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1.
Cell ; 184(22): 5541-5558.e22, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34644528

RESUMEN

Retrotransposons mediate gene regulation in important developmental and pathological processes. Here, we characterized the transient retrotransposon induction during preimplantation development of eight mammals. Induced retrotransposons exhibit similar preimplantation profiles across species, conferring gene regulatory activities, particularly through long terminal repeat (LTR) retrotransposon promoters. A mouse-specific MT2B2 retrotransposon promoter generates an N-terminally truncated Cdk2ap1ΔN that peaks in preimplantation embryos and promotes proliferation. In contrast, the canonical Cdk2ap1 peaks in mid-gestation and represses cell proliferation. This MT2B2 promoter, whose deletion abolishes Cdk2ap1ΔN production, reduces cell proliferation and impairs embryo implantation, is developmentally essential. Intriguingly, Cdk2ap1ΔN is evolutionarily conserved in sequence and function yet is driven by different promoters across mammals. The distinct preimplantation Cdk2ap1ΔN expression in each mammalian species correlates with the duration of its preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence.


Asunto(s)
Secuencia Conservada , Desarrollo Embrionario/genética , Proteínas Quinasas/metabolismo , Retroelementos/genética , Proteínas Supresoras de Tumor/metabolismo , Animales , Secuencia de Bases , Blastocisto/metabolismo , Proliferación Celular , Evolución Molecular , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Madre Embrionarias Humanas/metabolismo , Humanos , Mamíferos/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Regiones Promotoras Genéticas , Isoformas de Proteínas/metabolismo
2.
Genes Dev ; 35(15-16): 1109-1122, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34301766

RESUMEN

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+ ; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Pulmonares , MicroARNs , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Metástasis de la Neoplasia/patología
3.
Nucleic Acids Res ; 51(20): e105, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37843111

RESUMEN

Cytosine base editors (CBEs), which enable precise C-to-T substitutions, have been restricted by potential safety risks, including DNA off-target edits, RNA off-target edits and additional genotoxicity such as DNA damages induced by double-strand breaks (DSBs). Though DNA and RNA off-target edits have been ameliorated via various strategies, evaluation and minimization of DSB-associated DNA damage risks for most CBEs remain to be resolved. Here we demonstrate that YE1, an engineered CBE variant with minimized DNA and RNA off-target edits, could induce prominent DSB-associated DNA damage risks, manifested as γH2AX accumulation in human cells. We then perform deaminase engineering for two deaminases lamprey LjCDA1 and human APOBEC3A, and generate divergent CBE variants with eliminated DSB-associated DNA damage risks, in addition to minimized DNA/RNA off-target edits. Furthermore, the editing scopes and sequence preferences of APOBEC3A-derived CBEs could be further diversified by internal fusion strategy. Taken together, this study provides updated evaluation platform for DSB-associated DNA damage risks of CBEs and further generates a series of safer toolkits with diversified editing signatures to expand their applications.


Asunto(s)
Citosina , Edición Génica , Humanos , ARN/genética , Daño del ADN , ADN/genética , Sistemas CRISPR-Cas
4.
Eur J Epidemiol ; 39(7): 701-714, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39088069

RESUMEN

As China faces demographic shifts and socioeconomic changes, the burden of Alzheimer's disease (AD) and associated cognitive impairments is increasing dramatically, with significant implications for public health and the economy. This systematic review and meta-analysis aims to provide a comprehensive assessment of the prevalence and incidence of AD across China. Drawing from an extensive search of international and Chinese databases up to August 27, 2023, including PubMed, Embase, and the Cochrane Library, we synthesized data from 105 studies. Our analysis reveals a combined prevalence of AD of 3.48% within a sample of 626,276 elderly individuals and an incidence rate of 7.90 per 1000 person-years. Subgroup and meta-regression analyses highlight age and gender as pivotal factors influencing these epidemiological patterns. Notably, significant heterogeneity exists due to variations in diagnostic criteria and study quality, impacting the comparability of findings. This meta-analysis underscores the need for continued research into demographic and modifiable risk factors influencing AD, while emphasizing standardized reporting practices to address these limitations and improve the understanding of AD's challenge in China.


Asunto(s)
Enfermedad de Alzheimer , Anciano , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/epidemiología , China/epidemiología , Incidencia , Prevalencia , Factores de Riesgo
5.
J Chem Phys ; 160(21)2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38828807

RESUMEN

In this paper, we introduce the Floquet mean-field dynamics and Floquet surface hopping approaches to study the nonadiabatic dynamics in periodically driven solid systems. We demonstrate that these two approaches can be formulated in both real and reciprocal spaces. Using the two approaches, we are able to simulate the interaction between electronic carriers and phonons under periodic drivings, such as strong light-matter interactions. Employing the Holstein and Peierls models, we show that strong light-matter interactions can effectively modulate the dynamics of electronic population and mobility. Notably, our study demonstrates the feasibility and effectiveness of modeling low-momentum carriers' interactions with phonons using a truncated reciprocal space basis, an approach impractical in real space frameworks. Moreover, we reveal that even with a significant truncation, carrier populations derived from surface hopping maintain greater accuracy compared to those obtained via mean-field dynamics. These results underscore the potential of our proposed methods in advancing the understanding of carrier-phonon interactions in various periodically driven materials.

6.
BMC Pregnancy Childbirth ; 24(1): 114, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38321376

RESUMEN

BACKGROUND: Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting. METHODS: This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses. RESULTS: Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66-0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39-0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease. CONCLUSION: This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.


Asunto(s)
Ácido Fólico , Defectos del Tubo Neural , Embarazo , Femenino , Humanos , Masculino , Estudios de Cohortes , Estudios Prospectivos , Estudios Retrospectivos , Defectos del Tubo Neural/prevención & control , Suplementos Dietéticos , China
7.
Neurosurg Rev ; 47(1): 384, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39085721

RESUMEN

"Low-lying" posterior communicating artery (PCoA) aneurysms require great attention in surgical clipping due to their distinct anatomical characteristics. In this study, we propose an easy method to immediately recognize "low-lying" PCoA aneurysms in neurosurgical practice. A total of 89 cases with "low-lying" PCoA aneurysms were retrospectively analyzed. All patients underwent preoperative digital subtraction angiography (DSA) examinations and microsurgical clipping. Cases were classified into the "low-lying" and regular groups based on intraoperative findings. The distance- and angle-relevant parameters that reflected the relative location of the aneurysms and tortuosity of the internal carotid artery were measured using 3D-DSA images. The data were sequentially integrated into a mathematical analysis to obtain the prediction model. Finally, we proposed a novel mathematical formula to preoperatively predict the existence of "low-lying" PCoA aneurysms with great accuracy. Neurosurgeons might benefit from this model, which enables them to directly identify "low-lying" PCoA aneurysms and make appropriate surgical decisions accordingly.


Asunto(s)
Angiografía de Substracción Digital , Aneurisma Intracraneal , Procedimientos Neuroquirúrgicos , Humanos , Aneurisma Intracraneal/cirugía , Aneurisma Intracraneal/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Adulto , Angiografía de Substracción Digital/métodos , Procedimientos Neuroquirúrgicos/métodos , Estudios Retrospectivos , Anciano , Angiografía Cerebral/métodos , Modelos Teóricos , Arteria Carótida Interna/cirugía , Arteria Carótida Interna/diagnóstico por imagen
8.
Artículo en Inglés | MEDLINE | ID: mdl-39060518

RESUMEN

Twin births are related with maternal and fetal adverse outcomes. Little was known about the comparability of the cognitive, behavioral development and brain structure between twins and singletons in early adolescence. This retrospective cohort study was based on data from the United States population-based, prospective, longitudinal observational Adolescent Brain Cognitive Development study. Children with complete twin status information were enrolled, and the exposure variable was twin status. Primary outcomes were cognitive, behavioral development and brain structure in early adolescence. Cognitive and behavioral outcomes were assessed by using the NIH Toolbox and Child Behavioral Checklist, respectively. Brain structure was evaluated by the cortical thickness, area, and volume extracted from the magnetic resonance imaging (MRI) data. Subgroup analyses were conducted by prematurity, birth weight, with sibling, genetic profiles, and twin types (zygosity). From 1st September 2016 to 15th November 2018, 11545 children (9477 singletons and 2068 twins) aged 9-10 years were enrolled. Twins showed mildly lower cognitive performance (|t|> 5.104, P-values < 0.001, False Discovery Rate [FDR] < 0.001), better behavioral outcome (|t|> 2.441, P-values < 0.015, FDR < 0.042), such as lower scores for multiple psychiatric disorders and behavioral issues, and smaller cortical volume (t = - 3.854, P-values < 0.001, FDR < 0.001) and cortical area (t = - 3.872, P-values < 0.001, FDR < 0.001). The observed differences still held when stratified for prematurity, birth weight, presence of siblings, genetic profiles, and twin types (zygosity). Furthermore, analyses on the two-year follow-up data showed consistent results with baseline data. Twin status is associated with lower cognitive and better behavioral development in early adolescence accompanied by altered brain structure. Clinicians should be aware of the possible difference when generalizing results from adolescent twin samples to singletons.

9.
Brief Bioinform ; 22(4)2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-33230537

RESUMEN

MOTIVATION: Annotating genetic variants from summary statistics of genome-wide association studies (GWAS) is crucial for predicting risk genes of various disorders. The multimarker analysis of genomic annotation (MAGMA) is one of the most popular tools for this purpose, where MAGMA aggregates signals of single nucleotide polymorphisms (SNPs) to their nearby genes. In biology, SNPs may also affect genes that are far away in the genome, thus missed by MAGMA. Although different upgrades of MAGMA have been proposed to extend gene-wise variant annotations with more information (e.g. Hi-C or eQTL), the regulatory relationships among genes and the tissue specificity of signals have not been taken into account. RESULTS: We propose a new approach, namely network-enhanced MAGMA (nMAGMA), for gene-wise annotation of variants from GWAS summary statistics. Compared with MAGMA and H-MAGMA, nMAGMA significantly extends the lists of genes that can be annotated to SNPs by integrating local signals, long-range regulation signals (i.e. interactions between distal DNA elements), and tissue-specific gene networks. When applied to schizophrenia (SCZ), nMAGMA is able to detect more risk genes (217% more than MAGMA and 57% more than H-MAGMA) that are involved in SCZ compared with MAGMA and H-MAGMA, and more of nMAGMA results can be validated with known SCZ risk genes. Some disease-related functions (e.g. the ATPase pathway in Cortex) are also uncovered in nMAGMA but not in MAGMA or H-MAGMA. Moreover, nMAGMA provides tissue-specific risk signals, which are useful for understanding disorders with multitissue origins.


Asunto(s)
Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Esquizofrenia/genética , Programas Informáticos , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino
10.
Brief Bioinform ; 22(4)2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-33367491

RESUMEN

The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method transcriptome-connectome correlation analysis (TCA), which integrates the brain functional magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets. Availability: All scripts are written in R. Scripts for the TCA method and related statistics result can be freely accessed at https://github.com/Soulnature/TCA. Additional data related to this paper may be requested from the authors.


Asunto(s)
Envejecimiento/metabolismo , Translocador Nuclear del Receptor de Aril Hidrocarburo/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Corteza Cerebral/metabolismo , Factores de Terminación de Péptidos/biosíntesis , Esquizofrenia/metabolismo , Transcriptoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad
11.
Cancer Cell Int ; 23(1): 26, 2023 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-36788565

RESUMEN

BACKGROUND: Mounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model. RESULTS: In general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration. CONCLUSIONS: This suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.

12.
Mol Psychiatry ; 27(6): 2720-2730, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35379909

RESUMEN

Neurological and psychiatric disorders have overlapped phenotypic profiles, but the underlying tissue-specific functional processes remain largely unknown. In this study, we explore the shared tissue-specificity among 14 neuropsychiatric disorders through the disrupted long-range gene regulations by GWAS-identified regulatory SNPs. Through Hi-C interactions, averagely 38.0% and 17.2% of the intergenic regulatory SNPs can be linked to target protein-coding genes in brain and non-brain tissues, respectively. Interestingly, while the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Compared to psychiatric disorders, neurological disorders present more prominently the neuroinflammatory processes in both brain and non-brain tissues, indicating an intrinsic difference in mechanisms. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters (e.g. the neurodevelopmental disorders) and unexpected disorder clusters (e.g. Parkinson's disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. In conclusion, disrupted long-range gene regulations in both brain and non-brain tissues contribute to the similarity among distinct clusters of neuropsychiatric disorders, and the tissue-specifically shared functions and regulators for disease clusters may provide insights for future therapeutic investigations.


Asunto(s)
Redes Reguladoras de Genes , Trastornos del Neurodesarrollo , Encéfalo , Regulación de la Expresión Génica , Redes Reguladoras de Genes/genética , Humanos , Trastornos del Neurodesarrollo/genética , Polimorfismo de Nucleótido Simple
13.
J Nanobiotechnology ; 21(1): 255, 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37542245

RESUMEN

The COVID-19 pandemic, which originated in Hubei, China, in December 2019, has had a profound impact on global public health. With the elucidation of the SARS-CoV-2 virus structure, genome type, and routes of infection, a variety of diagnostic methods have been developed for COVID-19 detection and surveillance. Although the pandemic has been declared over, we are still significantly affected by it in our daily lives in the post-pandemic era. Among the various diagnostic methods, nanomaterials, especially metallic nanomaterials, have shown great potential in the field of bioanalysis due to their unique physical and chemical properties. This review highlights the important role of metallic nanosensors in achieving accurate and efficient detection of COVID-19 during the pandemic outbreak and spread. The sensing mechanisms of each diagnostic device capable of analyzing a range of targets, including viral nucleic acids and various proteins, are described. Since SARS-CoV-2 is constantly mutating, strategies for dealing with new variants are also suggested. In addition, we discuss the analytical tools needed to detect SARS-CoV-2 variants in the current post-pandemic era, with a focus on achieving rapid and accurate detection. Finally, we address the challenges and future directions of metallic nanomaterial-based COVID-19 detection, which may inspire researchers to develop advanced biosensors for COVID-19 monitoring and rapid response to other virus-induced pandemics based on our current achievements.


Asunto(s)
COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Pandemias , Prueba de COVID-19
14.
J Nanobiotechnology ; 21(1): 415, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37946192

RESUMEN

Nucleic acid aptamer-based nanomicelles have great potential for nanomedicine and nanotechnology applications. However, amphiphilic aptamer micelles are known to be inherently unstable upon interaction with cell membranes in the physiological environment, thus potentially compromising their specific targeting against cancer cells. This flaw is addressed in the present work which reports a superstable micellar nanodelivery system as an amphiphilic copolymer self-assembled micelle composed of nucleic acid aptamer and polyvalent hydrophobic poly(maleic anhydride-alt-1-octadecene) (C18PMH). Using Ce6 as a drug model, these C18-aptamer micelles exhibit efficient tumor-targeting and -binding ability, facilitating the entry of Ce6 into targeted cells for photodynamic therapy. In addition, they can be loaded with other hydrophobic drugs and still demonstrate favorable therapeutic effects. As such, these C18-aptamer micelles can serve as a universal platform for loading multiple drugs, providing a safer and more effective solution for treating cancer.


Asunto(s)
Neoplasias , Ácidos Nucleicos , Humanos , Micelas , Sistemas de Liberación de Medicamentos , Polímeros/química , Neoplasias/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Ácidos Nucleicos/uso terapéutico , Portadores de Fármacos/química , Línea Celular Tumoral
15.
Nano Lett ; 22(7): 2826-2834, 2022 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-35344667

RESUMEN

Metal "X" Frameworks (MXFs) constructed from metal ions and biomacromolecules ("X components") via coordination interactions show crystalline structures and diverse functionalities. Here, a series of MXFs composed of various metal ions (e.g., Zn2+, Hf4+, Ca2+) and DNA oligodeoxynucleotides were reported. With MXF consisting of Hf4+ and CpG oligodeoxynucleotides as the example, we show that such Hf-CpG MXF can achieve high-Z elements-enhanced photon radiotherapy and further trigger robust tumor-specific immune responses, thus showing efficient tumor suppression ability. In vivo experiments showed that external beam radiotherapy applied on tumors locally injected with Hf-CpG MXF result in the thorough elimination of primary tumors, complete inhibition of tumor metastasis, and protection against tumor rechallenge by triggering robust antitumor immune responses. Our findings provide a blueprint for fabricating a variety of rationally designed MXFs with desired functions and present the strategy of stimulating whole-body systemic immune responses by only local treatment of radiotherapy.


Asunto(s)
Inmunoterapia , Neoplasias , ADN , Humanos , Inmunidad , Neoplasias/terapia , Oligodesoxirribonucleótidos/farmacología
16.
Angew Chem Int Ed Engl ; 62(50): e202307020, 2023 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-37920913

RESUMEN

Chemo-dynamic therapy (CDT) based on the Fenton or Fenton-like reaction has emerged as a promising approach for cancer treatment. However, autophagy-mediated self-protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal-DNA nanocomplexes (DACs-Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn-based catalyst in DACs-Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs-Mn inhibited the expression of autophagy-associated proteins, thereby improving the efficacy of CDT. By disrupting the self-protective pathway of cells under severe oxidative stress, this novel approach of DACs-Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor-specific oxidative damage. Notably, the Metal-DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.


Asunto(s)
ADN Catalítico , Nanopartículas , Neoplasias , Animales , Ratones , Línea Celular Tumoral , Neoplasias/patología , Metales , Radical Hidroxilo/metabolismo , Autofagia , Peróxido de Hidrógeno/metabolismo , Microambiente Tumoral
17.
Appl Environ Microbiol ; 88(2): e0161821, 2022 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-34788067

RESUMEN

Lanthipeptides belong to a family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) containing (methyl)lanthionine residues. Commonly, class I lanthipeptides are synthesized by a gene cluster encoding a precursor peptide (LanA), biosynthetic machinery (LanBTC), a protease (LanP), a two-component regulatory system (LanRK), and an immunity system (LanI and LanFEG). Although nisin and subtilin are highly similar class I lanthipeptides, the cross-regulation by LanRK and the cross-immunity by LanI and LanFEG between the nisin and subtilin systems have been proven to be very low. Here, the possibility of the cross-functionality of LanBTC to modify and transport nisin precursor (NisA) and subtilin precursor (SpaS) was evaluated in Bacillus subtilis and Lactococcus lactis. Interestingly, we found that a promiscuous NisBC-SpaT complex is able to synthesize and export nisin precursor, as efficiently as the native nisin biosynthetic machinery NisBTC, in L. lactis but not B. subtilis. The assembly of the NisBC-SpaT complex at a single microdomain, close to the old cell pole, was observed by fluorescence microscopy in L. lactis. In contrast, such a complex was not formed in B. subtilis. Furthermore, the isolation of the NisBC-SpaT complex and its subcomplexes from the cytoplasmic membrane of L. lactis by pulldown assays was successfully conducted. Our work demonstrates that the association of LanBC with LanT is critical for the efficient biosynthesis and secretion of the lanthipeptide precursor with complete modifications and suggests a cooperative mechanism between LanBC and LanT in the modification and transport processes. IMPORTANCE A multimeric synthetase LanBTC complex has been proposed for the in vivo production of class I lanthipeptides. However, it has been demonstrated that LanB, LanC, and LanT can perform their functionality in vivo and in vitro, independently of other Lan proteins. The role of protein-protein interactions, especially between the modification complex LanBC and the transport system LanT, in the biosynthesis process of lanthipeptides is still unclear. In this study, the importance of the presence of a well-installed LanBTC complex in the cell membrane for lanthipeptide biosynthesis and transport was reinforced. In L. lactis, the recruitment of SpaT from the peripheral cell membrane to the cell poles by the NisBC complex was observed, which may explain the mechanism by which the secretion of the premature peptide is prevented.


Asunto(s)
Lactococcus lactis , Nisina , Bacillus subtilis/genética , Proteínas Bacterianas/metabolismo , Transporte Biológico , Lactococcus lactis/metabolismo , Ligasas/metabolismo , Nisina/metabolismo
18.
Chemistry ; 28(68): e202202589, 2022 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-36063109

RESUMEN

An innovative strategy for circularly polarized luminescence (CPL) of carbon dots (CDs) has been developed: The achiral CDs displayed contrary supramolecular chirality and opposite CPL in two different bi-solvent systems, which are due to the formation of self-assembled helical nanostructures with two diverse assembly modes (P and M) in aggregate state via intermolecular π-π interactions and differential hydrogen bonding (H-bonding) without the need of any additional element of chirality.


Asunto(s)
Carbono , Nanoestructuras , Solventes , Luminiscencia , Enlace de Hidrógeno
19.
Soft Matter ; 18(16): 3125-3129, 2022 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-35411907

RESUMEN

A novel helix hydrogel with a G-quartet structure was synthesized from guanosine (Gua) and its derivative 5'-guanosine monophosphate (5'-GMP) under a molecular crowding environment. The chirality of the hydrogel is adjusted by controlling the gelling speed. The chiral hydrogel can induce an achiral dye Thioflavin T (ThT) to realize circularly polarized fluorescence (CPL). The CPL dissymmetry factor |glum| of the dye-hydrogels can reach 3 × 10-2 and can be switched easily.


Asunto(s)
Hidrogeles , Luminiscencia , Fluorescencia
20.
Entropy (Basel) ; 24(2)2022 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-35205445

RESUMEN

In the era of the interconnection of all things, the security of the Internet of Things (IoT) has become a new challenge. The theoretical basis of unconditional security can be guaranteed by using quantum keys, which can form a QKD network-based security protection system of quantum Internet of Things (Q-IoT). However, due to the low generation rate of the quantum keys, the lack of a reasonable key allocation scheme can reduce the overall service quality. Therefore, this paper proposes a dynamic on-demand key allocation scheme, named DDKA-QKDN, to better meet the requirements of lightweight in the application scenario of Q-IoT and make efficient use of quantum key resources. Taking the two processes of the quantum key pool (QKP) key allocation and the QKP key supplement into account, the scheme dynamically allocates quantum keys and supplements the QKP on demand, which quantitatively weighs the quantum key quantity and security requirements of key requests in proportion. The simulation results show that the system efficiency and the ability of QKP to provide key request services are significantly improved by this scheme.

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