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Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.
Assuntos
Chaperonina com TCP-1 , Macroautofagia , Agregados Proteicos , Animais , Camundongos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Proteínas de Transporte/metabolismo , Chaperonina com TCP-1/metabolismo , Proteína Sequestossoma-1/metabolismoRESUMO
Lung cancer is a major contributor to cancer deaths worldwide and is on the rise. Although surgical resection has been widely used as a standard therapy for lung cancer patients, the relapse rate after surgery is high. It is still unclear whether there is a potential drug that can reduce the probability of postsurgical recurrence in lung cancer patients. We used 5 typical lung cancer cell lines as well as 41 lung cancer tissue samples and paracancer tissue samples to investigate the expression levels of interferon regulatory factor 6 (IRF6) and tumor suppressor candidate 2 (TUSC2, also known as FUS1). We also treated lung cancer cells (H322 and A549) with different concentrations of sevoflurane to study its influence on lung cancer cell tumorigenesis. Lentivirus-mediated gain-of-function studies of IRF6 and FUS1 were applied to validate the role of IRF6 and FUS1 in lung cancer. Next, we used short hairpin RNA-mediated loss of function of IRF6 and luciferase, chromatin immunoprecipitation assays to validate the regulatory role of IRF6 on FUS1. Our findings reported that IRF6 was upregulated in lung cancer tissues, while FUS1 was downregulated. Functional assays revealed that sevoflurane inhibits lung cancer development by downregulating IRF6 expression. Luciferase and chromatin immunoprecipitation-quantitative real-time PCR assays uncovered that IRF6 represses FUS1 transcriptional expression in lung cancer cells. We have shown that sevoflurane prevents lung cancer development by downregulating IRF6 to stimulate FUS1 transcription, indicating that sevoflurane can be used as the potential anesthetic drug in surgical resection to reduce postoperative tumor relapse in lung cancer patients.
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Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon , Neoplasias Pulmonares , Sevoflurano , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sevoflurano/farmacologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Animais , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Feminino , Células A549RESUMO
Ultrasound (US)-mediated piezocatalytic tumor therapy has attracted much attention due to its notable tissue-penetration capabilities, noninvasiveness, and low oxygen dependency. Nevertheless, the efficiency of piezocatalytic therapy is limited due to an inadequate piezoelectric response, low separation of electron-hole (e--h+) pairs, and complex tumor microenvironment (TME). Herein, an ultrathin two-dimensional (2D) sulfur-vacancy-engineered (Sv-engineered) Cu@SnS2-x nanosheet (NS) with an enhanced piezoelectric effect was constructed via the heterovalent substitution strategy of Sn4+ by Cu2+. The introduction of Cu2+ ion not only causes changes in the crystal structure to increase polarization but also generates rich Sv to decrease band gap from 2.16 to 1.62 eV and inhibit e--h+ pairs recombination, collectively leading to the highly efficient generation of reactive oxygen species under US irradiation. Moreover, Cu@SnS2-x shows US-enhanced TME-responsive Fenton-like catalytic activity and glutathione depletion ability, further aggravating the oxidative stress. Both in vitro and in vivo results prove that the Sv-engineered Cu@SnS2-x NSs can significantly kill tumor cells and achieve high-efficiency piezocatalytic tumor therapy in a biocompatible manner. Overall, this study provides a new avenue for sonocatalytic therapy and broadens the application of 2D piezoelectric materials.
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Cobre , Nanoestruturas , Enxofre , Cobre/química , Enxofre/química , Humanos , Camundongos , Animais , Nanoestruturas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sulfetos/química , Microambiente Tumoral/efeitos dos fármacos , Compostos de Estanho/química , Catálise , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Neoplasias/tratamento farmacológico , Terapia por Ultrassom , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
BACKGROUND: Skin cutaneous melanoma (SKCM) is an aggressive and life-threatening skin cancer. G-protein coupled receptor 143 (GPR143) belongs to the superfamily of G protein-coupled receptors. METHODS: We used the TCGA, GTEx, CCLE, and the Human Protein Atlas databases to examine the mRNA and protein expression of GPR143. In addition, we performed a survival analysis and evaluated the diagnostic efficacy using the Receiver-Operating Characteristic (ROC) curve. Through CIBERSORT, R programming, TIMER, Gene Expression Profiling Interactive Analysis, Sangerbox, and Kaplan-Meier plotter database analyses, we explored the relationships between GPR143, immune infiltration, and gene marker expression of immune infiltrated cells. Furthermore, we investigated the proteins that potentially interact with GPR143 and their functions using R programming and databases including STRING, GeneMANIA, and GSEA. Meanwhile, the cBioPortal, UALCNA, and the MethSurv databases were used to examine the genomic alteration and methylation of GPR143 in SKCM. The Connectivity Map database was used to discover potentially effective therapeutic molecules against SKCM. Finally, we conducted cell experiments to investigate the potential role of GPR143 in SKCM. RESULTS: We demonstrated a significantly high expression level of GPR143 in SKCM compared with normal tissues. High GPR143 expression and hypomethylation status of GPR143 were associated with a poorer prognosis. ROC analysis showed that the diagnostic efficacy of the GPR143 was 0.900. Furthermore, GPR143 expression was significantly correlated with immune infiltration in SKCM. We identified 20 neighbor genes and the pathways they enriched were anabolic process of pigmentation, immune regulation, and so on. Genomic alteration analysis revealed significantly different copy number variations related to GPR143 expression in SKCM, and shallow deletion could lead to high expression of GPR143. Ten potential therapeutic drugs against SKCM were identified. GPR143 knockdown inhibited melanoma cell proliferation, migration, and colony formation while promoting apoptosis. CONCLUSIONS: Our findings suggest that GPR143 serves as a novel diagnostic and prognostic biomarker and is associated with the progression of SKCM.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Neoplasias Cutâneas/genética , Variações do Número de Cópias de DNA , Apoptose , Biologia Computacional , Proteínas do Olho , Glicoproteínas de MembranaRESUMO
Lithium metal batteries (LMBs) with high-voltage nickel-rich cathodes show great potential as energy storage devices due to their exceptional capacity and power density. However, the detrimental parasitic side reactions at the cathode electrolyte interface result in rapid capacity decay. Herein, a polymerizable electrolyte additive, pyrrole-1-propionic acid (PA), which can be in situ electrochemically polymerized on the cathode surface and involved in forming cathode electrolyte interphase (CEI) film during cycling is proposed. The formed CEI film prevents the formation of microcracks in LiNi0.8Co0.1Mn0.1O2 (NCM811) secondary particles and mitigates parasitic reactions. Additionally, the COO- anions of PA promote the acceleration of Li+ transport from cathode particles and increase charging rates. The Li||NCM811 batteries with PA in the electrolyte exhibit a high capacity retention of 83.83% after 200 cycles at 4.3 V, and maintain 80.88% capacity after 150 cycles at 4.6 V. This work provides an effective strategy for enhancing interface stability of high-voltage nickel-rich cathodes by forming stable CEI film.
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Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).
Assuntos
Fármacos Anti-HIV , HIV-1 , Produtos do Gene vif do Vírus da Imunodeficiência Humana , HIV-1/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Descoberta de Drogas , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Proteólise/efeitos dos fármacos , Simulação de Dinâmica MolecularRESUMO
Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.
Assuntos
Anticonvulsivantes , Bloqueadores dos Canais de Cálcio , Cardiomegalia , Quinase 3 da Glicogênio Sintase , Complexo de Endopeptidases do Proteassoma , Zonisamida , Animais , Camundongos , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Cardiomegalia/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/farmacologia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Zonisamida/farmacologia , Zonisamida/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêuticoRESUMO
Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.
Assuntos
Antioxidantes , Arsênio , Diferenciação Celular , Fígado , Mitofagia , Compostos Organofosforados , Proteínas Quinases , Animais , Mitofagia/efeitos dos fármacos , Camundongos , Fígado/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Proteínas Quinases/metabolismo , Diferenciação Celular/efeitos dos fármacos , Compostos Organofosforados/toxicidade , Compostos Organofosforados/farmacologia , Arsênio/toxicidade , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Células Dendríticas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Masculino , Linfócitos T Reguladores/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacosRESUMO
CoFe@C was first prepared by calcining the precursor of CoFe-metal-organic framework-74 (CoFe-MOF-74), then an electrochemical sensor for the determination of neohesperidin dihydrochalcone (NHDC) was constructed, which was stemmed from the novel CoFe@C/Nafion composite film modified glassy carbon electrode (GCE). The CoFe@C/Nafion composite was verified by field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). Electrochemical impedance spectroscopy (EIS) was used to evaluate its electrical properties as a modified material for an electrochemical sensor. Compared with CoFe-MOF-74 precursor modified electrode, CoFe@C/Nafion electrode exhibited a great synergic catalytic effect and extremely increased the oxidation peak signal of NHDC. The effects of various experimental conditions on the oxidation of NHDC were investigated and the calibration plot was tested. The results bespoken that CoFe@C/Nafion GCE has good reproducibility and anti-interference under the optimal experimental conditions. In addition, the differential pulse current response of NHDC was linear with its concentration within the range 0.08 ~ 20 µmol/L, and the linear regression coefficient was 0.9957. The detection limit was as low as 14.2 nmol/L (S/N = 3). In order to further verify the feasibility of the method, it was successfully used to determine the content of NHDC in Chinese medicine, with a satisfactory result, good in accordance with that of high performance liquid chromatography (HPLC).
Assuntos
Chalconas , Cobalto , Técnicas Eletroquímicas , Eletrodos , Limite de Detecção , Estruturas Metalorgânicas , Cobalto/química , Estruturas Metalorgânicas/química , Chalconas/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Hesperidina/análogos & derivados , Hesperidina/análise , Hesperidina/química , Polímeros de Fluorcarboneto/química , Oxirredução , Carbono/química , Reprodutibilidade dos Testes , Ferro/químicaRESUMO
Aqueous zinc-metal batteries are prospective energy storge devices due to their intrinsically high safety and cost effectiveness. Yet, uneven deposition of zinc ions in electrochemical reduction and side reactions at the anode interface significantly hinder their development and application. Here, we propose a solvation-interface attenuation strategy enabled by a frustrated tertiary amine amphiphilic dipolymer electrolyte additive. The configuration of superhydrophilic segments with covalently bonded lipophilic spacers enables coupled steric hindrance/coordination, which establishes a balanced push-pull dynamic of dipolymer-H2O-Zn2+. Such interplay reconstructs the solvation structure of Zn2+ and allows the formation of a stable dipolymer-inorganic hybrid solid electrolyte interface (SEI) layer. This SEI layer effectively shields the zinc-metal anode from water and anions, significantly reducing side reactions. In addition, the dipolymer adsorbed at the zinc-metal anode interface regulates the interfacial electrochemical reduction kinetics and ensures uniform zinc deposition. As a result, the Zn-Zn symmetric cells with dipolymer-containing electrolyte exhibit remarkable cycling stability exceeding 5800â h (242â days). The Zn-NVO batteries and Zn-AC hybrid ion supercapacitors also deliver stable cycling for up to 1440â h (60â days) with high-capacity retention over 80 %. This research demonstrates the potential to facilitate the development and commercialization of zinc-based energy storage devices.
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Sonodynamic therapy (SDT) has garnered growing interest owing to its high tissue penetration depth and minimal side effects. However, the lack of efficient sonosensitizers remains the primary limiting factor for the clinical application of this treatment method. Here, defect-repaired graphene phase carbon nitride (g-C3N4) nanosheets are prepared and utilized for enhanced SDT in anti-tumor treatment. After defect engineering optimization, the bulk defects of g-C3N4 are significantly reduced, resulting in higher crystallinity and exhibiting a polyheptazine imide (PHI) structure. Due to the more extended conjugated structure of PHI, facilitating faster charge transfer on the surface, it exhibits superior SDT performance for inducing apoptosis in tumor cells. This work focuses on introducing a novel carbon nitride nanomaterial as a sonosensitizer and a strategy for optimizing sonosensitizer performance by reducing bulk defects.
Assuntos
Neoplasias , Terapia por Ultrassom , Humanos , Nitrilas/química , Neoplasias/tratamento farmacológico , Apoptose , Espécies Reativas de OxigênioRESUMO
A honeycomb-ring hybrid random mesh structure is designed to achieve low stray light performance. The honeycomb-ring hybrid random mesh comprises the random honeycomb and random ring, achieving two random superpositions in the structure distribution. The stray light distribution is very low by the combination design with different random hybrid structures. In order to illustrate the advantages of the hybrid random structure, we design a random honeycomb network by randomly offsetting vertices. At the same time, for the random honeycomb structure, we replace each vertex with the ring structure with the size of the ring randomly controlled. Thus, the corresponding honeycomb-ring hybrid random structure is obtained. Compared with the random honeycomb, the maximal normalized high-order diffraction energy of the honeycomb-ring hybrid random mesh is about a 62.85% drop, and the shielding performance is increased by about 50%. At the same time, the optical transmittance remains nearly unchanged. Due to the enjoyable property of the designed honeycomb-ring hybrid random mesh, a sample was prepared for performance verification. The measurement results show that it achieves eminent diffraction pattern distribution with the maximal normalized high-order diffraction energy of about -31.8â dB. At the same time, the average optical transmittance exceeds 86%, and the electromagnetic shielding effectiveness (SE) in the Ku band is greater than 26â dB. Based on the fine photoelectric performance of the honeycomb-ring hybrid random mesh structure, it has great application potential for high-quality optical windows.
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In this Letter, an ultracompact terahertz (THz) mode division multiplexer based on THz spoof surface plasmon polaritons (SPPs) is proposed. Compared with traditional optical multiplexing devices, the proposed mode multiplexer can be designed with a reduced footprint by exploiting more degrees of freedom in the parameters of the unit cell, namely a rectangular metallic pillar. The ultracompact mode division multiplexer can simultaneously support the propagation of four mode channels: the TM0, TM1, TM2, and TM3 modes. Then, we numerically evaluate the performance of a cascaded plasmonic mode division circuit composed of a mode multiplexer and demultiplexer. The cross talk and excess loss of the whole circuit are lower than -15â dB and 3.7â dB, respectively, for all four mode channels at a center frequency of 0.65 THz. The footprint of the whole device is about 27 × 2.3 mm and the length of each coupling region is about 2.7 mm. For the first time, to the best of our knowledge, a mode division multiplexer based on THz spoof SPPs is reported, which will form core devices for future THz on-chip multimode communication systems.
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Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Ciclo Celular , Divisão Celular , Quinase 4 Dependente de CiclinaRESUMO
Large White pigs are extensively utilized in China for their remarkable characteristics of rapid growth and the high proportion of lean meat. The economic traits of pigs, comprising reproductive and meat quality traits, play a vital role in swine production. In this study, 2295 individuals, representing three different genetic backgrounds Large White pig populations were used: 500 from the Canadian line, 295 from the Danish line, and 1500 from the American line. The GeneSeek 50K GGP porcine HD array was employed to genotype the three pig populations. Firstly, genomic selective signature regions were identified using the pairwise fixation index (FST) and locus-specific branch length (LSBL). By applying a top 1% threshold for both parameters, a total of 888 candidate selective windows were identified, harbouring 1571 genes. Secondly, the investigation of regions of homozygosity (ROH) was performed utilizing the PLINK software. In total, 25 genomic regions exhibiting a high frequency of ROHs were detected, leading to the identification of 1216 genes. Finally, the identified potential functional genes from candidate genomic regions were annotated, and several important candidate genes associated with reproductive traits (ADCYAP1, U2, U6, CETN1, Thoc1, Usp14, GREB1L, FGF12) and meat quality traits (MiR-133, PLEKHO1, LPIN2, SHANK2, FLVCR1, MYL4, SFRP1, miR-486, MYH3, STYX) were identified. The findings of this study provide valuable insights into the genetic basis of economic traits in Large White pigs and may have potential use in future pig breeding programs.
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Genômica , MicroRNAs , Animais , Suínos/genética , Canadá , Homozigoto , GenótipoRESUMO
Due to rising living standards, it is important to improve wheat's quality traits by adjusting its storage protein genes. The introduction or locus deletion of high molecular weight subunits could provide new options for improving wheat quality and food safety. In this study, digenic and trigenic wheat lines were identified, in which the 1Dx5+1Dy10 subunit, and NGli-D2 and Sec-1s genes were successfully polymerized to determine the role of gene pyramiding in wheat quality. In addition, the effects of ω-rye alkaloids during 1BL/1RS translocation on quality were eliminated by introducing and utilizing 1Dx5+1Dy10 subunits through gene pyramiding. Additionally, the content of alcohol-soluble proteins was reduced, the Glu/Gli ratio was increased and high-quality wheat lines were obtained. The sedimentation values and mixograph parameters of the gene pyramids under different genetic backgrounds were significantly increased. Among all the pyramids, the trigenic lines in Zhengmai 7698, which was the genetic background, had the highest sedimentation value. The mixograph parameters of the midline peak time (MPT), midline peak value (MPV), midline peak width (MPW), curve tail value (CTV), curve tail width (CTW), midline value at 8 min (MTxV), midline width at 8 min (MTxW) and midline integral at 8 min (MTxI) of the gene pyramids were markedly enhanced, especially in the trigenic lines. Therefore, the pyramiding processes of the 1Dx5+1Dy10, Sec-1S and NGli-D2 genes improved dough elasticity. The overall protein composition of the modified gene pyramids was better than that of the wild type. The Glu/Gli ratios of the type I digenic line and trigenic lines containing the NGli-D2 locus were higher than that of the type II digenic line without the NGli-D2 locus. The trigenic lines with Hengguan 35 as the genetic background had the highest Glu/Gli ratio among the specimens. The unextractable polymeric protein (UPP%) and Glu/Gli ratios of the type II digenic line and trigenic lines were significantly higher than those of the wild type. The UPP% of the type II digenic line was higher than that of the trigenic lines, while the Glu/Gli ratio was slightly lower than that of the trigenic lines. In addition, the celiac disease (CD) epitopes' level of the gene pyramids significantly decreased. The strategy and information reported in this study could be very useful for improving wheat processing quality and reducing wheat CD epitopes.
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Doença Celíaca , Triticum , Triticum/genética , Triticum/metabolismo , Doença Celíaca/genética , Translocação Genética , Fenótipo , Epitopos/metabolismo , Glutens/químicaRESUMO
Ambient air pollution is a major public health concern impacting all aspects of human health. There is a lack of studies on the impact of ambient air pollution on health-related quality of life (HRQoL) of older Chinese adults. Our study answers two questions: How concentrations of ambient air pollutants are associated with HRQoL among older adults in China and, second, what are the possible mechanisms through which ambient air pollution affects HRQoL. From the 2018 National Health Service Survey, we sampled 5717 aged 65 years or older residents for the eastern province of Shandong, China. Data on individual exposures to PM2.5 and PM10 (particulate matter with diameter less than or equal to 2.5 µm and 10 µm) and sulfur dioxide (SO2) were collected from the ChinaHighAirPollutants (CHAP) datasets. Mixed-effects Tobit regression models and mixed-effects ordered Probit regression models were employed to examine the associations of long-term exposure to ambient air pollution with the European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) scale comprising mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Socioeconomic, demographic and behavioral factors relating to HRQoL were also examined. The results show that for each 1 µg/m3 increase, EQ-5D-3L scores fell 0.002 for PM2.5; 0.001 for PM10 and 0.002 for SO2. Long term exposure to PM2.5, PM10 and SO2 were also associated with increased prevalence of pain/discomfort and anxiety/depression. The reduced HRQoL effects of ambient air pollution were exacerbated by higher socioeconomic status (affluent, urban and higher level of education). Our findings suggested that HRQoL of older Chinese adults was not only associated with demographic, socioeconomic, and health-related factors, but also negatively correlated with air pollution, especially through increased pain/discomfort and anxiety/depression. The paper proposes policy recommendations.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Humanos , Idoso , Qualidade de Vida , Medicina Estatal , Poluição do Ar/análise , Poluentes Atmosféricos/análise , Material Particulado/análise , China/epidemiologia , Exposição Ambiental/análise , Dióxido de Nitrogênio/análiseRESUMO
The research results are inconsistent that assessing whether the increased obliquity of the distal articular surface of the medial cuneiform leads to an increase in hallux valgus angle. Thus, this study investigated the relationship between distal medial cuneiform obliquity and hallux valgus by measuring various angles in weightbearing anteroposterior radiographs of the foot. In total, 679 feet of 538 patients with the radiographs were included in the study. We measured radiographic parameters including hallux valgus angle, first to second intermetatarsal angle, metatarsus adductus angle, first metatarsus cuneiform angle, distal medial cuneiform angle, and first proximal metatarsal articular angle. The surface morphology (flat or curved) of the first tarsometatarsal joint was also recorded. Our results analysis revealed a weak negative correlation between distal medial cuneiform angle and both hallux valgus angle and first to second intermetatarsal angle, contrary to our assumption. So we believe that distal medial cuneiform angle was relatively constant and it cannot be used as a characteristic angle for quantifying hallux valgus. First metatarsus cuneiform angle was a characteristic indicator of hallux valgus and was positively correlated with its severity (p < .000), indicating that it can be used to measure the size of hallux valgus. It can also be used as a reference factor for the first metatarsal osteotomy in clinical bunion orthopedics. First tarsometatarsal joint morphology was unrelated to hallux valgus, whereas metatarsus adductus angle, and first proximal metatarsal articular angle should be considered in hallux valgus.
Assuntos
Joanete , Hallux Valgus , Hallux , Ossos do Metatarso , Metatarso Varo , Humanos , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Hallux/cirurgia , Ossos do Metatarso/diagnóstico por imagem , Ossos do Metatarso/cirurgia , OsteotomiaRESUMO
A complex dynamic interplay exists between epidemic transmission and vaccination, which is significantly influenced by human behavioral responses. We construct a research framework combining both the function modeling of the cumulative global COVID-19 information and limited individuals' information processing capacity employing the Gompertz model for growing processes. Meanwhile, we built a function representing the decision to get vaccinated following benefit-cost analysis considered the choices made by people in each scenario have an influence from altruism, free-riding and immunity escaping capacity. Through the mean-field calculation analysis and using a fourth-order Runge-Kutta method with constant step size, we obtain plots from numerical simulations. We found that only when the total number of infectious individuals proves sufficient to reach and exceed a certain level will the individuals face a better trade-off in determining whether to get vaccinated against the diseases based on that information. Besides, authoritative media have a higher decisive influence and efforts should be focused on extending the duration of vaccine protection, which is beneficial to inhibit the outbreaks of epidemics. Our work elucidates that reducing the negative payoff brought about by the free-riding behavior for individuals or improving the positive payoff from the altruistic motivation helps to control the disease in cultures that value social benefits, vaccination willingness is generally stronger. We also note that at a high risk of infection, the decision of vaccination is highly correlated with global epidemic information concerning COVID-19 infection, while at times of lower risk, it depends on the game theoretic vaccine strategy. The findings demonstrate that improving health literacy, ensuring open and transparent information on vaccine safety and efficacy as a public health priority can be an effective strategy for mitigating inequalities in health education, as well as alleviating the phenomenon that immunity escaping abilities is more likely to panic by populations with high levels of education. In addition, prosocial nudges are great ways to bridge these immunity gaps that can contribute to implementing government public health control measures, creating a positive feedback loop.
RESUMO
Although immunotherapy has a broad clinical application prospect, it is still hindered by low immune responses and immunosuppressive tumor microenvironment. Herein, a simple and drug-free inorganic nanomaterial, alkalescent sodium bicarbonate nanoparticles (NaHCO3 NPs), is prepared via a fast microemulsion method for amplified cancer immunotherapy. The obtained alkalescent NaHCO3 regulates lactic acid metabolism through acid-base neutralization so as to reverse the mildly acidic immunosuppressive tumor environment. Additionally, it can further release high amounts of Na+ ions inside tumor cells and induce a surge in intracellular osmolarity, and thus activate the pyroptosis pathway and immunogenic cell death (ICD), release damage-associated molecular patterns (DAMPs) and inflammatory factors, and improve immune responses. Collectively, NaHCO3 NPs observably inhibit primary/distal tumor growth and tumor metastasis through acid neutralization remitted immunosuppression and pyroptosis induced immune activation, showing an enhanced antitumor immunity efficiency. This work provides a new paradigm for lactic acid metabolism and pyroptosis mediated tumor treatment, which has a potential for application in clinical tumor immunotherapy.