias/prevenção & controle , Pandemias/estatística & dados numéricos , Dinâmica Populacional/estatística & dados numéricos , Reprodutibilidade dos Testes , SARS-CoV-2/patogenicidade , Fluxo de Trabalho
18.
Front Immunol ; 12: 694959, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421904

RESUMO

Avian Tembusu virus (TMUV) is a novel flavivirus causing severe egg drop and fatal encephalitis in avian in Asia. In the present study, we screened the structural and functional requirements of TMUV capsid protein (CP) for viral morphogenesis using reverse genetics methods in combination with replicon packaging assays. TMUV-CP showed dramatic functional and structural flexibility, and even though 44 residues were removed from the N-terminus, it was still capable of packaging replicon RNA; in addition, 33 residues were deleted from the C-terminus (containing nearly the entire α4-helix), and infectious particles were still produced, although α4-α4' is supposedly vital for CP dimerization and nucleocapsid formation. We further analyzed two mutants (ΔC20-43 and ΔC64-96 viruses) with relatively large deletions that still replicated well in BHK-21 cells. Our data indicate that internal deletions within CP impaired viral replication or assembly, resulting in attenuated virus proliferation in cells and attenuated virulence in duck embryos, and these deletion mutations are quite stable in cell culture. An in vivo assay indicated that both ΔC20-43 virus and ΔC64-96 virus were highly attenuated in ducklings but still immunogenic. Single-dose immunization with ΔC20-43 virus or ΔC64-96 virus could protect ducklings from a lethal challenge with good antigen clearance. Together, our data shed light on replication/assembly defective TMUV with internal deletions in CP and provide an effective approach to attenuate viral virulence in live vaccines without changing the antigen composition.

19.
Cell Rep ; 36(8): 109573, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433047

RESUMO

MicroRNAs (miRNAs) have been shown to modulate gene expression noise, but less is known about how miRNAs with different properties may regulate noise differently. Here, we investigate the role of competing RNAs and the composition of miRNA response elements (MREs) in modulating noise. We find that weak competing RNAs could introduce lower noise than strong competing RNAs. In comparison with a single MRE, both repetitive and composite MREs can reduce the noise at low expression, but repetitive MREs can elevate the noise remarkably at high expression. We further observed the behavior of a synthetic cell-type classifier with miRNAs as inputs and find that miRNAs and MREs that could introduce higher noise tend to enhance cell state transition. These results provide a systematic and quantitative understanding of the function of miRNAs in controlling gene expression noise and the utilization of miRNAs to modulate the behavior of synthetic gene circuits.

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