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1.
Cell ; 187(13): 3319-3337.e18, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38810645

RESUMO

The development of perennial crops holds great promise for sustainable agriculture and food security. However, the evolution of the transition between perenniality and annuality is poorly understood. Here, using two Brassicaceae species, Crucihimalaya himalaica and Erysimum nevadense, as polycarpic perennial models, we reveal that the transition from polycarpic perennial to biennial and annual flowering behavior is a continuum determined by the dosage of three closely related MADS-box genes. Diversification of the expression patterns, functional strengths, and combinations of these genes endows species with the potential to adopt various life-history strategies. Remarkably, we find that a single gene among these three is sufficient to convert winter-annual or annual Brassicaceae plants into polycarpic perennial flowering plants. Our work delineates a genetic basis for the evolution of diverse life-history strategies in plants and lays the groundwork for the generation of diverse perennial Brassicaceae crops in the future.


Assuntos
Brassicaceae , Flores , Regulação da Expressão Gênica de Plantas , Brassicaceae/genética , Brassicaceae/fisiologia , Produtos Agrícolas/genética , Flores/genética , Flores/fisiologia , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genoma de Planta , Fenômenos Fisiológicos Vegetais , Mapeamento Cromossômico , Mutação
2.
Nature ; 600(7890): 695-700, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34880504

RESUMO

Surveys are a crucial tool for understanding public opinion and behaviour, and their accuracy depends on maintaining statistical representativeness of their target populations by minimizing biases from all sources. Increasing data size shrinks confidence intervals but magnifies the effect of survey bias: an instance of the Big Data Paradox1. Here we demonstrate this paradox in estimates of first-dose COVID-19 vaccine uptake in US adults from 9 January to 19 May 2021 from two large surveys: Delphi-Facebook2,3 (about 250,000 responses per week) and Census Household Pulse4 (about 75,000 every two weeks). In May 2021, Delphi-Facebook overestimated uptake by 17 percentage points (14-20 percentage points with 5% benchmark imprecision) and Census Household Pulse by 14 (11-17 percentage points with 5% benchmark imprecision), compared to a retroactively updated benchmark the Centers for Disease Control and Prevention published on 26 May 2021. Moreover, their large sample sizes led to miniscule margins of error on the incorrect estimates. By contrast, an Axios-Ipsos online panel5 with about 1,000 responses per week following survey research best practices6 provided reliable estimates and uncertainty quantification. We decompose observed error using a recent analytic framework1 to explain the inaccuracy in the three surveys. We then analyse the implications for vaccine hesitancy and willingness. We show how a survey of 250,000 respondents can produce an estimate of the population mean that is no more accurate than an estimate from a simple random sample of size 10. Our central message is that data quality matters more than data quantity, and that compensating the former with the latter is a mathematically provable losing proposition.


Assuntos
Vacinas contra COVID-19/administração & dosagem , Pesquisas sobre Atenção à Saúde , Vacinação/estatística & dados numéricos , Benchmarking , Viés , Big Data , COVID-19/epidemiologia , COVID-19/prevenção & controle , Centers for Disease Control and Prevention, U.S. , Conjuntos de Dados como Assunto/normas , Feminino , Pesquisas sobre Atenção à Saúde/normas , Humanos , Masculino , Projetos de Pesquisa , Tamanho da Amostra , Mídias Sociais , Estados Unidos/epidemiologia , Hesitação Vacinal/estatística & dados numéricos
3.
Proc Natl Acad Sci U S A ; 120(6): e2221637120, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36716376

RESUMO

Lipids establish the specialized thylakoid membrane of chloroplast in eukaryotic photosynthetic organisms, while the molecular basis of lipid transfer from other organelles to chloroplast remains further elucidation. Here we revealed the structural basis of Arabidopsis Sec14 homology proteins AtSFH5 and AtSFH7 in transferring phosphatidic acid (PA) from endoplasmic reticulum (ER) to chloroplast, and whose function in regulating the lipid composition of chloroplast and thylakoid development. AtSFH5 and AtSFH7 localize at both ER and chloroplast, whose deficiency resulted in an abnormal chloroplast structure and a decreased thickness of stacked thylakoid membranes. We demonstrated that AtSFH5, but not yeast and human Sec14 proteins, could specifically recognize and transfer PA in vitro. Crystal structures of the AtSFH5-Sec14 domain in complex with L-α-phosphatidic acid (L-α-PA) and 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA) revealed that two PA ligands nestled in the central cavity with different configurations, elucidating the specific binding mode of PA to AtSFH5, different from the reported phosphatidylethanolamine (PE)/phosphatidylcholine (PC)/phosphatidylinositol (PI) binding modes. Quantitative lipidomic analysis of chloroplast lipids showed that PA and monogalactosyldiacylglycerol (MGDG), particularly the C18 fatty acids at sn-2 position in MGDG were significantly decreased, indicating a disrupted ER-to-plastid (chloroplast) lipid transfer, under deficiency of AtSFH5 and AtSFH7. Our studies identified the role and elucidated the structural basis of plant SFH proteins in transferring PA between organelles, and suggested a model for ER-chloroplast interorganelle phospholipid transport from inherent ER to chloroplast derived from endosymbiosis of a cyanobacteriumproviding a mechanism involved in the adaptive evolution of cellular plastids.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Cloroplastos , Ácidos Fosfatídicos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cloroplastos/metabolismo , Ácidos Fosfatídicos/metabolismo , Tilacoides/metabolismo
4.
Clin Microbiol Rev ; 37(1): e0010322, 2024 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-38095438

RESUMO

Wastewater-based surveillance (WBS) has undergone dramatic advancement in the context of the coronavirus disease 2019 (COVID-19) pandemic. The power and potential of this platform technology were rapidly realized when it became evident that not only did WBS-measured SARS-CoV-2 RNA correlate strongly with COVID-19 clinical disease within monitored populations but also, in fact, it functioned as a leading indicator. Teams from across the globe rapidly innovated novel approaches by which wastewater could be collected from diverse sewersheds ranging from wastewater treatment plants (enabling community-level surveillance) to more granular locations including individual neighborhoods and high-risk buildings such as long-term care facilities (LTCF). Efficient processes enabled SARS-CoV-2 RNA extraction and concentration from the highly dilute wastewater matrix. Molecular and genomic tools to identify, quantify, and characterize SARS-CoV-2 and its various variants were adapted from clinical programs and applied to these mixed environmental systems. Novel data-sharing tools allowed this information to be mobilized and made immediately available to public health and government decision-makers and even the public, enabling evidence-informed decision-making based on local disease dynamics. WBS has since been recognized as a tool of transformative potential, providing near-real-time cost-effective, objective, comprehensive, and inclusive data on the changing prevalence of measured analytes across space and time in populations. However, as a consequence of rapid innovation from hundreds of teams simultaneously, tremendous heterogeneity currently exists in the SARS-CoV-2 WBS literature. This manuscript provides a state-of-the-art review of WBS as established with SARS-CoV-2 and details the current work underway expanding its scope to other infectious disease targets.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Vigilância Epidemiológica Baseada em Águas Residuárias , RNA Viral , Águas Residuárias
5.
Am J Pathol ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38762117

RESUMO

The evaluation of morphologic features, such as inflammation, gastric atrophy, and intestinal metaplasia, is crucial for diagnosing gastritis. However, artificial intelligence analysis for nontumor diseases like gastritis is limited. Previous deep learning models have omitted important morphologic indicators and cannot simultaneously diagnose gastritis indicators or provide interpretable labels. To address this, an attention-based multi-instance multilabel learning network (AMMNet) was developed to simultaneously achieve the multilabel diagnosis of activity, atrophy, and intestinal metaplasia with only slide-level weak labels. To evaluate AMMNet's real-world performance, a diagnostic test was designed to observe improvements in junior pathologists' diagnostic accuracy and efficiency with and without AMMNet assistance. In this study of 1096 patients from seven independent medical centers, AMMNet performed well in assessing activity [area under the curve (AUC), 0.93], atrophy (AUC, 0.97), and intestinal metaplasia (AUC, 0.93). The false-negative rates of these indicators were only 0.04, 0.08, and 0.18, respectively, and junior pathologists had lower false-negative rates with model assistance (0.15 versus 0.10). Furthermore, AMMNet reduced the time required per whole slide image from 5.46 to only 2.85 minutes, enhancing diagnostic efficiency. In block-level clustering analysis, AMMNet effectively visualized task-related patches within whole slide images, improving interpretability. These findings highlight AMMNet's effectiveness in accurately evaluating gastritis morphologic indicators on multicenter data sets. Using multi-instance multilabel learning strategies to support routine diagnostic pathology deserves further evaluation.

6.
Plant Physiol ; 195(2): 1069-1088, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38330431

RESUMO

Powdery mildew (PM) is one of the most widespread and prevalent diseases that affects a wide range of crops. In cucumber (Cucumis sativus L.), previous forward genetic studies have identified MILDEW RESISTANCE LOCUS O 8 (CsMLO8) as necessary but alone insufficient for cucumber PM resistance (PMR) and suggested the involvement of other members of the CsMLO family. However, the function of other CsMLO family members in cucumber remains largely unknown. Here, we developed a highly efficient multiplex gene editing system in cucumber to generate a series of Csmlo mutants from all the 13 family members. Systematic analysis of these mutants revealed growth effects of these CsMLO family members on development and PMR. Importantly, we obtained the Csmlo1/8/11 triple mutant with complete resistance to PM. Transcriptome and proteome analysis of PM-resistant Csmlo mutants suggested that the kinesin-like calmodulin-binding protein (KCBP)-interacting Ca2+-binding protein (CsKIC), calmodulin-like protein 28 (CsCML28), and Ca2+-dependent protein kinase 11 (CsCPK11)-mediated calcium signaling pathway is involved in PMR. CsMLO8 interacted directly with CsKIC, and the simultaneous silencing of both genes resulted in a phenotype that resembled the silencing of CsKIC alone. Silencing CsCML28 and CsCPK11 increased susceptibility to PM, whereas overexpressing CsCPK11 through genetic transformation enhanced cucumber's PMR, demonstrating their positive regulatory roles in PMR. Given the importance of PMR for cucurbit crops, this research provides unprecedented insights into the function of the proteins encoded by the CsMLO gene family as well as the plant defense response to PM pathogen.


Assuntos
Cucumis sativus , Resistência à Doença , Edição de Genes , Doenças das Plantas , Cucumis sativus/genética , Cucumis sativus/microbiologia , Resistência à Doença/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Edição de Genes/métodos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ascomicetos/fisiologia , Ascomicetos/patogenicidade , Mutação/genética , Regulação da Expressão Gênica de Plantas
7.
Ann Neurol ; 95(5): 901-906, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38400794

RESUMO

We determined the genetic association between specific human leucocyte antigen (HLA) loci and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Our results showed that autoimmune GFAP astrocytopathy was associated with HLA-A*3303 (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.32-3.06, p = 0.00072, padj. = 0.046) and HLA-DBP1*0501 (OR = 0.51, 95% CI = 0.36-0.71, p = 0.000048, padj. = 0.0062). Moreover, HLA-A*3303 carriers with the disease had a longer hospital stay (p = 0.0005) than non-carriers. This study for the first time provides evidence for a role of genetic factor in the development of autoimmune GFAP astrocytopathy. ANN NEUROL 2024;95:901-906.


Assuntos
Astrócitos , Proteína Glial Fibrilar Ácida , Antígenos HLA-A , Cadeias beta de HLA-DP , Humanos , Proteína Glial Fibrilar Ácida/genética , Masculino , Feminino , Pessoa de Meia-Idade , Cadeias beta de HLA-DP/genética , Adulto , Antígenos HLA-A/genética , Astrócitos/metabolismo , Astrócitos/patologia , Idoso
8.
Nat Chem Biol ; 19(9): 1063-1071, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37169959

RESUMO

The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design.


Assuntos
Retículo Endoplasmático , Proteínas de Membrana , Humanos , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico/fisiologia , Canais de Translocação SEC/antagonistas & inibidores , Canais de Translocação SEC/química , Canais de Translocação SEC/metabolismo
9.
FASEB J ; 38(2): e23387, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38193649

RESUMO

Human brain microvascular endothelial cells (HBMVECs) and microglia play critical roles in regulating cerebral homeostasis during ischemic stroke. However, the role of HBMVECs-derived exosomes in microglia polarization after stroke remains unknown. We isolated exosomes (Exos) from oxygen glucose deprivation (OGD)-exposed HBMVECs, before added them into microglia. Microglia polarization markers were tested using RT-qPCR or flow cytometry. Inflammatory cytokines were measured with ELISA. Endothelial cell damage was assessed by cell viability, apoptosis, apoptosis-related proteins, oxidative stress, and angiogenic activity using CCK-8, flow cytometry, western blot, ELISA, and endothelial tube formation assay, respectively. We also established middle cerebral artery occlusion (MCAO) mice model to examine the function of circ_0000495 on stroke in vivo. Our study found that HBMVECs-Exos reduced M2 markers (IL-10, CD163, and CD206), increased M1 markers (TNF-α, IL-1ß, and IL-12), CD86-positive cells, and inflammatory cytokines (TNF-α and IL-1ß), indicating the promotion of microglial M1-polarization. Microglial M1-polarization induced by HBMVECs-Exos reduced viability and promoted apoptosis and oxidative stress, revealing the aggravation of endothelial cell damage. However, circ_0000495 silencing inhibited HBMVECs-Exos-induced alterations. Mechanistically, circ_0000495 adsorbed miR-579-3p to upregulate toll-like receptor 4 (TLR4) in microglia; miR-579-3p suppressed HBMVECs-Exos-induced alterations via declining TLR4; furthermore, Yin Yang 1 (YY1) transcriptionally activated circ_0000495 in HBMVECs. Importantly, circ_0000495 aggravated ischemic brain injury in vivo via activating TLR4/nuclear factor-κB (NF-κB) pathway. Collectively, OGD-treated HBMVECs-Exos transmitted circ_0000495 to regulate miR-579-3p/TLR4/NF-κB axis in microglia, thereby facilitating microglial M1-polarization and endothelial cell damage.


Assuntos
Exossomos , MicroRNAs , Acidente Vascular Cerebral , Animais , Camundongos , Humanos , Células Endoteliais , Microglia , Receptor 4 Toll-Like/genética , NF-kappa B , Fator de Necrose Tumoral alfa , Encéfalo , Hipóxia , Oxigênio , Citocinas , MicroRNAs/genética
10.
EMBO Rep ; 24(11): e56850, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37846507

RESUMO

The remodeling and stiffening of the extracellular matrix (ECM) is a well-recognized modulator of breast cancer progression. How changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remain poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We show that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs) and as a consequence impedes cell contraction and migration, independent of its role in autophagy. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn alters the mechanical properties of breast cancer cells and their response to mechanical stimuli. ULK1/2 and the well-characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Taken together, our study reveals ULK1/2 as important regulator of PXN-dependent mechanotransduction.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Paxilina/metabolismo , Mecanotransdução Celular , Fosforilação , Movimento Celular , Serina/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
11.
J Immunol ; 210(1): 72-81, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36426999

RESUMO

Fish possess a powerful IFN system to defend against aquatic virus infections. Nevertheless, spring viremia of carp virus (SVCV) causes large-scale mortality in common carp and significant economic losses to aquaculture. Therefore, it is necessary to investigate the strategies used by SVCV to escape the IFN response. In this study, we show that the SVCV nucleoprotein (N protein) negatively regulates cellular IFN production by degrading stimulator of IFN genes (STING) via the autophagy-lysosome-dependent pathway. First, overexpression of N protein inhibited the IFN promoter activation induced by polyinosinic-polycytidylic acid and STING. Second, the N protein associated with STING and experiments using a dominant-negative STING mutant demonstrated that the N-terminal transmembrane domains of STING were indispensable for this interaction. Then, the N protein degraded STING in a dose-dependent and autophagy-lysosome-dependent manner. Intriguingly, in the absence of STING, individual N proteins could not elicit host autophagic flow. Furthermore, the autophagy factor Beclin1 was found to interact with the N protein to attenuate N protein-mediated STING degradation after beclin1 knockdown. Finally, the N protein remarkably weakened STING-enhanced cellular antiviral responses. These findings reveal that SVCV uses the host autophagic process to achieve immune escape, thus broadening our understanding of aquatic virus pathogenesis.


Assuntos
Carpas , Doenças dos Peixes , Infecções por Rhabdoviridae , Rhabdoviridae , Animais , Proteínas do Nucleocapsídeo , Viremia , Proteína Beclina-1 , Rhabdoviridae/fisiologia , Lisossomos , Autofagia
12.
Proc Natl Acad Sci U S A ; 119(13): e2119883119, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35312369

RESUMO

SignificanceWe present a groundbreaking advance in completely nonprecious hydrogen fuel cell technologies achieving a record power density of 200 mW/cm2 with Ni@CNx anode and Co-Mn cathode. The 2-nm CNx coating weakens the O-binding energy, which effectively mitigates the undesirable surface oxidation during hydrogen oxidation reaction (HOR) polarization, leading to a stable fuel cell operation for Ni@CNx over 100 h at 200 mA/cm2, superior to a Ni nanoparticle counterpart. Ni@CNx exhibited a dramatically enhanced tolerance to CO relative to Pt/C, enabling the use of hydrogen gas with trace amounts of CO, critical for practical applications. The complete removal of precious metals in fuel cells lowers the catalyst cost to virtually negligible levels and marks a milestone for practical alkaline fuel cells.

13.
J Proteome Res ; 23(4): 1232-1248, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38407963

RESUMO

The aim of this study was to identify serum diagnostic biomarkers associated with the severity of obstructive sleep apnea (OSA) during pregnancy. Differentially expressed proteins (DEPs) were identified in the control (C), mild (O), and moderate (MO) OSA groups (n = 3 in each group). Bioinformatics analysis was conducted to identify the underlying functions, pathways, and networks of the proteins. Receiver operating characteristic curves were used to assess the diagnostic value of the identified DEPs. The enzyme-linked immunoassay was performed to detect serum levels of the complement C1r subcomponent (C1R) and alpha-2-macroglobulin (A2M) in 79 pregnant women with OSA (mild OSA [n = 32]; moderate OSA [n = 29], and severe OSA [n = 18]) and 65 healthy pregnant women without OSA. Pearson's correlation analysis was conducted to analyze the correlation between C1R and A2M levels and OSA clinicopathological factors. In total, 141 DEPs, 29 DEPs, and 103 DEPs were identified in the three groups (i.e., the mild OSA vs control group, the moderate OSA vs mild apnea group, and the moderate OSA vs control group, respectively). C1R and A2M were identified as continuously up-regulated proteins, and the levels of C1R and A2M were associated with OSA severity. C1R and A2M were found to be correlated with body mass index, systolic blood pressure, apnea-hypopnea index, oxygen desaturation index, time with saturation below 90%, and lowest SaO2. Adverse maternal and neonatal outcomes were observed in pregnant women with OSA. C1R and A2M have been identified as diagnostic biomarkers and are associated with the severity of OSA during pregnancy.


Assuntos
Gestantes , Apneia Obstrutiva do Sono , Feminino , Humanos , Recém-Nascido , Gravidez , alfa-Macroglobulinas , Biomarcadores , Complemento C1r/metabolismo , Polissonografia , Proteoma , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/complicações , Fatores de Transcrição
14.
J Cell Mol Med ; 28(9): e18377, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38686488

RESUMO

There are few effective therapeutic strategies for temporomandibular joint osteoarthritis (TMJOA) due to the unclear pathology and mechanisms. We aimed to confirm the roles of GPX4 and ferroptosis in TMJOA progression. ELISA assay was hired to evaluate concentrations of ferroptosis-related markers. The qRT-PCR assay was hired to assess gene mRNA level. Western blot assay and immunohistochemistry were hired to verify the protein level. CCK-8 assay was hired to detect cell viability. Human fibroblast-like synoviocytes (FLSs) were cultured to confirm the effects of GPX4 and indicated inhibitors, and further verified the effects of GPX4 and ferroptosis inhibitors in TMJOA model rats. Markers of ferroptosis including 8-hidroxy-2-deoxyguanosine (8-OHdG) and iron were notably increased in TMJOA tissues and primary OA-FLSs. However, the activity of the antioxidant system including the glutathione peroxidase activity, glutathione (GSH) contents, and glutathione/oxidized glutathione (GSH/GSSG) ratio was notably inhibited in TMJOA tissues, and the primary OA-FLSs. Furthermore, the glutathione peroxidase 4 (GPX4) expression was down-regulated in TMJOA tissues and primary OA-FLSs. Animal and cell experiments have shown that ferroptosis inhibitors notably inhibited ferroptosis and promoted HLS survival as well as up-regulated GPX4 expression. Also, GPX4 knockdown promoted ferroptosis and GPX4 overexpression inhibited ferroptosis. GPX4 also positively regulated cell survival which was the opposite with ferroptosis. In conclusion, GPX4 and ferroptosis regulated the progression of TMJOA. Targeting ferroptosis might be an effective therapeutic strategy for TMJOA patients in the clinic.


Assuntos
Ferroptose , Osteoartrite , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Articulação Temporomandibular , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Ferroptose/genética , Ferroptose/efeitos dos fármacos , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Ratos Sprague-Dawley , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Articulação Temporomandibular/patologia , Articulação Temporomandibular/metabolismo
15.
J Cell Physiol ; 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38764331

RESUMO

Early-onset preeclampsia, which occurrs before 34 weeks of gestation, is the most dangerous classification of preeclampsia, which is a pregnancy-specific disease that causes 1% of maternal deaths. G protein-coupled receptor 124 (GPR124) is significantly expressed at various stages of the human reproductive process, particularly during embryogenesis and angiogenesis. Our prior investigation demonstrated a notable decrease in GPR124 expression in the placentas of patients with early-onset preeclampsia compared to that in normal pregnancy placentas. However, there is a lack of extensive investigation into the molecular processes that contribute to the role of GPR124 in placenta development. This study aimed to examine the mechanisms by which GPR124 affects the occurrence of early-onset preeclampsia and its function in trophoblast. Proliferative, invasive, migratory, apoptotic, and inflammatory processes were identified in GPR124 knockdown, GPR124 overexpression, and normal HTR8/SVneo cells. The mechanism of GPR124-mediated cell function in GPR124 knockdown HTR8/SVneo cells was examined using inhibitors of the JNK or P38 MAPK pathway. Downregulation of GPR124 was found to significantly inhibit proliferation, invasion and migration, and promote apoptosis of HTR8/SVneo cells when compared to the control and GPR124 overexpression groups. This observation is consistent with the pathological characteristics of preeclampsia. In addition, GPR124 overexpression inhibits the secretion of pro-inflammatory cytokines interleukin (IL)-8 and interferon-γ (IFN-γ) while enhancing the secretion of the anti-inflammatory cytokine interleukin (IL)-4. Furthermore, GPR124 suppresses the activation of P-JNK and P-P38 within the JNK/P38 MAPK pathway. The invasion, apoptosis, and inflammation mediated by GPR124 were partially restored by suppressing the JNK and P38 MAPK pathways in HTR8/SVneo cells. GPR124 plays a crucial role in regulating trophoblast proliferation, invasion, migration, apoptosis, and inflammation via the JNK and P38 MAPK pathways. Furthermore, the effect of GPR124 on trophoblast suggests its involvement in the pathogenesis of early-onset preeclampsia.

16.
J Cell Physiol ; 239(6): e31267, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38558303

RESUMO

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 µg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.


Assuntos
Proliferação de Células , Fibronectinas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Neoplasias do Colo do Útero , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibronectinas/metabolismo , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Integrinas/metabolismo , Progressão da Doença
17.
Clin Infect Dis ; 78(6): 1522-1530, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38530249

RESUMO

BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up. RESULTS: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC. CONCLUSIONS: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC.


Assuntos
Infecções Assintomáticas , COVID-19 , Características da Família , SARS-CoV-2 , Humanos , COVID-19/transmissão , COVID-19/diagnóstico , COVID-19/epidemiologia , Criança , Estudos Prospectivos , Masculino , Feminino , Canadá/epidemiologia , Pré-Escolar , SARS-CoV-2/isolamento & purificação , Infecções Assintomáticas/epidemiologia , Estados Unidos/epidemiologia , Lactente , Adolescente , Estudos de Casos e Controles
18.
J Am Chem Soc ; 146(8): 5643-5649, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38327018

RESUMO

We developed a method for the enantioselective synthesis of germanium-stereogenic compounds by the desymmetric carbene insertion of dihydrogermanes. A chiral rhodium phosphate catalyst decomposes diaryldiazo-methanes to generate rhodium carbenes that insert enantioselectively into one of the two Ge-H bonds of dihydrogermanes to form germanium-stereogenic compounds under mild reaction conditions. By this method, a variety of chiral germanes with germanium-stereogenic centers were synthesized in high yields and excellent enantioselectivities. Kinetic studies of the reaction showed that the diazo decomposition process was the rate-determining step. The remaining Ge-H bond of the chiral germane products provides a possibility for preparing chiral tetra-substituted germanium-stereogenic compounds.

19.
J Am Chem Soc ; 146(25): 17377-17383, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38871485

RESUMO

A prominent feature of modern electrochemical technologies, such as fuel cells and electrolysis, is the employing of polyelectrolytes instead of liquid electrolytes. Unlike the well-studied electrode/liquid electrolyte interfaces, however, the catalytic characteristics of electrode/polyelectrolyte interfaces remain largely unexplored, mostly due to the lack of reliable probing methods. Herein, we report a universally applicable approach to investigating electrocatalytic reactions at electrode/polyelectrolyte interfaces under normal electrochemical conditions. By coating a thin layer of anion-exchange membrane (AEM) onto the electrode surface, solutions with bulky organic cations were well separated, thus a pure electrode/polyelectrolyte interface can be established in a regular electrochemical setup and studied using in situ spectroscopies, e.g., attenuated total reflectance surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS). We found that the blank Au surface was inert toward the CO2 reduction reaction (CO2RR) in the absence of alkali metal cations, whereas coating with an AEM can dramatically turn on the catalytic activity. ATR-SEIRAS revealed that the hydrogen bond network of water at the Au/AEM interface was enhanced in comparison to that on the blank Au surface, which facilitated the hydrogenation process of the CO2RR. These findings further our fundamental understanding of the catalytic behavior of electrode/polyelectrolyte interfaces and benefit the development of relevant electrochemical technologies.

20.
J Am Chem Soc ; 146(5): 3458-3470, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38270100

RESUMO

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

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