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1.
Proc Natl Acad Sci U S A ; 121(18): e2307090121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38648487

RESUMO

G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors that are highly modular and could potentially be used to determine GPCR agonist localization across the brain. We previously engineered integrator sensors for the mu- and kappa-opioid receptor agonists called M- and K-Single-chain Protein-based Opioid Transmission Indicator Tool (SPOTIT), respectively. Here, we engineered red versions of the SPOTIT sensors for multiplexed imaging of GPCR agonists. We also modified SPOTIT to create an integrator sensor design platform called SPOTIT for all GPCRs (SPOTall). We used the SPOTall platform to engineer sensors for the beta 2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. Finally, we demonstrated the application of M-SPOTIT and B2AR-SPOTall in detecting exogenously administered morphine, isoproterenol, and epinephrine in the mouse brain via locally injected viruses. The SPOTIT and SPOTall sensor design platform has the potential for unbiased agonist detection of many synthetic and endogenous neuromodulators across the brain.


Assuntos
Receptores Acoplados a Proteínas G , Animais , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Camundongos , Células HEK293 , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/metabolismo , Isoproterenol/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Morfina/farmacologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Técnicas Biossensoriais/métodos
2.
Nat Methods ; 20(1): 112-122, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36481965

RESUMO

Natural or engineered peptides serve important biological functions. A general approach to achieve chemical-dependent activation of short peptides will be valuable for spatial and temporal control of cellular processes. Here we present a pair of chemically activated protein domains (CAPs) for controlling the accessibility of both the N- and C-terminal portion of a peptide. CAPs were developed through directed evolution of an FK506-binding protein. By fusing a peptide to one or both CAPs, the function of the peptide is blocked until a small molecule displaces them from the FK506-binding protein ligand-binding site. We demonstrate that CAPs are generally applicable to a range of short peptides, including a protease cleavage site, a dimerization-inducing heptapeptide, a nuclear localization signal peptide, and an opioid peptide, with a chemical dependence up to 156-fold. We show that the CAPs system can be utilized in cell cultures and multiple organs in living animals.


Assuntos
Peptídeo Hidrolases , Peptídeos , Animais , Peptídeos/química , Endopeptidases/metabolismo , Proteínas de Ligação a Tacrolimo/genética
3.
Brief Bioinform ; 25(5)2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39175132

RESUMO

Numerous studies have demonstrated that microRNAs (miRNAs) are critically important for the prediction, diagnosis, and characterization of diseases. However, identifying miRNA-disease associations through traditional biological experiments is both costly and time-consuming. To further explore these associations, we proposed a model based on hybrid high-order moments combined with element-level attention mechanisms (HHOMR). This model innovatively fused hybrid higher-order statistical information along with structural and community information. Specifically, we first constructed a heterogeneous graph based on existing associations between miRNAs and diseases. HHOMR employs a structural fusion layer to capture structure-level embeddings and leverages a hybrid high-order moments encoder layer to enhance features. Element-level attention mechanisms are then used to adaptively integrate the features of these hybrid moments. Finally, a multi-layer perceptron is utilized to calculate the association scores between miRNAs and diseases. Through five-fold cross-validation on HMDD v2.0, we achieved a mean AUC of 93.28%. Compared with four state-of-the-art models, HHOMR exhibited superior performance. Additionally, case studies on three diseases-esophageal neoplasms, lymphoma, and prostate neoplasms-were conducted. Among the top 50 miRNAs with high disease association scores, 46, 47, and 45 associated with these diseases were confirmed by the dbDEMC and miR2Disease databases, respectively. Our results demonstrate that HHOMR not only outperforms existing models but also shows significant potential in predicting miRNA-disease associations.


Assuntos
MicroRNAs , MicroRNAs/genética , Humanos , Biologia Computacional/métodos , Predisposição Genética para Doença , Algoritmos , Neoplasias da Próstata/genética , Modelos Genéticos
4.
Hum Mol Genet ; 32(14): 2326-2334, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37133443

RESUMO

Fertilization is a fundamental process of development, and the blocking mechanisms act at the zona pellucida (ZP) and plasma membrane of the egg to prevent any additional sperm from binding, permeating and fusing after fertilization. In clinical practice, some couples undergoing recurrent IVF failures that mature oocytes had abnormal fertilization for unknown reason. Ovastacin encoded by ASTL cleave the ZP protein ZP2 and play a key role in preventing polyspermy. Here, we identified bi-allelic variants in ASTL that are mainly characterized by fertilization problems in humans. All four independent affected individuals had bi-allelic frameshift variants or predicted damaging missense variants, which follow a Mendelian recessive inheritance pattern. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential. This work presents strong evidence that pathogenic variants in ASTL cause female infertility and provides a new genetic marker for the diagnosis of fertilization problems.


Assuntos
Infertilidade Feminina , Sêmen , Humanos , Masculino , Feminino , Camundongos , Animais , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/metabolismo , Sêmen/metabolismo , Oócitos/metabolismo , Infertilidade Feminina/genética , Fertilização/genética , Metaloproteases/genética
5.
Hum Genomics ; 18(1): 79, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39010135

RESUMO

The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families' blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17-58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70-82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59-54.20) and 51.09 (49.22-52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P < 0.001). The average number of de novo indels among the multifetal reduction group and the newborn group was 26.26 (23.27-29.05) and 5.17 (4.82-5.52), respectively. To conclude, it has been observed that the quantity of de novo indels in the newborns experiences a significant decrease when compared to that in the aspirated embryonic tissues (7-9 weeks). This phenomenon is evident across all genomic regions, highlighting the adverse effects of de novo indels on the fetus and emphasizing the significance of embryonic implantation and intrauterine growth in human genetic selection mechanisms.


Assuntos
Feto , Humanos , Feminino , Gravidez , Recém-Nascido , Masculino , Adulto , Polimorfismo de Nucleotídeo Único/genética , Implantação do Embrião/genética , Genoma Humano/genética , Mutação INDEL/genética , Genômica , Sequenciamento Completo do Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Desenvolvimento Fetal/genética
6.
Cell Mol Life Sci ; 81(1): 81, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334797

RESUMO

Papillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.


Assuntos
Metabolismo dos Lipídeos , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Metabolismo dos Lipídeos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Metilação de DNA , Linhagem Celular Tumoral , Proliferação de Células , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo
7.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042776

RESUMO

Sympathetic innervation regulates energy balance, and the nerve density in the adipose tissues changes under various metabolic states, resulting in altered neuronal control and conferring resilience to metabolic challenges. However, the impact of the immune milieu on neuronal innervation is not known. Here, we examined the regulatory role on nerve plasticity by eosinophils and found they increased cell abundance in response to cold and produced nerve growth factor (NGF) in the white adipose tissues (WAT). Deletion of Ngf from eosinophils or depletion of eosinophils impairs cold-induced axonal outgrowth and beiging process. The spatial proximity between sympathetic nerves, IL-33-expressing stromal cells, and eosinophils was visualized in both human and mouse adipose tissues. At the cellular level, the sympathetic adrenergic signal induced calcium flux in the stromal cells and subsequent release of IL-33, which drove the up-regulation of IL-5 from group 2 innate lymphoid cells (ILC2s), leading to eosinophil accretion. We propose a feed-forward loop between sympathetic activity and type 2 immunity that coordinately enhances sympathetic innervation and promotes energy expenditure.


Assuntos
Tecido Adiposo/metabolismo , Axônios/metabolismo , Plasticidade Celular/fisiologia , Eosinófilos/imunologia , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Cálcio , Feminino , Humanos , Imunidade Inata , Interleucina-33/metabolismo , Linfócitos/imunologia , Camundongos , Pessoa de Meia-Idade , Fator de Crescimento Neural/metabolismo , Células Estromais/metabolismo , Sistema Nervoso Simpático/fisiologia
8.
Proc Natl Acad Sci U S A ; 119(36): e2205562119, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36037332

RESUMO

Hydrogen peroxide (H2O2) molecules play important roles in many green chemical reactions. However, the high activation energy limits their application efficiency, and there is still huge controversy about the activation path of H2O2 molecules over the presence of *OOH intermediates. Here, we confirmed the formation of the key species *OOH in the heterogeneous system, via in situ shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS), isotope labeling, and theoretical calculation. In addition, we found that compared with *H2O2, *OOH was more conducive to the charge transfer behavior with the catalyst and the activation of an O-O bond. Furthermore, we proposed to improve the local coordination structure and electronic density of the YFeO3 catalyst by regulating the surface relaxation with Ti modification so as to reduce the activation barrier of H2O2 and to improve the production efficiency of •OH. As a result, the kinetics rates of the Fenton-like (photo-Fenton) reaction had been significantly increased several times. The •OH free radical activity mechanism and molecular transformation pathways of 4-chloro phenol (4-CP) were also revealed. This may provide a clearer vision for the further study of H2O2 activation and suggest a means of designing catalysts for efficient H2O2 activation.


Assuntos
Peróxido de Hidrogênio , Processos Fotoquímicos , Catálise , Peróxido de Hidrogênio/química , Ferro/química , Luz , Fenol
9.
Nano Lett ; 24(15): 4649-4657, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38572971

RESUMO

Deep-seated bacterial infections (DBIs) are stubborn and deeply penetrate tissues. Eliminating deep-seated bacteria and promoting tissue regeneration remain great challenges. Here, a novel radical-containing hydrogel (SFT-B Gel) cross-linked by a chaotropic effect was designed for the sensing of DBIs and near-infrared photothermal therapy (NIR-II PTT). A silk fibroin solution stained with 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tris(1-methylpyridin-1-ium) (TPT3+) was employed as the backbone, which could be cross-linked by a closo-dodecaborate cluster (B12H122-) through a chaotropic effect to form the SFT-B Gel. More interestingly, the SFT-B Gel exhibited the ability to sense DBIs, which could generate a TPT2+• radical with obvious color changes in the presence of bacteria. The radical-containing SFT-B Gel (SFT-B★ Gel) possessed strong NIR-II absorption and a remarkable photothermal effect, thus demonstrating excellent NIR-II PTT antibacterial activity for the treatment of DBIs. This work provides a new approach for the construction of intelligent hydrogels with unique properties using a chaotropic effect.


Assuntos
Fototerapia , Terapia Fototérmica , Hidrogéis/farmacologia
10.
Stroke ; 55(2): 423-431, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38095120

RESUMO

BACKGROUND: Iron status has been associated with functional outcomes after ischemic stroke (IS). Nonetheless, this association may be affected by confounders. We perform Mendelian randomization to clarify the causal association between iron status and functional outcome after IS. METHODS: We obtained summary-level statistics related to iron status biomarkers from a meta-analysis of a gene-wide association study conducted by the Genetics of Iron Status Consortium, which included 11 discovery cohorts and 8 replication cohorts. We also took genetic variants related to 4 biomarkers of iron status from combining gene-wide association study results of Iceland, the United Kingdom, and Denmark to perform a replicate Mendelian randomization analysis. This data set included 4 iron status biomarkers, namely, ferritin, total iron binding capacity, iron, and transferrin saturation (TSAT). The confounders in these data sets have been adjusted to mitigate the collider bias. We acquired summary statistics data sets for functional outcomes following IS from the gene-wide association study meta-analysis conducted by the Genetics of Ischemic Stroke Functional Outcome Consortium. The genetic estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Scale score, including 3741 cases with good functional outcomes (modified Rankin Scale score, 0-2) and 2280 subjects with poor functional outcomes poststroke (modified Rankin Scale score, 3-6). Inverse variance weighting was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Reported with odds ratios (ORs) of stroke outcome with per SD unit increase in genetically determined iron status biomarker, TSAT and iron were associated with poor functional outcome after IS (TSAT: OR, 1.36 [95% CI, 1.23-1.50]; P=2.27×10-9; iron: OR, 1.44 [95% CI, 1.13-1.85]; P=0.0033). In replicate Mendelian randomization analysis, the detrimental effects of iron on poor functional outcome after IS remained stable (OR, 1.60 [95% CI, 1.24-2.08]; P=0.0003). In the meta-analysis, iron and TSAT were associated with poor functional outcomes after IS (TSAT: ORmeta, 1.35 [95% CI, 1.23-1.48]; iron: ORmeta, 1.51 [95% CI, 1.27-1.81]). Through sensitivity analyses and reverse Mendelian randomization analyses, we confirmed the robustness of the results. CONCLUSIONS: Our study provides evidence suggesting a potential causal relationship between iron status and poor functional outcomes after IS. Future studies are required to illuminate the underlying mechanism.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ferro , Ferritinas , Causalidade , Acidente Vascular Cerebral/genética , Biomarcadores , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética
11.
Stroke ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39417225

RESUMO

BACKGROUND: This study aims to perform a comprehensive analysis of stroke burden from the Global Burden of Disease 2021. METHODS: We conducted a comprehensive analysis of the burden, including prevalence, incidence, mortality, and disability-adjusted life year rates, for stroke across 204 countries and regions from 1990 to 2021 using data from the Global Burden of Disease 2021. We calculated the estimated annual percentage change (EAPC) and performed a joinpoint regression analysis to identify the trends. We also explored the association between the stroke burden and sociodemographic index. RESULTS: The age-standardized prevalence, incidence, mortality, and disability-adjusted life year rates for stroke were 1099.310, 141.553, 87.454, and 1886.196 per 100 000 persons in 2021, respectively. The general stroke burden trends declined in EAPC analysis (age-standardized prevalence: EAPC, -0.37; age-standardized incidence: EAPC, -0.99; age-standardized mortality: EAPC, -1.81; and disability-adjusted life year: EAPC, -1.76). However, we found an increasing burden of stroke in East Asia and Southern Sub-Saharan Africa (EAPC >0). The global burdens of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke showed a similar trend. The stroke, intracerebral hemorrhage, and ischemic stroke burdens were heavier in men than in women, except for that of subarachnoid hemorrhage in women. Our joinpoint regression analysis revealed that the age-standardized burden rates of stroke decreased from 1990 to 2021 (average annual percent change <0), whereas an upward trend was observed between 2019 and 2021 (average annual percent change >0). The burden of stroke was inversely proportional to the sociodemographic index (P<0.05), except in the case of subarachnoid hemorrhage. The actual stroke burden showed an increasing trend for stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke in 2021 (during the coronavirus pandemic). CONCLUSIONS: We found age-standardized rates of stroke burden declining over time, but some areas exhibited a notable increase in the prevalence, incidence, mortality, and disability-adjusted life year rates.

12.
J Am Chem Soc ; 146(32): 22675-22688, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39088029

RESUMO

Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.


Assuntos
Carbono , Dissulfetos , Pró-Fármacos , Dissulfetos/química , Pró-Fármacos/química , Animais , Camundongos , Carbono/química , Humanos , Liberação Controlada de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Linhagem Celular Tumoral , Nanoestruturas/química , Dimerização , Doxorrubicina/química , Doxorrubicina/farmacologia
13.
Emerg Infect Dis ; 30(7): 1434-1437, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38916639

RESUMO

We investigated Alongshan virus infection in reindeer in northeastern China. We found that 4.8% of the animals were viral RNA-positive, 33.3% tested positive for IgG, and 19.1% displayed neutralizing antibodies. These findings suggest reindeer could serve as sentinel animal species for the epidemiologic surveillance of Alongshan virus infection.


Assuntos
Anticorpos Antivirais , Rena , Animais , Rena/virologia , China/epidemiologia , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Infecções por Bunyaviridae/veterinária , Infecções por Bunyaviridae/epidemiologia , Infecções por Bunyaviridae/virologia , RNA Viral , Imunoglobulina G/sangue
14.
Int J Cancer ; 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39276114

RESUMO

Esophageal cancer has a poor prognosis and survival rate due to its high incidence in Asia, lack of early symptoms and limited treatment options. In recent years, many clinical trials have demonstrated that immunotherapy has greatly improved the survival of patients with esophageal cancer. In addition, the combination of neoadjuvant immunotherapy with other popular therapeutic regimens has shown good efficacy and safety. In this review, we summarize the progress of clinical trials and some breakthroughs in neoadjuvant immunotherapy for esophageal cancer in recent years and suggest the possibility of multimodal neoadjuvant immunotherapy regimens, as well as directions for future development.

15.
Am J Transplant ; 24(10): 1837-1856, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38642712

RESUMO

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.


Assuntos
Carcinoma Hepatocelular , Rejeição de Enxerto , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Estudos Retrospectivos , Masculino , Feminino , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Rejeição de Enxerto/etiologia , Seguimentos , Prognóstico , Sobrevivência de Enxerto/efeitos dos fármacos , Taxa de Sobrevida , Fatores de Risco
16.
Clin Immunol ; 263: 110227, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38643891

RESUMO

T-DM1 (Trastuzumab Emtansine) belongs to class of Antibody-Drug Conjugates (ADC), where cytotoxic drugs are conjugated with the antibody Trastuzumab to specifically target HER2-positive cancer cells. Platelets, as vital components of the blood system, intricately influence the immune response to tumors through complex mechanisms. In our study, we examined platelet surface proteins in the plasma of patients before and after T-DM1 treatment, categorizing them based on treatment response. We identified a subgroup of platelets with elevated expression of CD63 and CD9 exclusively in patients with favorable treatment responses, while this subgroup was absent in patients with poor responses. Another noteworthy discovery was the elevated expression of CD36 in the platelet subgroups of patients exhibiting inadequate responses to treatment. These findings suggest that the expression of these platelet surface proteins may be correlated with the prognosis of T-DM1 treatment. These indicators offer valuable insights for predicting the therapeutic response to T-DM1 and may become important references in future clinical practice, contributing to a better understanding of the impact of ADC therapies and optimizing personalized cancer treatment strategies.


Assuntos
Ado-Trastuzumab Emtansina , Plaquetas , Neoplasias da Mama , Humanos , Feminino , Plaquetas/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/sangue , Ado-Trastuzumab Emtansina/uso terapêutico , Pessoa de Meia-Idade , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Adulto , Idoso , Maitansina/uso terapêutico , Maitansina/análogos & derivados
17.
Hum Genet ; 143(9-10): 1049-1060, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38252283

RESUMO

Preimplantation embryonic arrest is an important pathogenesis of female infertility, but little is known about the genetic factors behind this phenotype. MEI4 is an essential protein for DNA double-strand break formation during meiosis, and Mei4 knock-out female mice are viable but sterile, indicating that MEI4 plays a crucial role in reproduction. To date, MEI4 has not been found to be associated with any human reproductive diseases. Here, we identified six compound heterozygous and homozygous MEI4 variants-namely, c.293C > T, p.(Ser98Leu), c.401C > G, p.(Pro134Arg), c.391C > G, p.(Pro131Ala), c.914A > T, p.(Tyr305Phe), c.908C > G, p.(Ala303Gly), and c.899A > T, p.(Gln300Leu)-in four independent families that were responsible for female infertility mainly characterized by preimplantation embryonic arrest. In vitro, we found that these variants reduced the interaction between MEI4 and DNA. In vivo, we generated a knock-in mouse model and demonstrated that female mice were infertile and were characterized by developmental defects during oogenesis. Our findings reveal the important roles of MEI4 in human reproduction and provide a new diagnostic marker for genetic counseling of clinical infertility patients.


Assuntos
Infertilidade Feminina , Mutação de Sentido Incorreto , Feminino , Animais , Camundongos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Humanos , Alelos , Blastocisto/metabolismo , Proteínas de Homeodomínio/genética , Linhagem , Masculino , Oogênese/genética , Camundongos Knockout , Meiose/genética
18.
Anal Chem ; 96(28): 11611-11618, 2024 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-38943567

RESUMO

Citrus Huanglongbing (HLB) is known as the cancer of citrus, where Candidatus Liberibacter asiaticus (CLas) is the most prevalent strain causing HLB. In this study, we report a novel electrochemiluminescence (ECL) biosensor for the highly sensitive detection of the CLas outer membrane protein (Omp) gene by coupling rolling circle amplification (RCA) with a CRISPR/Cas12a-responsive smart DNA hydrogel. In the presence of the target, a large number of amplicons are generated through RCA. The amplicons activate the trans-cleavage activity of CRISPR/Cas12a through hybridizing with crRNA, triggering the response of smart DNA hydrogel to release the encapsulated AuAg nanoclusters (AuAg NCs) on the electrode and therefore leading to a decreased ECL signal. The ECL intensity change (I0 - I) is positively correlated with the concentration of the target in the range 50 fM to 5 nM, with a limit of detection of 40 fM. The performance of the sensor has also been evaluated with 10 samples of live citrus leaves (five HLB negative and five HLB positive), and the result is in excellent agreement with the gold standard qPCR result. The sensing strategy has expanded the ECL versatility for detecting varying levels of dsDNA or ssDNA in plants with high sensitivity.


Assuntos
Proteínas da Membrana Bacteriana Externa , Citrus , Técnicas Eletroquímicas , Medições Luminescentes , Técnicas Eletroquímicas/métodos , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/química , Citrus/microbiologia , Citrus/química , Hidrogéis/química , Técnicas Biossensoriais/métodos , DNA/química , DNA/genética , Sistemas CRISPR-Cas/genética , Liberibacter/genética , Liberibacter/química , Técnicas de Amplificação de Ácido Nucleico , Doenças das Plantas/microbiologia , Ouro/química , Nanopartículas Metálicas/química , Limite de Detecção
19.
BMC Plant Biol ; 24(1): 95, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331719

RESUMO

BACKGROUND: Spirodela polyrrhiza is a simple floating aquatic plant with great potential in synthetic biology. Sodium nitroprusside (SNP) stimulates plant development and increases the biomass and flavonoid content in some plants. However, the molecular mechanism of SNP action is still unclear. RESULTS: To determine the effect of SNP on growth and metabolic flux in S. polyrrhiza, the plants were treated with different concentrations of SNP. Our results showed an inhibition of growth, an increase in starch, soluble protein, and flavonoid contents, and enhanced antioxidant enzyme activity in plants after 0.025 mM SNP treatment. Differentially expressed transcripts were analysed in S. polyrrhiza after 0.025 mM SNP treatment. A total of 2776 differentially expressed genes (1425 upregulated and 1351 downregulated) were identified. The expression of some genes related to flavonoid biosynthesis and NO biosynthesis was upregulated, while the expression of some photosynthesis-related genes was downregulated. Moreover, SNP stress also significantly influenced the expression of transcription factors (TFs), such as ERF, BHLH, NAC, and WRKY TFs. CONCLUSIONS: Taken together, these findings provide novel insights into the mechanisms of underlying the SNP stress response in S. polyrrhiza and show that the metabolic flux of fixed CO2 is redirected into the starch synthesis and flavonoid biosynthesis pathways after SNP treatment.


Assuntos
Plantas , Transcriptoma , Nitroprussiato/farmacologia , Antioxidantes , Perfilação da Expressão Gênica , Flavonoides , Amido
20.
Small ; 20(24): e2310636, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38412413

RESUMO

Several DNA-damaging antitumor agents, including ruthenium complexes, induce immunogenic cell death (ICD). In this study, an arginyl-glycyl-aspartic acid (RGD) peptide-modified carboline ruthenium complex (KS-Ru) is synthesized as a chemotherapeutic nanodrug and an ICD inducer. The RGD peptide, an integrin ligand, provides tumor-specific targeting and promotes self-assembly of the KS-Ru complex. The pH-responsive self-assembly is assessed through transmission and scanning electron microscopy. Additionally, in vitro cytotoxic activity and anti-metastasis ability are evaluated using MTT and Transwell assays, respectively, along with cellular immunofluorescence staining and imaging flow cytometry. The ability of the complex to inhibit primary tumor formation and lung metastasis in vivo is evaluated using Lewis lung cancer and A549 xenograft models. Furthermore, the tumor immune microenvironment is evaluated using single-cell flow mass cytometry. KS-Ru translocates to the nucleus, causing DNA damage and inducing ICD. Within the lysosomes, KS-Ru self-assembled into nanoflowers, leading to lysosomal swelling and apoptosis. Notably, the as-synthesized pH-dependent ruthenium nanomedicine achieves dual functionality-chemotherapy and immunotherapy. Moreover, the pH-responsive self-assembly of KS-Ru enables simultaneous mechanisms in the lysosome and nucleus, thereby lowering the likelihood of drug resistance. This study provides valuable insight for the design of novel ruthenium-based nanoantitumor drugs.


Assuntos
DNA , Morte Celular Imunogênica , Lisossomos , Rutênio , Rutênio/química , Rutênio/farmacologia , Concentração de Íons de Hidrogênio , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , DNA/química , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Células A549 , Linhagem Celular Tumoral
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