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FANCD2 protein, a key coordinator and effector of the interstrand crosslink repair pathway, is also required to prevent excessive nascent strand degradation at hydroxyurea-induced stalled forks. The RAD51 recombinase has also been implicated in regulation of resection at stalled replication forks. The mechanistic contributions of these proteins to fork protection are not well understood. Here, we used purified FANCD2 and RAD51 to study how each protein regulates DNA resection at stalled forks. We characterized three mechanisms of FANCD2-mediated fork protection: (1) The N-terminal domain of FANCD2 inhibits the essential DNA2 nuclease activity by directly binding to DNA2 accounting for over-resection in FANCD2 defective cells. (2) Independent of dimerization with FANCI, FANCD2 itself stabilizes RAD51 filaments to inhibit multiple nucleases, including DNA2, MRE11 and EXO1. (3) Unexpectedly, we uncovered a new FANCD2 function: by stabilizing RAD51 filaments, FANCD2 acts to stimulate the strand exchange activity of RAD51. Our work biochemically explains non-canonical mechanisms by which FANCD2 and RAD51 protect stalled forks. We propose a model in which the strand exchange activity of FANCD2 provides a simple molecular explanation for genetic interactions between FANCD2 and BRCA2 in the FA/BRCA fork protection pathway.
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ADN Helicasas , Replicación del ADN , Recombinasa Rad51 , Humanos , ADN Helicasas/genética , Reparación del ADN , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Inestabilidad Genómica , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismoRESUMEN
Monitoring the health conditions of the environment and humans is essential for ensuring human well-being, promoting global health, and achieving sustainability. Innovative biosensors are crucial in accurately monitoring health conditions, uncovering the hidden connections between the environment and human well-being, and understanding how environmental factors trigger autoimmune diseases, neurodegenerative diseases, and infectious diseases. This review evaluates the use of nanoplasmonic biosensors that can monitor environmental health and human diseases according to target analytes of different sizes and scales, providing valuable insights for preventive medicine. We begin by explaining the fundamental principles and mechanisms of nanoplasmonic biosensors. We investigate the potential of nanoplasmonic techniques for detecting various biological molecules, extracellular vesicles (EVs), pathogens, and cells. We also explore the possibility of wearable nanoplasmonic biosensors to monitor the physiological network and healthy connectivity of humans, animals, plants, and organisms. This review will guide the design of next-generation nanoplasmonic biosensors to advance sustainable global healthcare for humans, the environment, and the planet.
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Soap bubbles exhibit abundant fascinating phenomena throughout the entire life of evolution with different fundamental physics governing them. Nevertheless, the complicated dynamics of small objects in soap films are still unrevealed. Here, we report the first observation of spontaneous particle ordering in a complicated galaxy of soap films without any external energy. The balance of interfacial tension at two liquid-gas interfaces is theoretically predicted to govern belted wetted particles (BWPs) traveling along a specified path spontaneously. Such spontaneous particle path-finding is found to depend on the particle size and hydrophilic properties. Spontaneous particle sorting is directly realized via these discrete and distinctive paths for different particles. The deformation of the soap membrane facilitates 1D/2D particle organization along the path. This observation represents the discovery of a new spontaneous order phenomenon in soap film systems and provides a new energy-free approach for particle separation and soft colloidal crystal assembly.
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Solar-blind ultraviolet (SBUV) to near-infrared (NIR) broadband photodetectors (BB-PD) have important applications in environmental monitoring and other applications. However, it is challenging to prepare SBUV-IR photosensitive materials via simple steps and to construct SBUV-IR broadband devices for multiplex detection with high sensitivity at different wavelengths. Here, self-powered and broadband photodetectors using a high-performance mixed dimensional Sb2O3 nanorod 1-dimension (1D)/monodisperse microdiamond-like PdTe2 3-dimension (3D)/Si (3D) heterojunction for multiplex detection of environmental pollutants with high sensitivity at broadband wavelength are developed. The 1D/3D mixed dimensional Sb2O3/PdTe2/Si structure combines the advantages of strong light absorption, high carrier transport efficiency of 1D Sb2O3 nanorods, and expansion of interface barrier caused by 3D microdiamond-like PdTe2 interlayer to improve the photocurrent density and self-powered ability. The efficient photogenerated charge separation enables anon/off ratio of more than 5 × 106. The device exhibits excellent photoelectric properties from 255 to 980 nm with the responsivity from 4.56 × 10-2 to 6.55 × 10-1 AW-1, the detectivity from 2.36 × 1012 to 3.39 × 1013 Jones, and the sensitivity from 3.90 × 107 to 1.10 × 1010 cm2 W-1 without external bias. Finally, the proposed device is applied for the multiplex monitoring of environmental pollution gases NO2 with the detection limit of 200 ppb and PM2.5 particles at mild pollution at broadband wavelength. The proposed BB-PD has great potential for multiplex detection of environmental pollutants and other analytes at broadband wavelength.
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INTRODUCTION AND OBJECTIVES: As a fatal clinical syndrome, acute liver failure (ALF) is characterized by overwhelming liver inflammation and hepatic cell death. Finding new therapeutic methods has been a challenge in ALF research. VX-765 is a known pyroptosis inhibitor and has been reported to prevent damage in a variety of diseases by reducing inflammation. However, the role of VX-765 in ALF is still unclear. MATERIALS AND METHODS: ALF model mice were treated with D-galactosamine (D-GalN) and lipopolysaccharide (LPS). LO2 cells were stimulated with LPS. Thirty subjects were enrolled in clinical experiments. The levels of inflammatory cytokines, pyroptosis-associated proteins and peroxisome proliferator-activated receptor α (PPARα) were detected using quantitative reverse transcription-polymerase chain reaction (qRTâPCR), western blotting and immunohistochemistry. An automatic biochemical analyzer was used to determine the serum aminotransferase enzyme levels. Hematoxylin and eosin (HE) staining was used to observe the pathological features of the liver. RESULTS: With the progression of ALF, the expression levels of interleukin (IL) -1ß, IL-18, caspase-1, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased. VX-765 could reduce the mortality rate of ALF mice, relieve liver pathological damage, and reduce inflammatory responses to protect against ALF. Further experiments showed that VX-765 could protect against ALF through PPARα, and this protective effect against ALF was reduced in the context of PPARα inhibition. CONCLUSIONS: As ALF progresses, inflammatory responses and pyroptosis deteriorate gradually. VX-765 can inhibit pyroptosis and reduce inflammatory responses to protect against ALF by upregulating PPARα expression, thus providing a possible therapeutic strategy for ALF.
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Fallo Hepático Agudo , PPAR alfa , Ratones , Animales , PPAR alfa/genética , PPAR alfa/metabolismo , Piroptosis , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/prevención & control , Hígado/patología , Inflamación/prevención & control , Inflamación/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND AIMS: Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. METHODS: RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance. RESULTS: LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. CONCLUSIONS: LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Histona Demetilasas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Oxaliplatino/uso terapéutico , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción Sp1/metabolismo , Animales , Apoptosis , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Desmetilación , Resistencia a Antineoplásicos/genética , Células Hep G2 , Humanos , Inmunoprecipitación , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Estrés Oxidativo , ARN Largo no Codificante/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The global outbreaks of deadly infectious diseases caused by pathogenic microorganisms have threatened public health worldwide and significantly motivated scientists to satisfy an urgent need for a rapid and accurate detection of pathogens. Traditionally, the culture-based technique is considered as the gold standard for pathogen detection, yet it has a long turnaround time due to the overnight culturing and pathogen isolation. Alternatively, nucleic acid amplification tests provide a relatively shorter turnaround time to identify whether pathogens exist in individuals with high sensitivity and high specificity. In most cases, nucleic acid amplification tests undergo three steps: sample preparation, nucleic acid amplification, and signal transduction. Despite the explosive advancement in nucleic acid amplification and signal transduction technologies, the complex and labor-intensive sample preparation steps remain a bottleneck to create a transformative integrated point-of-care (POC) molecular diagnostic device. Researchers have attempted to simplify and integrate the sample preparations for nucleic acid-based molecular diagnostic devices with innovative progress in integration strategies, engineered materials, reagent storages, and fluid actuation. Therefore, understanding the know-how and obtaining truthful knowledge of existing integrated POC molecular diagnostic devices comprising sample preparations, nucleic acid amplification, and signal transduction can generate innovative solutions to achieve personalized precision medicine and improve global health.In this Account, we discuss the challenges of automated sample preparation solutions integrated with nucleic acid amplification and signal transduction for rapid and precise home diagnostics. Blood, nasal swab, saliva, urine, and stool are emphasized as the most commonly used clinical samples for integrated POC molecular diagnostics of infectious diseases. Even though these five types of samples possess relatively correlated biomarkers due to the human body's circulatory system, each shows unique properties and exclusive advantages for molecular diagnostics in specific situations, which are included in this Account. We examine different integrated POC devices for sample preparation, which includes pathogen isolation and enrichment from the crude sample and nucleic acid purification from isolated pathogens. We present the promising on-chip integration approaches for nucleic acid amplification. We also investigate the on-chip integration methods for reagent storage, which is crucial to simplify the manual operation for end-users. Finally, we present several integrated POC molecular diagnostic devices for infectious diseases. The integrated sample preparation and nucleic acid amplification approach reviewed here can potentially impact the next generation of POC molecular home diagnostic chips, which will significantly impact public health, emergency medicine, and global biosecurity.
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Patología Molecular , Sistemas de Atención de Punto , Bioaseguramiento , Humanos , Técnicas de Amplificación de Ácido NucleicoRESUMEN
Edaravone, an antioxidant protective agent, has anti-cerebral ischemic reperfusion injury (CIRI) effects, but its anti-CIRI mechanism is unclear. The aim of this study is to investigate the anti-CIRI mechanism of edaravone based on the nuclear factor-E2-related factor 2 (Nrf2)/ferroportin (FPN) pathway that regulates ferroptosis-mediated cerebral ischemia-reperfusion injury. We evaluated the brain injury by constructing a middle cerebral artery occlusion and reperfusion (MCAO/R) model in rats. The results showed that cerebral infarct volume and neurological impairment scores were increased in cerebral ischemia-reperfusion rats, with impaired sensorimotor ability; furthermore, brain tissue glutathione (GSH) content was decreased, Fe2+, malondialdehyde (MDA) and lipide peroxide (LPO) content were increased, and the expression level of glutathione peroxidase 4 (GPX4), a key protein of ferroptosis, was also decreased. Meanwhile, the Nrf2 expression level was increased and the FPN expression level was decreased after cerebral ischemia-reperfusion, while the levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were increased. However, edaravone exhibited a protective effect on cerebral infarct and neurological and sensorimotor function in relevant tests. In addition, we also found that edaravone decreased the contents of Fe2+, MDA, and LPO in the brain tissue of MCAO/R rats and increased GSH content to inhibit ferroptosis. Furthermore, Western blot showed that after treatment with edaravone, the expression of Nrf2, GPX4, and FPN was up-regulated, the nuclear location of Nrf2 was increased, and the levels of inflammation-related indicators IL-6, IL-1ß, TNF-α, and MPO were lower than in the MCAO/R group. Our results demonstrated that edaravone inhibits ferroptosis to attenuate CIRI, probably through the activation of the Nrf2/FPN pathway.
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Isquemia Encefálica , Ferroptosis , Daño por Reperfusión , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Proteínas de Transporte de Catión , Edaravona/farmacología , Glutatión , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Daño por Reperfusión/metabolismoRESUMEN
The multifunctional human DNA2 (hDNA2) nuclease/helicase is required to process DNA ends for homology-directed recombination repair (HDR) and to counteract replication stress. To participate in these processes, hDNA2 must localize to the nucleus and be recruited to the replication or repair sites. However, because hDNA2 lacks the nuclear localization signal that is found in its yeast homolog, it is unclear how its migration into the nucleus is regulated during replication or in response to DNA damage. Here, we report that the E3 ligase TRAF6 binds to and mediates the K63-linked polyubiquitination of hDNA2, increasing the stability of hDNA2 and promoting its nuclear localization. Inhibiting TRAF6-mediated polyubiquitination abolishes the nuclear localization of hDNA2, consequently impairing DNA end resection and HDR. Thus, the current study reveals a mechanism for the regulation of hDNA2 localization and establishes that TRAF6-mediated hDNA2 ubiquitination activates DNA repair pathways to maintain nuclear genome integrity.
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Núcleo Celular/metabolismo , ADN Helicasas/metabolismo , Genoma Humano/genética , Inestabilidad Genómica , Poliubiquitina/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , ADN/genética , ADN/metabolismo , Daño del ADN , ADN Helicasas/genética , Reparación del ADN , Células HEK293 , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular , Unión Proteica , Interferencia de ARN , Factor 6 Asociado a Receptor de TNF/genética , UbiquitinaciónRESUMEN
OBJECTIVE: Regulatory T cells (Tregs) induce immune tolerance in patients after organ transplantation. Various immunosuppressors can affect Tregs function through different mechanisms. PD-1 and TIGIT are important receptors on Tregs surface. Here, we investigated the effects of Tacrolimus and mycophenolate mofetil (MMF) on the inhibitory function of Tregs and explored the regulatory mechanism in patients after liver transplantation. METHODS: Thirty patients that underwent a liver transplant and 15 healthy people were enrolled. Fifteen patients received Tacrolimus only, and 15 received a combination of Tacrolimus and MMF. Tregs and effector T cells (Teffs) were isolated using magnetic beads and were mixed at different ratios of 0:1, 1:4, 1:2 and 1:1. An inhibition assay was performed by adding anti-PD-1 and anti-TIGIT when the mixture ratio was 1:1. The Tregs inhibition rate was determined and the levels of IFN-γ and TNF-α were measured. RESULTS: As the ratios of Tregs to Teffs in the mixture increased, the Tregs inhibition rate increased and the levels of IFN-γ and TNF-α decreased. At each mixture ratio, Tacrolimus + MMF group had the highest Tregs inhibition rate compared to Tacrolimus and control group. At the specific mixture ratio of 1:1, the addition of both anti- PD-1 and anti-TIGIT led to lower Tregs inhibition rate and higher IFN-γ and TNF-α levels in all three groups as opposed to the addition of each antibody separately. Additionally, both the decrease in the Tregs inhibition rate and the increase in the IFN-γ and TNF-α levels were the most for Tacrolimus + MMF group among all cases, either adding antibodies alone or mixed. CONCLUSION: Tacrolimus and MMF enhanced the function of Tregs by synergistically affecting PD-1 and TIGIT in liver transplant patients.
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Trasplante de Hígado/tendencias , Ácido Micofenólico/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores Inmunológicos/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Tacrolimus/administración & dosificación , Adulto , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of HCC resistance to sorafenib remain unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC-3), overexpressed in HCC patients, plays an important oncogenic role in HCC; however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that ACTR was one of the most upregulated genes in sorafenib-resistant HCC xenografts. ACTR increases sorafenib resistance through regulation of the Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and is associated with poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c-Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Resistencia a Antineoplásicos/fisiología , Neoplasias Hepáticas/metabolismo , Coactivador 3 de Receptor Nuclear/metabolismo , Sorafenib/farmacología , Animales , Carcinoma Hepatocelular/patología , Glucólisis/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
During nuclear DNA replication, proofreading-deficient DNA polymerase α (Pol α) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol δ or Pol ε. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol α replication errors in a MutSα-dependent, MutLα-independent mismatch repair process we call Pol α-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5' ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism.
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Reparación de la Incompatibilidad de ADN , ADN Polimerasa I/metabolismo , ADN/metabolismo , Endonucleasas de ADN Solapado/metabolismo , Proteína MutS de Unión a los Apareamientos Incorrectos del ADN/metabolismo , Animales , Células Cultivadas , Reparación de la Incompatibilidad de ADN/genética , Replicación del ADN/genética , Embrión de Mamíferos , Femenino , Endonucleasas de ADN Solapado/clasificación , Endonucleasas de ADN Solapado/genética , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Ratones Transgénicos , Proteína MutS de Unión a los Apareamientos Incorrectos del ADN/genética , Saccharomyces cerevisiaeRESUMEN
BACKGROUND: The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is widely used as a complementary screening tool for dementia. However, there are few studies concerning the efficacy of the IQCODE for assessing the severity of cognitive impairments in patients with Alzheimer's disease (AD). We aimed to evaluate the efficacy of the IQCODE for assessing the severity of dementia in patients with AD. METHODS: According to the clinical dementia rating (CDR), 394 patients with AD were enrolled and classified into three groups: mild, moderate and severe groups. The IQCODE scores of each group were determined by interviewing the informants with the short version of the 16-item IQCODE. The correlations of the IQCODE score with the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale (DRS) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were analysed. Statistical analyses were conducted to examine the differences in the IQCODE scores among the three groups. RESULTS: The validity coefficients of the IQCODE with the MMSE, DRS and ADAS-Cog were - 0.528, - 0.436, and 0.477, respectively. The sensitivity was 66.1%, and the specificity was 59.8% when using a cut-off score of 65 to discriminate between mild-moderate dementia. When 75 was used as the threshold between moderate-severe dementia, the sensitivity and the specificity were 73.9 and 67.7%, respectively. CONCLUSIONS: The IQCODE is moderately effective for assessing the severity of cognitive impairment in patients with AD.
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Enfermedad de Alzheimer/complicaciones , Cognición/fisiología , Disfunción Cognitiva/epidemiología , Tamizaje Masivo/métodos , Encuestas y Cuestionarios , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , China/epidemiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana EdadRESUMEN
Efficient delivery of genes and therapeutic agents to the interior of the cell is critical for modern biotechnology. Herein, a new type of chemical-free cell poration method-hypersonic poration-is developed to improve the cellular uptake, especially the nucleus uptake. The hypersound (≈GHz) is generated by a designed piezoelectric nano-electromechanical resonator, which directly induces normal/shear stress and "molecular bombardment" effects on the bilayer membranes, and creates reversible temporal nanopores improving the membrane permeability. Both theory analysis and cellular uptake experiments of exogenous compounds prove the high delivery efficiency of hypersonic poration. Since target molecules in cells are accumulated with the treatment, the delivered amount can be controlled by tuning the treatment time. Furthermore, owing to the intrinsic miniature of the resonator, localized drug delivery at a confined spatial location and tunable arrays of the resonators that are compatible with multiwell plate can be achieved. The hypersonic poration method shows great delivery efficacy combined with advantage of scalability, tunable throughput, and simplification in operation and provides a potentially powerful strategy in the field of molecule delivery, cell transfection, and gene therapy.
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BACKGROUND: Drug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers. METHODS: To reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients. RESULTS: We observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients. CONCLUSION: Altogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/genética , Endonucleasas de ADN Solapado/genética , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción YY1/metabolismo , Antineoplásicos/farmacología , Secuencia de Bases , Sitios de Unión , Neoplasias de la Mama/mortalidad , Línea Celular , Secuencia Conservada , Femenino , Humanos , Estimación de Kaplan-Meier , Motivos de Nucleótidos , Pronóstico , Regiones Promotoras Genéticas , Unión ProteicaRESUMEN
Zinc oxide (ZnO) nanostructures are promising candidates as electronic components for biological and chemical applications. In this study, ZnO ultra-fine nanowire (NW) and nanoflake (NF) hybrid structures have been prepared by Au-assisted chemical vapor deposition (CVD) under ambient pressure. Their surface morphology, lattice structures, and crystal orientation were investigated by scanning electron microscopy (SEM), x-ray diffraction (XRD), and transmission electron microscopy (TEM). Two types of ZnO nanostructures were successfully integrated as gate electrodes in extended-gate field-effect transistors (EGFETs). Due to the amphoteric properties of ZnO, such devices function as pH sensors. We found that the ultra-fine NWs, which were more than 50 µm in length and less than 100 nm in diameter, performed better in the pH sensing process than NW-NF hybrid structures because of their higher surface-to-volume ratio, considering the Nernst equation and the Gouy-Chapman-Stern model. Furthermore, the surface coating of (3-Aminopropyl)triethoxysilane (APTES) protects ZnO nanostructures in both acidic and alkaline environments, thus enhancing the device stability and extending its pH sensing dynamic range.
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Passively Q-switched mode-locking performance of Nd:GdTaO4 crystal using molybdenum disulfide (MoS2) as a saturable absorber at 1066 nm was demonstrated for the first time. The MoS2 saturable absorber was prepared simply by transferring the MoS2 suspension onto a quartz substrate. By inserting the MoS2 saturable absorber into the Nd:GdTaO4 laser, stable Q-switched modelocked operation can be achieved. At the pump power of 4 W, the maximum average output power of 0.156 W was obtained with the optical conversion efficiency of 3.9%.
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Extracellular vesicles (EVs) are promising tools for the early diagnosis of diseases, and bacterial membrane vesicles (MVs) are especially important in health and environment monitoring. However, detecting EVs or bacterial MVs presents significant challenges for the clinical translation of EV-based diagnostics. In this Review, we provide a comprehensive discussion on the basics of nanoplasmonic sensing and emphasize recent developments in nanoplasmonics-based optical sensors to effectively identify EVs or bacterial MVs. We explore various nanoplasmonic sensors tailored for EV or bacterial MV detection, emphasizing the application of localized surface plasmon resonance through gold nanoparticles and their multimers. Additionally, we highlight advanced EV detection techniques based on surface plasmon polaritons using plasmonic thin film and nanopatterned structures. Furthermore, we evaluate the improved detection capability of surface-enhanced Raman spectroscopy in identifying and classifying these vesicles, aided by plasmonic nanostructures. Nanoplasmonic sensing techniques have remarkable precision and sensitivity, making them a potential tool for accurate EV detection in clinical applications, facilitating point-of-care molecular diagnostics. Finally, we summarize the challenges associated with nanoplasmonic EV or bacterial MV sensors and offer insights into potential future directions for this evolving field.
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An improved electroosmotic method is proposed in this paper to enhance the non-uniform effect and efficiency of electroosmotic process. Such method is electroosmotic flow with injection of calcium chloride through the anode, followed by injection through the central tube (a tube at the midpoint between the anode and the cathode) with a suitable time interval between injections. Experimental results indicate that using this method can significantly improve the non-uniform reduction in water content throughout the soil, mitigate the formation of cracks in the anode section, and therefore considerably inhibit the increase in the electric resistance. After treatment, the drained water could be raised to 3.59 times more than that of pure electroosmotic flow, and 1.3 times that of simultaneous injection through both the anode and the central tube with considerably slight increase in power consumption. Moreover, the area of cementation was also expanded, approximately twice larger than that of pure electroosmotic flow and one and a half that of simultaneous injection. It is also worth noting that the proposed method performs better with the same power consumption. The results demonstrate that electroosmotic flow with a suitable time interval between injections could improve the efficiency of electroosmotic process and expand the treatment region in soils, hence can be a promising and economic technique for soil improvement in practical engineering.
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Constitutive activation of Hedgehog (Hh) signaling has been implicated in many cancers including hepatocellular carcinoma (HCC). Among them, the terminal glioma-associated oncogene homolog 1 (Gli1) regulates the expression of critical genes in the Hh pathway. The current study aims to evaluate the anti-HCC effect of the Gli1 inhibitor, GANT61. In vitro analysis including cell counting kit-8 (CCK-8) assay, flow cytometry, and migration and invasion assay were adopted to evaluate the effect of GANT61 on HCC cell lines. In vivo, xenograft studies were also performed to verify the effect of GANT61 on HCC. By CCK-8 assay, we found that GANT61 could significantly reduce the growth of HCC cell lines Huh7 and hemophagocytic lymphohistiocytosis (HLE), and their IC50 concentrations were 4.481 and 6.734 µM, respectively. Flow cytometry shows that GANT61 induced cell cycle arrest in the G2/M phase and accelerated apoptosis of both HLE and Huh7 cells. While migration and invasion assay shows that GANT61 weakens cells' migration and invasion ability. Besides that, GANT61 inhibits the expression of Gli1, FoxM1, CyclinD1, and Bcl-2, upregulates the level of Bax protein, and also reverses the epithelial-mesenchymal transition program by downregulating the expression of Vimentin and N-Cadherin and upregulating the expression of epithelial E-Cadherin expression. Furthermore, GANT61 inhibits the growth of subcutaneous xenografts of Huh7 cells in nude mice. Overall, this study suggests that Gli1 is a potential target for therapy and GANT61 shows promising therapeutic potential for future treatment in HCC.