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1.
Front Pediatr ; 12: 1418991, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38978841

RESUMO

Objective: The purpose of this study is to compare the intraoperative and postoperative outcomes of a trans-umbilical single-site plus one robot-assisted surgery and a trans-umbilical single-site laparoscopic surgery in the treatment of choledochal cysts. Methods: We retrospectively analyzed clinical data from 49 children diagnosed with choledochal cysts who were admitted to our hospital between June 2020 and December 2023. Among these patients, 24 underwent a trans-umbilical single-site plus one Da Vinci robot-assisted surgery (the robot group) and 25 underwent a trans-umbilical single-site laparoscopic-assisted surgery (the laparoscopic group). We compared differences in intraoperative and postoperative outcomes between the two groups. Results: There was no significant difference between the two groups of patients in terms of gender, age, weight, clinical symptoms, maximum cyst diameter, type, postoperative complications, and facial expression, leg movement, activity, crying, and comfortability (FLACC) scoring (p > 0.05). Compared with the patients in the laparoscopic group, those in the robot group had less intraoperative bleeding [10 (8-12) vs. 15 (11.5-18) ml, p < 0.001] and required less postoperative drainage tube indwelling time [5 (4-6) vs. 7 (5.5-8) day, p < 0.001], less postoperative fasting time [4 (3-4) vs. 6 (5-7) days, p < 0.001], and less postoperative hospitalization time [6 (6-7) vs. 8 (6-10) days, p < 0.001], but they required more operative time [385.5 (317.0-413.3) vs. 346.0 (287.0-376.5) min, p = 0.050] and consumed more hospitalization expenses (79,323 ± 3,124 vs. 31,121 ± 2,918 yuan, p < 0.001). Conclusion: The results of this study showed a shorter hospitalization time, quicker postoperative recovery, and less tissue damage but a higher cost and a longer operation time in patients who chose robotic surgery rather than laparoscopic surgery. With the continuous expansion of the scale of installed robot-assisted surgical systems and the gradual accumulation of the technical experience of surgeons, robot-assisted surgery may slowly surpass, and shows a trend to replace, laparoscopy because of its advantages.

2.
Nucleic Acids Res ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953168

RESUMO

Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the human and pig parasitic nematode Ascaris to characterize the DSBs. Using END-seq, we demonstrate that DSBs are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3'-overhangs before the addition of neotelomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends may be due to the sequestration of the eliminated DNA into micronuclei, preventing neotelomere formation at their ends. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris, ensuring chromosomal breakage and providing a fail-safe mechanism for PDE. Overall, our data indicate that telomere healing of DSBs is specific to the break sites responsible for nematode PDE.

3.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 41(3): 485-493, 2024 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-38932534

RESUMO

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder. Due to the subtlety of symptoms in the early stages of AD, rapid and accurate clinical diagnosis is challenging, leading to a high rate of misdiagnosis. Current research on early diagnosis of AD has not sufficiently focused on tracking the progression of the disease over an extended period in subjects. To address this issue, this paper proposes an ensemble model for assisting early diagnosis of AD that combines structural magnetic resonance imaging (sMRI) data from two time points with clinical information. The model employs a three-dimensional convolutional neural network (3DCNN) and twin neural network modules to extract features from the sMRI data of subjects at two time points, while a multi-layer perceptron (MLP) is used to model the clinical information of the subjects. The objective is to extract AD-related features from the multi-modal data of the subjects as much as possible, thereby enhancing the diagnostic performance of the ensemble model. Experimental results show that based on this model, the classification accuracy rate is 89% for differentiating AD patients from normal controls (NC), 88% for differentiating mild cognitive impairment converting to AD (MCIc) from NC, and 69% for distinguishing non-converting mild cognitive impairment (MCInc) from MCIc, confirming the effectiveness and efficiency of the proposed method for early diagnosis of AD, as well as its potential to play a supportive role in the clinical diagnosis of early Alzheimer's disease.


Assuntos
Doença de Alzheimer , Diagnóstico Precoce , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Humanos , Imageamento por Ressonância Magnética/métodos , Progressão da Doença , Algoritmos
4.
Curr Protoc ; 4(6): e1074, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38923794

RESUMO

Ascariasis, caused by both Ascaris lumbricoides and Ascaris suum, is the most prevalent parasitic disease worldwide, affecting both human and porcine populations. However, due to the difficulties of assessing the early events of infection in humans, most studies of human ascariasis have been restricted to the chronic intestinal phase. Therefore, the Ascaris mouse model has become a fundamental tool for investigating the immunobiology and pathogenesis of the early infection stage referred to as larval ascariasis because of the model's practicality and ability to replicate the natural processes involved. The Ascaris mouse model has been widely used to explore factors such as infection resistance/susceptibility, liver inflammation, lung immune-mediated pathology, and co-infections and, notably, as a pivotal element in preclinical vaccine trials. Exploring the immunobiology of larval ascariasis may offer new insights into disease development and provide a substantial understanding of key components that trigger a protective immune response. This article focuses on creating a comprehensive guide for conducting Ascaris experimental infections in the laboratory as a foundation for future research efforts. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Acquisition and embryonation of Ascaris suum eggs from adult females Alternate Protocol: Cleaning and purification of Ascaris suum from female A. suum uteri Basic Protocol 2: Preparation of Ascaris suum eggs and murine infection Basic Protocol 3: Measurement of larval burden and Ascaris-larva-induced pathogenesis Basic Protocol 4: In vitro hatching and purification of Ascaris L3 larvae Support Protocol: Preparation of crude antigen from Ascaris infectious stages Basic Protocol 5: Ultrastructure-expansion microscopy (U-ExM) of Ascaris suum larval stages.


Assuntos
Ascaríase , Ascaris suum , Modelos Animais de Doenças , Larva , Ascaríase/parasitologia , Ascaríase/imunologia , Animais , Camundongos , Ascaris suum/imunologia , Larva/imunologia , Feminino , Ascaris/imunologia , Ascaris/patogenicidade , Humanos
5.
Cell Mol Life Sci ; 81(1): 221, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38763964

RESUMO

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.


Assuntos
Hormônio Foliculoestimulante , Células da Granulosa , Folículo Ovariano , Proteína Sequestossoma-1 , Ubiquitinação , Proteínas WT1 , Animais , Hormônio Foliculoestimulante/metabolismo , Hormônio Foliculoestimulante/farmacologia , Feminino , Proteínas WT1/metabolismo , Proteínas WT1/genética , Camundongos , Folículo Ovariano/metabolismo , Folículo Ovariano/efeitos dos fármacos , Células da Granulosa/metabolismo , Células da Granulosa/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Camundongos Endogâmicos C57BL , Autofagia/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Humanos , Camundongos Knockout
6.
RSC Adv ; 14(22): 15591-15596, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38746836

RESUMO

A strategy allowing the switchable divergent synthesis of chiral indole derivatives was established via chiral phosphoric acid-catalyzed asymmetric dearomatization of 2,3-disubstituted indoles using naphthoquinone monoimines as electrophiles. The products were switched between chiral indolenines and fused indolines according to the post-processing conditions. Both two types of products were obtained in good to high yields with generally excellent enantioselectivities. NaBH4 was found to work as a promoter as well as a reductant in the cyclization process leading to fused indolines.

7.
bioRxiv ; 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38559121

RESUMO

Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well-characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the nematode Ascaris to study the timing of PDE breaks and examine the DSBs and their end processing. Using END-seq, we characterize the DSB ends and demonstrate that DNA breaks are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3' overhangs before the addition of telomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends in Ascaris may be due to the sequestration of the eliminated DNA into micronuclei, preventing their ends from telomere healing. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris, ensuring chromosomal breakage and providing a fail-safe mechanism for nematode PDE.

8.
Curr Biol ; 34(10): 2147-2161.e5, 2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38688284

RESUMO

An increasing number of metazoans undergo programmed DNA elimination (PDE), where a significant amount of DNA is selectively lost from the somatic genome during development. In some nematodes, PDE leads to the removal and remodeling of the ends of all germline chromosomes. In several species, PDE also generates internal breaks that lead to sequence loss and increased numbers of somatic chromosomes. The biological significance of these karyotype changes associated with PDE and the origin and evolution of nematode PDE remain largely unknown. Here, we assembled the single germline chromosome of the nematode Parascaris univalens and compared the karyotypes, chromosomal gene organization, and PDE features among other nematodes. We show that PDE in Parascaris converts an XX/XY sex-determination system in the germline into an XX/XO system in the somatic cells. Comparisons of Ascaris, Parascaris, and Baylisascaris ascarid chromosomes suggest that PDE existed in the ancestor of these nematodes, and their current distinct germline karyotypes were derived from fusion events of smaller ancestral chromosomes. The DNA breaks involved in PDE resolve these fused germline chromosomes into their pre-fusion karyotypes. These karyotype changes may lead to alterations in genome architecture and gene expression in the somatic cells. Cytological and genomic analyses further suggest that satellite DNA and the heterochromatic chromosome arms are dynamic and may play a role during meiosis. Overall, our results show that chromosome fusion and PDE have been harnessed in these ascarids to sculpt their karyotypes, altering the genome organization and serving specific functions in the germline and somatic cells.


Assuntos
Cariótipo , Animais , Masculino , Cromossomos/genética , Nematoides/genética , Feminino , DNA de Helmintos/genética
9.
Adv Sci (Weinh) ; 11(18): e2307834, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38460155

RESUMO

Targeting cancer-specific metabolic processes is a promising therapeutic strategy. Here, this work uses a compound library that directly inhibits metabolic enzymes to screen the potential metabolic targets in lung adenocarcinoma (LUAD). SHIN1, the specific inhibitor of serine hydroxymethyltransferase 1/2 (SHMT1/2), has a highly specific inhibitory effect on LUAD cells, and this effect depends mainly on the overexpression of SHMT2. This work clarifies that mitogen-activated protein kinase 1 (MAPK1)-mediated phosphorylation at Ser90 is the key mechanism underlying SHMT2 upregulation in LUAD and that this phosphorylation stabilizes SHMT2 by reducing STIP1 homology and U-box containing protein 1 (STUB1)-mediated ubiquitination and degradation. SHMT2-Ser90 dephosphorylation decreases S-adenosylmethionine levels in LUAD cells, resulting in reduced N6-methyladenosine (m6A) levels in global RNAs without affecting total protein or DNA methylation. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analyses further demonstrate that SHMT2-Ser90 dephosphorylation accelerates the RNA degradation of oncogenic genes by reducing m6A modification, leading to the inhibition of tumorigenesis. Overall, this study elucidates a new regulatory mechanism of SHMT2 during oncogenesis and provides a theoretical basis for targeting SHMT2 as a therapeutic target in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Adenosina , Carcinogênese , Glicina Hidroximetiltransferase , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação/genética
10.
Front Nutr ; 11: 1323553, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38439921

RESUMO

Background: Peanut is an important source of dietary protein for human beings, but it is also recognized as one of the eight major food allergens. Binding of IgE antibodies to specific epitopes in peanut allergens plays important roles in initiating peanut-allergic reactions, and Ara h 2 is widely considered as the most potent peanut allergen and the best predictor of peanut allergy. Therefore, Ara h 2 IgE epitopes can serve as useful biomarkers for prediction of IgE-binding variations of Ara h 2 and peanut in foods. This study aimed to develop and validate an IgE epitope-specific antibodies (IgE-EsAbs)-based sandwich ELISA (sELISA) for detection of Ara h 2 and measurement of Ara h 2 IgE-immunoreactivity changes in foods. Methods: DEAE-Sepharose Fast Flow anion-exchange chromatography combining with SDS-PAGE gel extraction were applied to purify Ara h 2 from raw peanut. Hybridoma and epitope vaccine techniques were employed to generate a monoclonal antibody against a major IgE epitope of Ara h 2 and a polyclonal antibody against 12 IgE epitopes of Ara h 2, respectively. ELISA was carried out to evaluate the target binding and specificity of the generated IgE-EsAbs. Subsequently, IgE-EsAbs-based sELISA was developed to detect Ara h 2 and its allergenic residues in food samples. The IgE-binding capacity of Ara h 2 and peanut in foods was determined by competitive ELISA. The dose-effect relationship between the Ara h 2 IgE epitope content and Ara h 2 (or peanut) IgE-binding ability was further established to validate the reliability of the developed sELISA in measuring IgE-binding variations of Ara h 2 and peanut in foods. Results: The obtained Ara h 2 had a purity of 94.44%. Antibody characterization revealed that the IgE-EsAbs recognized the target IgE epitope(s) of Ara h 2 and exhibited high specificity. Accordingly, an IgE-EsAbs-based sELISA using these antibodies was able to detect Ara h 2 and its allergenic residues in food samples, with high sensitivity (a limit of detection of 0.98 ng/mL), accuracy (a mean bias of 0.88%), precision (relative standard deviation < 16.50%), specificity, and recovery (an average recovery of 98.28%). Moreover, the developed sELISA could predict IgE-binding variations of Ara h 2 and peanut in foods, as verified by using sera IgE derived from peanut-allergic individuals. Conclusion: This novel immunoassay could be a user-friendly method to monitor low level of Ara h 2 and to preliminary predict in vitro potential allergenicity of Ara h 2 and peanut in processed foods.

11.
Materials (Basel) ; 17(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473492

RESUMO

Using metal additive manufacturing processes can make up for traditional forging technologies when forming complex-shaped parts. At the same time, metal additive manufacturing has a fast forming speed and excellent manufacturing flexibility, so it is widely used in the aerospace industry and other fields. The fatigue strength of metal additive manufacturing is related to the microstructure of the epitaxially grown columnar grains and crystallographic texture. The crystal plasticity finite element method is widely used in the numerical simulation of the microstructure and macro-mechanical response of materials, which provides a strengthening and toughening treatment and can reveal the inner rules of material deformation. This paper briefly introduces common metal additive manufacturing processes. In terms of additive manufacturing fatigue, crystal plasticity simulations are summarized and discussed with regard to several important influencing factors, such as the microstructure, defects, surface quality, and residual stress.

12.
ACS Nano ; 18(14): 10184-10195, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38529933

RESUMO

Heterointerface engineering is an attractive approach to modulating electromagnetic (EM) parameters and EM wave absorption performance. However, the weak interfacial interactions and poor impedance matching would lead to unsatisfactory EM absorption performance due to the limitation of the construction materials and design strategies. Herein, multilevel heterointerface engineering is proposed by in situ growing nanosheet-like NiCoO2 and selenides with abundant interface structures on 3D-printed graphene aerogel (GA) skeletons, which strengthens the interfacial effect and improves the dielectric polarization loss. Benefiting from the features of substantially enhanced polarization loss and optimized impedance matching, the graphene/S-NiCoO2/selenides (G/S-NCO/Se) have achieved brilliant EM wave absorption performance with a strong reflection loss (RL) value of -60.7 dB and a broad effective absorption bandwidth (EAB) of 8 GHz, which is about six times greater than that of the graphene aerogel (-9.8 dB). Moreover, it is further confirmed by charge density differences and off-axis electron holography that a large amount of polarized charge accumulates at the interface, leading to significant polarization relaxation behaviors. This work provides a deep understanding of the effect of a multilevel heterogeneous interface on dielectric polarization loss, which injects a fresh and infinite vitality for designing high-efficiency EM wave absorbers.

13.
Adv Parasitol ; 123: 51-123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38448148

RESUMO

The ascarids are a large group of parasitic nematodes that infect a wide range of animal species. In humans, they cause neglected diseases of poverty; many animal parasites also cause zoonotic infections in people. Control measures include hygiene and anthelmintic treatments, but they are not always appropriate or effective and this creates a continuing need to search for better ways to reduce the human, welfare and economic costs of these infections. To this end, Le Studium Institute of Advanced Studies organized a two-day conference to identify major gaps in our understanding of ascarid parasites with a view to setting research priorities that would allow for improved control. The participants identified several key areas for future focus, comprising of advances in genomic analysis and the use of model organisms, especially Caenorhabditis elegans, a more thorough appreciation of the complexity of host-parasite (and parasite-parasite) communications, a search for novel anthelmintic drugs and the development of effective vaccines. The participants agreed to try and maintain informal links in the future that could form the basis for collaborative projects, and to co-operate to organize future meetings and workshops to promote ascarid research.


Assuntos
Anti-Helmínticos , Zoonoses , Animais , Humanos , Zoonoses/prevenção & controle , Caenorhabditis elegans , Academias e Institutos , Pesquisa , Anti-Helmínticos/uso terapêutico
14.
Sensors (Basel) ; 24(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38543976

RESUMO

Wireless sensor networks (WSNs) are gaining traction in the realm of network communication, renowned for their adaptability, configuration, and flexibility. The forthcoming network traffic within WSNs can be forecasted through temporal sequence models. In this correspondence, we present a method (TSENet) that can accurately predict the traffic in the cellular network. TSENet is composed of transformers and self-attention network. We have designed a temporal transformer module specifically for extracting temporal features. This module accomplishes this by modeling the traffic flow within each grid of the communication network at both near-term and periodical intervals. Simultaneously, we amalgamate the spatial features of each grid with information from its correlated grids, generating spatial predictions within the spatial transformer. Furthermore, we employ self-attention aggregation to capture dependencies between external factor features and cellular data features. Empirical assessments performed on a genuine cellular traffic dataset offer compelling evidence substantiating the efficacy of TSENet.

15.
Theranostics ; 14(4): 1371-1389, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38389850

RESUMO

Rationale: Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI. Methods: We used whole genome sequencing (WGS), conditional knockout mouse models combined with laser capture microdissection (LCM), and RNA/ChIP sequencing to analyze the crucial roles of polycomb repressive complex 1 (PRC1) in clinical POI and mammalian folliculogenesis. Results: A deletion mutation of MEL18, the key component of PRC1, was identified in a 17-year-old patient. However, deleting Mel18 in granulosa cells (GCs) did not induce infertility until its homolog, Bmi1, was deleted simultaneously. Double deficiency of BMI1/MEL18 eliminated PRC1 catalytic activity, upregulating cyclin-dependent kinase inhibitors (CDKIs) and thus blocking GC proliferation during primary-to-secondary follicle transition. This defect led to damaged intercellular crosstalk, eventually resulting in gonadotropin response failure and infertility. Conclusions: Our findings highlighted the pivotal role of PRC1 as an epigenetic regulator of gene transcription networks in GC proliferation during early folliculogenesis. In the future, a better understanding of molecular details of PRC1 structural and functional abnormalities may contribute to POI diagnosis and therapeutic options.


Assuntos
Infertilidade , Insuficiência Ovariana Primária , Adolescente , Animais , Feminino , Humanos , Camundongos , Núcleo Celular , Proliferação de Células/genética , Mamíferos , Complexo Repressor Polycomb 1/genética , Insuficiência Ovariana Primária/genética , Reprodução , Modelos Animais de Doenças , Camundongos Knockout
16.
Sci Bull (Beijing) ; 69(8): 1122-1136, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38302330

RESUMO

In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.


Assuntos
Células da Granulosa , Folículo Ovariano , Feminino , Autofagia/genética , Hormônio Foliculoestimulante/farmacologia , Células da Granulosa/metabolismo , Folículo Ovariano/metabolismo , Transdução de Sinais
17.
Cell Res ; 34(4): 295-308, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38326478

RESUMO

Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (TFH) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (TFR) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, TFH cells and TFR cells.


Assuntos
Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores , Animais , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos B , Centro Germinativo/metabolismo , Autoantígenos/metabolismo
18.
Lab Chip ; 24(4): 642-657, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38165771

RESUMO

As a class of antibodies that specifically bind to a virus and block its entry, neutralizing monoclonal antibodies (neutralizing mAbs) have been recognized as a top choice for combating COVID-19 due to their high specificity and efficacy in treating serious infections. Although conventional approaches for neutralizing mAb development have been optimized for decades, there is an urgent need for workflows with higher efficiency due to time-sensitive concerns, including the high mutation rate of SARS-CoV-2. One promising approach is the identification of neutralizing mAb candidates via single-cell RNA sequencing (RNA-seq), as each B cell has a unique transcript sequence corresponding to its secreted antibody. The state-of-the-art high-throughput single-cell sequencing technologies, which have been greatly facilitated by advances in microfluidics, have greatly accelerated the process of neutralizing mAb development. Here, we provide an overview of the general procedures for high-throughput single-cell RNA-seq enabled by breakthroughs in droplet microfluidics, introduce revolutionary approaches that combine single-cell RNA-seq to facilitate the development of neutralizing mAbs against SARS-CoV-2, and outline future steps that need to be taken to further improve development strategies for effective treatments against infectious diseases.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Humanos , SARS-CoV-2/genética , Testes de Neutralização , Anticorpos Monoclonais/metabolismo , Microfluídica , Análise de Sequência de RNA , Anticorpos Antivirais
19.
Sci Total Environ ; 917: 170438, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38286283

RESUMO

Uncertainty in methane (CH4) exchanges across wetlands and grasslands in the Qinghai-Tibetan Plateau (QTP) is projected to increase due to continuous permafrost degradation and asymmetrical seasonal warming. Temperature plays a vital role in regulating CH4 exchange, yet the seasonal patterns of temperature dependencies for CH4 fluxes over the wetlands and grasslands on the QTP remain poorly understood. Here, we demonstrated a stronger warming response of CH4 exchanges during the non-growing season compared to the growing season on the QTP. Analyzing 9745 daily observations and employing four methods -regression fitting of temperature-CH4 flux, temperature dependence calculations, field-based and model-based control experiments-we found that warming intensified CH4 emissions in wetlands and uptakes in grasslands. Specifically, the average reaction intensity in the non-growing season surpasses that in the growing season by 1.89 and 4.80 times, respectively. This stronger warming response of CH4 exchanges during the non-growing season significantly increases the regional CH4 exchange on the QTP. Our research reveals that CH4 exchanges in the QTP have a higher warming sensitivity in non-growing seasons, which meanwhile are dominated by a larger warming rate than the annual average. The combined effects of these two factors will significantly alter the CH4 source/sink on the QTP. Neglecting these impacts would lead to inaccurate estimations of CH4 source/sink over the QTP under climate warming.

20.
Nat Prod Res ; : 1-7, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38289060

RESUMO

Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%. Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM. Compared with the normal group, the expression of Bcl-2 protein in OGD/R-injured PC12 cells was downregulated (p < 0.01), and that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins were upregulated (p < 0.01, p < 0.001). Compared with the OGD/R group, 25 µM texasin could upregulate the expression of Bcl-2 protein (p < 0.01), and downregulate that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins (p < 0.01, p < 0.001). The 7-OH and 1-O of texasin formed H-bonds with residues Cys891 of the hinge ß-strand of PERK, which is crucial for kinase inhibitors. The above results suggest that the method established in the present study achieved rapid preparation of high-purity texasin. Texasin might inhibit neuronal apoptosis via the regulation of endoplasmic reticulum stress PERK/eIF2α/ATF4/CHOP signalling pathway to exert a protective effect on OGD/R-injured PC12 cells. Aiding by molecular docking, texasin was assumed to be a potential PERK inhibitor.

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