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1.
Mol Cell ; 84(9): 1711-1726.e11, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38569554

RESUMO

N6-methyladenosine (m6A) is a crucial RNA modification that regulates diverse biological processes in human cells, but its co-transcriptional deposition and functions remain poorly understood. Here, we identified the RNA helicase DDX21 with a previously unrecognized role in directing m6A modification on nascent RNA for co-transcriptional regulation. DDX21 interacts with METTL3 for co-recruitment to chromatin through its recognition of R-loops, which can be formed co-transcriptionally as nascent transcripts hybridize onto the template DNA strand. Moreover, DDX21's helicase activity is needed for METTL3-mediated m6A deposition onto nascent RNA following recruitment. At transcription termination regions, this nexus of actions promotes XRN2-mediated termination of RNAPII transcription. Disruption of any of these steps, including the loss of DDX21, METTL3, or their enzymatic activities, leads to defective termination that can induce DNA damage. Therefore, we propose that the R-loop-DDX21-METTL3 nexus forges the missing link for co-transcriptional modification of m6A, coordinating transcription termination and genome stability.


Assuntos
Adenosina , Adenosina/análogos & derivados , RNA Helicases DEAD-box , Exorribonucleases , Instabilidade Genômica , Metiltransferases , Estruturas R-Loop , RNA Polimerase II , Terminação da Transcrição Genética , Humanos , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Adenosina/metabolismo , Adenosina/genética , Exorribonucleases/metabolismo , Exorribonucleases/genética , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Células HEK293 , Cromatina/metabolismo , Cromatina/genética , Dano ao DNA , Células HeLa , RNA/metabolismo , RNA/genética , Transcrição Gênica , Metilação de RNA
2.
Cell ; 164(1-2): 279-292, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26771496

RESUMO

Mammalian interspecific hybrids provide unique advantages for mechanistic studies of speciation, gene expression regulation, and X chromosome inactivation (XCI) but are constrained by their limited natural resources. Previous artificially generated mammalian interspecific hybrid cells are usually tetraploids with unstable genomes and limited developmental abilities. Here, we report the generation of mouse-rat allodiploid embryonic stem cells (AdESCs) by fusing haploid ESCs of the two species. The AdESCs have a stable allodiploid genome and are capable of differentiating into all three germ layers and early-stage germ cells. Both the mouse and rat alleles have comparable contributions to the expression of most genes. We have proven AdESCs as a powerful tool to study the mechanisms regulating X chromosome inactivation and to identify X inactivation-escaping genes, as well as to efficiently identify genes regulating phenotypic differences between species. A similar method could be used to create hybrid AdESCs of other distantly related species.


Assuntos
Fusão Celular/métodos , Quimera/genética , Células-Tronco Embrionárias/citologia , Células Híbridas , Camundongos , Ratos , Animais , Diferenciação Celular , Corpos Embrioides , Células-Tronco Embrionárias/metabolismo , Feminino , Haploidia , Masculino , Camundongos Endogâmicos , Ratos Endogâmicos F344 , Especificidade da Espécie , Inativação do Cromossomo X
3.
Proc Natl Acad Sci U S A ; 121(15): e2321759121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38579009

RESUMO

Adjacent plant cells are connected by specialized cell wall regions, called middle lamellae, which influence critical agricultural characteristics, including fruit ripening and organ abscission. Middle lamellae are enriched in pectin polysaccharides, specifically homogalacturonan (HG). Here, we identify a plant-specific Arabidopsis DUF1068 protein, called NKS1/ELMO4, that is required for middle lamellae integrity and cell adhesion. NKS1 localizes to the Golgi apparatus and loss of NKS1 results in changes to Golgi structure and function. The nks1 mutants also display HG deficient phenotypes, including reduced seedling growth, changes to cell wall composition, and tissue integrity defects. These phenotypes are comparable to qua1 and qua2 mutants, which are defective in HG biosynthesis. Notably, genetic interactions indicate that NKS1 and the QUAs work in a common pathway. Protein interaction analyses and modeling corroborate that they work together in a stable protein complex with other pectin-related proteins. We propose that NKS1 is an integral part of a large pectin synthesis protein complex and that proper function of this complex is important to support Golgi structure and function.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Adesão Celular/genética , Pectinas/metabolismo , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Parede Celular/metabolismo
4.
Nano Lett ; 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602471

RESUMO

Mimicking the function of human skin is highly desired for electronic skins (e-skins) to perceive the tactile stimuli by both their intensity and spatial location. The common strategy using pixelated pressure sensor arrays and display panels greatly increases the device complexity and compromises the portability of e-skins. Herein, we tackled this challenge by developing a user-interactive iontronic skin that simultaneously achieves electrical pressure sensing and on-site, nonpixelated pressure mapping visualization. By merging the electrochromic and iontronic pressure sensing units into an integrated multilayer device, the interlayer charge transfer is regulated by applied pressure, which induces both color shifting and a capacitance change. The iontronic skin could visualize the trajectory of dynamic forces and reveal both the intensity and spatial information on various human activities. The integration of dual-mode pressure responsivity, together with the scalable fabrication and explicit signal output, makes the iontronic skin highly promising in biosignal monitoring and human-machine interaction.

5.
Nano Lett ; 24(10): 3176-3185, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38436575

RESUMO

Inspired by the reverse thrust generated by fuel injection, micromachines that are self-propelled by bubble ejection are developed, such as microrods, microtubes, and microspheres. However, controlling bubble ejection sites to build micromachines with programmable actuation and further enabling mechanical transmission remain challenging. Here, bubble-propelled mechanical microsystems are constructed by proposing a multimaterial femtosecond laser processing method, consisting of direct laser writing and selective laser metal reduction. The polymer frame of the microsystems is first printed, followed by the deposition of catalytic platinum into the desired local site of the microsystems by laser reduction. With this method, a variety of designable microrotors with selective bubble ejection sites are realized, which enable excellent mechanical transmission systems composed of single and multiple mechanical components, including a coupler, a crank slider, and a crank rocker system. We believe the presented bubble-propelled mechanical microsystems could be extended to applications in microrobotics, microfluidics, and microsensors.

6.
J Cell Mol Med ; 28(1): e18064, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38031653

RESUMO

With the increasing incidence of oral cancer in the world, it has become a hotspot to explore the pathogenesis and prevention of oral cancer. It has been proved there is a strong link between periodontal pathogens and oral cancer. However, the specific molecular and cellular pathogenic mechanisms remain to be further elucidated. Emerging evidence suggests that periodontal pathogens-induced epithelial-mesenchymal transition (EMT) is closely related to the progression of oral cancer. Cells undergoing EMT showed increased motility, aggressiveness and stemness, which provide a pro-tumour environment and promote malignant metastasis of oral cancer. Plenty of studies proposed periodontal pathogens promote carcinogenesis via EMT. In the current review, we discussed the association between the development of oral cancer and periodontal pathogens, and summarized various mechanisms of EMT caused by periodontal pathogens, which are supposed to play an important role in oral cancer, to provide targets for future research in the fight against oral cancer.


Assuntos
Neoplasias Bucais , Porphyromonas gingivalis , Humanos , Neoplasias Bucais/patologia , Transição Epitelial-Mesenquimal , Carcinogênese , Fusobacterium nucleatum
7.
J Am Chem Soc ; 146(25): 17041-17053, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38865208

RESUMO

A large amount of lithium-ion storage in Si-based anodes promises high energy density yet also results in large volume expansion, causing impaired cyclability and conductivity. Instead of restricting pulverization of Si-based particles, herein, we disclose that single-walled carbon nanotubes (SWNTs) can take advantage of volume expansion and induce interfacial reactions that stabilize the pulverized Si-based clusters in situ. Operando Raman spectroscopy and density functional theory calculations reveal that the volume expansion by the lithiation of Si-based particles generates ∼14% tensile strains in SWNTs, which, in turn, strengthens the chemical interaction between Li and C. This chemomechanical coupling effect facilitates the transformation of sp2-C at the defect of SWNTs to Li-C bonds with sp3 hybridization, which also initiates the formation of new Si-C chemical bonds at the interface. Along with this process, SWNTs can also induce in situ reconstruction of the 3D architecture of the anode, forming mechanically strengthened networks with high electrical and ionic conductivities. As such, with the addition of only 1 wt % of SWNTs, graphite/SiOx composite anodes can deliver practical performance well surpassing that of commercial graphite anodes. These findings enrich our understanding of strain-induced interfacial reactions, providing a general principle for mitigating the degradation of alloying or conversion-reaction-based electrodes.

8.
Mol Med ; 30(1): 73, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822233

RESUMO

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.


Assuntos
Apoptose , Proliferação de Células , Depsipeptídeos , Mesotelioma Maligno , Mesotelioma , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/patologia , Linhagem Celular Tumoral , Camundongos , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Células Epitelioides/patologia , Ciclo Celular/efeitos dos fármacos
9.
Anal Chem ; 96(1): 220-228, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38109169

RESUMO

Nucleic acid detection of pathogens in a point-of-need (PON) manner is of great significance yet remains challenging for sensitive and accurate visual discrimination. Here, we report a CRISPR-Cas12a-mediated lateral flow assay for PON detection of Salmonella typhimurium (S.ty) that is a prevailing pathogen disseminated through tainted food. The variation of the fluorescence color of the test line is exploited to interpret the results, enabling the discrimination between positive and negative samples on the basis of a hue-recognition mechanism. By leveraging the cleavage activity of Cas12a and hue-recognition readout, the assay facilitated by recombinase polymerase amplification can yield a visual detection limit of 1 copy µL-1 for S.ty genomic DNA within 1 h. The assay also displays a high specificity toward S.ty in fresh chicken samples, as well as a sensitivity 10-fold better than that of the commercial test strip. Moreover, a semiquantitative detection of S.ty ranging from 0 to 4 × 103 CFU/mL by the naked eye is made possible, thanks to the easily discernible color change of the test line. This approach provides an easy, rapid, accurate, and user-friendly solution for the PON detection of Salmonella and other pathogens.


Assuntos
Sistemas CRISPR-Cas , Salmonella typhimurium , Animais , Sistemas CRISPR-Cas/genética , Salmonella typhimurium/genética , Bioensaio , Galinhas , Alimentos , Técnicas de Amplificação de Ácido Nucleico
10.
Small ; : e2311172, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351480

RESUMO

Ruthenium oxide is currently considered as the promising alternative to Ir-based catalysts employed for proton exchange membrane water electrolyzers but still faces the bottlenecks of limited durability and slow kinetics. Herein, a 2D amorphous/crystalline heterophase ac-Cr0.53 Ru0.47 O2-δ substitutional solid solution with pervasive grain boundaries (GBs) is developed to accelerate the kinetics of acidic oxygen evolution reaction (OER) and extend the long-term stability simultaneously. The ac-Cr0.53 Ru0.47 O2-δ shows a super stability with a slow degradation rate and a remarkable mass activity of 455 A gRu -1 at 1.6 V vs RHE, which is ≈3.6- and 5.9-fold higher than those of synthesized RuO2 and commercial RuO2 , respectively. The strong interaction of Cr-O-Ru local units in synergy with the specific 2D structural characteristics of ac-Cr0.53 Ru0.47 O2-δ dominates its enhanced stability. Meanwhile, high-density GBs and the shortened Ru-O bonds tailored by amorphous/crystalline structure and Cr-O-Ru interaction regulate the adsorption and desorption rates of oxygen intermediates, thus accelerating the overall acidic OER kinetics.

11.
Opt Lett ; 49(11): 3275-3278, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824382

RESUMO

It is known that light extraction efficiency (LEE) for AlGaN-based deep ultraviolet (DUV) light-emitting diodes (LEDs) can be enhanced by using an inclined sidewall of mesa. However, the reported optimal inclined angles are different. In this work, to explore the origin for enhancing the LEE of DUV LED by using inclined sidewalls, we investigate the effect of an inclined sidewall angle on the LEE for AlGaN-based DUV LEDs with different mesa diameters by using ray tracing. It is found that when compared to large-size DUV LEDs with inclined sidewall, the LEE of small-size DUV LEDs with inclined sidewall is enhanced from both the bottom and side surfaces due to the reduced scattering length and material absorption. Additionally, the optimal inclined sidewall angle is recommended within the range of 25°-65°, and the optimal angle for DUV LEDs decreases as the chip size increases. It can be attributed to the fact that there are two scattering mechanisms for the inclined sidewall. For smaller chip sizes, most of the light is directly scattered into escape cones by the inclined sidewall, resulting in a larger optimal angle. For larger chip sizes, the light firstly experiences total internal reflections by the out-light plane and then is scattered into escape cones by the inclined sidewalls, leading to a smaller optimal angle.

12.
Cytotherapy ; 26(6): 606-615, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38483364

RESUMO

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) hold great promise in the treatment of diabetic retinopathy (DR), as evidenced by increasing preclinical and clinical studies. However, the absence of standardized and industrialized clinical-grade donor cells hampers the continued development and large-scale clinical application of MSCs-based therapies for DR. Previously, we have identified a unique population of MSCs generated from a clinical-grade human embryonic stem cell (hESC) line under Good Manufacturing Practice conditions that could be a potential source to address the issues. Here, we investigated the therapeutic potential of the clinical-grade hESC line-derived MSCs (hESC-MSCs) on db/db mice with DR. METHODS: hESC-MSCs were initially characterized by morphological assessment, flow cytometry analysis and trilineage differentiation assays. These cells (5 × 106 cells) were then transplanted intravenously into 12-week-old db/db mice via tail vein, with phosphate-buffered saline transplantation and untreated groups used as controls. The retinal alterations in neural functions and microvascular perfusions, and inflammatory responses in peripheral blood and retina were evaluated at 4 and 6 weeks after transplantation using electroretinography, optical coherence tomography angiography and flow cytometry, respectively. Body weight and fasting blood glucose (FBG) levels were also measured to investigate their systemic implications. RESULTS: Compared with controls, intravenous transplantation of hESC-MSCs could significantly: (i) enhance impaired retinal electroretinography functions (including amplitudes of a-, b-wave and oscillatory potentials) at 4 weeks after transplantation; (ii) alleviate microvascular dysfunctions, especially in the inner retina with significance (including reducing non-perfusion area and increasing vascular area density) at 4 weeks after transplantation; (iii) decrease FBG levels at 4 weeks after transplantation and induce weight loss up to 6 weeks after transplantation and (iv) increase both peripheral blood and retinal interleukin-10 levels at 4 weeks after transplantation and modulate peripheral blood inflammatory cytokines and chemokines levels, such as monocyte chemotactic protein-1, up to 6 weeks after transplantation. CONCLUSIONS: The findings of our study indicated that intravenous transplantation of hESC-MSCs ameliorated retinal neural and microvascular dysfunctions, regulated body weight and FBG and modulated peripheral blood and retinal inflammation responses in a mouse model of DR. These results suggest that hESC-MSCs could be a potentially effective clinical-grade cell source for the treatment of DR.


Assuntos
Retinopatia Diabética , Células-Tronco Embrionárias Humanas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Humanos , Retinopatia Diabética/terapia , Camundongos , Células-Tronco Embrionárias Humanas/citologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Diferenciação Celular , Retina , Modelos Animais de Doenças , Diabetes Mellitus Experimental/terapia
13.
Curr Pain Headache Rep ; 28(5): 439-451, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38502437

RESUMO

PURPOSE OF REVIEW: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH. RECENT FINDINGS: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.


Assuntos
Modelos Animais de Doenças , Cefaleia do Tipo Tensional , Cefaleia do Tipo Tensional/fisiopatologia , Cefaleia do Tipo Tensional/tratamento farmacológico , Cefaleia do Tipo Tensional/terapia , Animais , Humanos
14.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34016749

RESUMO

Worldwide cardiovascular diseases such as stroke and heart disease are the leading cause of mortality. While guidewire/catheter-based minimally invasive surgery is used to treat a variety of cardiovascular disorders, existing passive guidewires and catheters suffer from several limitations such as low steerability and vessel access through complex geometry of vasculatures and imaging-related accumulation of radiation to both patients and operating surgeons. To address these limitations, magnetic soft continuum robots (MSCRs) in the form of magnetic field-controllable elastomeric fibers have recently demonstrated enhanced steerability under remotely applied magnetic fields. While the steerability of an MSCR largely relies on its workspace-the set of attainable points by its end effector-existing MSCRs based on embedding permanent magnets or uniformly dispersing magnetic particles in polymer matrices still cannot give optimal workspaces. The design and optimization of MSCRs have been challenging because of the lack of efficient tools. Here, we report a systematic set of model-based evolutionary design, fabrication, and experimental validation of an MSCR with a counterintuitive nonuniform distribution of magnetic particles to achieve an unprecedented workspace. The proposed MSCR design is enabled by integrating a theoretical model and the genetic algorithm. The current work not only achieves the optimal workspace for MSCRs but also provides a powerful tool for the efficient design and optimization of future magnetic soft robots and actuators.

15.
PLoS Genet ; 17(8): e1009705, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34437539

RESUMO

Whole-genome duplication and genome compaction are thought to have played important roles in teleost fish evolution. Ayu (or sweetfish), Plecoglossus altivelis, belongs to the superorder Stomiati, order Osmeriformes. Stomiati is phylogenetically classified as sister taxa of Neoteleostei. Thus, ayu holds an important position in the fish tree of life. Although ayu is economically important for the food industry and recreational fishing in Japan, few genomic resources are available for this species. To address this problem, we produced a draft genome sequence of ayu by whole-genome shotgun sequencing and constructed linkage maps using a genotyping-by-sequencing approach. Syntenic analyses of ayu and other teleost fish provided information about chromosomal rearrangements during the divergence of Stomiati, Protacanthopterygii and Neoteleostei. The size of the ayu genome indicates that genome compaction occurred after the divergence of the family Osmeridae. Ayu has an XX/XY sex-determination system for which we identified sex-associated loci by a genome-wide association study by genotyping-by-sequencing and whole-genome resequencing using wild populations. Genome-wide association mapping using wild ayu populations revealed three sex-linked scaffolds (total, 2.03 Mb). Comparison of whole-genome resequencing mapping coverage between males and females identified male-specific regions in sex-linked scaffolds. A duplicate copy of the anti-Müllerian hormone type-II receptor gene (amhr2bY) was found within these male-specific regions, distinct from the autosomal copy of amhr2. Expression of the Y-linked amhr2 gene was male-specific in sox9b-positive somatic cells surrounding germ cells in undifferentiated gonads, whereas autosomal amhr2 transcripts were detected in somatic cells in sexually undifferentiated gonads of both genetic males and females. Loss-of-function mutation for amhr2bY induced male to female sex reversal. Taken together with the known role of Amh and Amhr2 in sex differentiation, these results indicate that the paralog of amhr2 on the ayu Y chromosome determines genetic sex, and the male-specific amh-amhr2 pathway is critical for testicular differentiation in ayu.


Assuntos
Mapeamento de Sequências Contíguas/métodos , Osmeriformes/genética , Receptores de Peptídeos/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Sequenciamento Completo do Genoma/métodos , Animais , Feminino , Proteínas de Peixes/genética , Mutação com Perda de Função , Masculino , Caracteres Sexuais , Sintenia
16.
Proc Natl Acad Sci U S A ; 118(35)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34446564

RESUMO

In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining cellular identity and functional states. The activity of lineage-specific and signal-induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent antiinflammatory drugs; however, the mechanisms by which they selectively attenuate inflammatory genes are not yet understood. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. A major unanswered question relates to the sequence of events that result in the formation of repressive regions. In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow-derived macrophages significantly attenuated their responses to both liposaccharides and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the antiinflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high-fat diet-induced adipose inflammation. Mechanistically, BRD9 colocalized at a subset of GR genomic binding sites, and depletion of BRD9 enhanced GR occupancy primarily at inflammatory-related genes to potentiate GR-induced repression. Collectively, these findings establish BRD9 as a genomic antagonist of GR at inflammatory-related genes in macrophages, and reveal a potential for BRD9 inhibitors to increase the therapeutic efficacies of glucocorticoids.


Assuntos
Montagem e Desmontagem da Cromatina , Dexametasona/farmacologia , Regulação da Expressão Gênica , Macrófagos/imunologia , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Fatores de Transcrição/genética
17.
Ren Fail ; 46(1): 2313861, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38344995

RESUMO

BACKGROUND: This study aimed to discuss the diagnostic value of multi-parameter ultrasound evaluation in sepsis complicated with acute kidney injury (AKI). METHODS: Patients were divided into an AKI group (n = 50) and a non-injury group (n = 50) based on the presence of AKI. The clinical characteristics were collected, and renal function parameters between the two groups were compared, including 24-h urine volume, serum creatinine, urea, serum cystatin C (CysC), renal parenchymal thickness (RPT), renal artery resistance index (RI), and multi-parameter ultrasound scoring (MPUS). Additionally, logistic regression analysis was conducted to determine the influencing factors of sepsis complicated with AKI. The prediction value was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: In the AKI group, creatinine, CysC, urea, MPUS score, RPT, and RI values were significantly higher, while the 24-h urine volume was lower than those in the non-injury group (p < 0.01). Moreover, multivariate logistic analysis indicated that high CysC and RI values were independent risk factors, whereas high 24-h urine volume and low MPUS were independent protective factors for sepsis-induced AKI. The ROC curve demonstrated that RI (AUC = 0.906) was more effective than 24-h urine volume (AUC = 0.797), CysC (AUC = 0.730), and MPUS (AUC = 0.794) in identifying sepsis-induced AKI. CONCLUSION: High RI values increase the risk of sepsis-induced AKI, whereas low MPUS may reduce it. RI showed high diagnosis values for sepsis complicated with AKI.


Assuntos
Injúria Renal Aguda , Sepse , Humanos , Sepse/complicações , Curva ROC , Fatores de Risco , Injúria Renal Aguda/diagnóstico por imagem , Injúria Renal Aguda/etiologia , Ureia , Creatinina , Biomarcadores
18.
Sensors (Basel) ; 24(12)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38931575

RESUMO

Vehicle detection is a research direction in the field of target detection and is widely used in intelligent transportation, automatic driving, urban planning, and other fields. To balance the high-speed advantage of lightweight networks and the high-precision advantage of multiscale networks, a vehicle detection algorithm based on a lightweight backbone network and a multiscale neck network is proposed. The mobile NetV3 lightweight network based on deep separable convolution is used as the backbone network to improve the speed of vehicle detection. The icbam attention mechanism module is used to strengthen the processing of the vehicle feature information detected by the backbone network to enrich the input information of the neck network. The bifpn and icbam attention mechanism modules are integrated into the neck network to improve the detection accuracy of vehicles of different sizes and categories. A vehicle detection experiment on the Ua-Detrac dataset verifies that the proposed algorithm can effectively balance vehicle detection accuracy and speed. The detection accuracy is 71.19%, the number of parameters is 3.8 MB, and the detection speed is 120.02 fps, which meets the actual requirements of the parameter quantity, detection speed, and accuracy of the vehicle detection algorithm embedded in the mobile device.

19.
Sensors (Basel) ; 24(10)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38794029

RESUMO

Most multi-target movements are nonlinear in the process of movement. The common multi-target tracking filtering methods directly act on the multi-target tracking system of nonlinear targets, and the fusion effect is worse under the influence of different perspectives. Aiming to determine the influence of different perspectives on the fusion accuracy of multi-sensor tracking in the process of target tracking, this paper studies the multi-target tracking fusion strategy of a nonlinear system with different perspectives. A GM-JMNS-CPHD fusion technique is introduced for random outlier selection in multi-target tracking, leveraging sensors with limited views. By employing boundary segmentation from distinct perspectives, the posterior intensity function undergoes decomposition into multiple sub-intensities through SOS clustering. The distribution of target numbers within the respective regions is then characterized by the multi-Bernoulli reconstruction cardinal distribution. Simulation outcomes demonstrate the robustness and efficacy of this approach. In comparison to other algorithms, this method exhibits enhanced robustness even amidst a decreased detection probability and heightened clutter rates.

20.
Sensors (Basel) ; 24(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38400251

RESUMO

A surface-enhanced Raman scattering (SERS) method for measuring nitrate nitrogen in aquaculture water was developed using a substrate of ß-cyclodextrin-modified gold nanoparticles (SH-ß-CD@AuNPs). Addressing the issues of low sensitivity, narrow linear range, and relatively poor selectivity of single metal nanoparticles in the SERS detection of nitrate nitrogen, we combined metal nanoparticles with cyclodextrin supramolecular compounds to prepare a AuNPs substrate enveloped by cyclodextrin, which exhibits ultra-high selectivity and Raman activity. Subsequently, vanadium(III) chloride was used to convert nitrate ions into nitrite ions. The adsorption mechanism between the reaction product benzotriazole (BTAH) of o-phenylenediamine (OPD) and nitrite ions on the SH-ß-CD@AuNPs substrate was studied through SERS, achieving the simultaneous detection of nitrate nitrogen and nitrite nitrogen. The experimental results show that BTAH exhibits distinct SERS characteristic peaks at 1168, 1240, 1375, and 1600 cm-1, with the lowest detection limits of 3.33 × 10-2, 5.84 × 10-2, 2.40 × 10-2, and 1.05 × 10-2 µmol/L, respectively, and a linear range of 0.1-30.0 µmol/L. The proposed method provides an effective tool for the selective and accurate online detection of nitrite and nitrate nitrogen in aquaculture water.

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