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1.
J Orthop Surg (Hong Kong) ; 32(1): 10225536241244825, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38607239

RESUMO

PURPOSE: This study aims to systematically review the efficacy and safety of total ankle replacement (TAR) and ankle fusion (AF) as treatment options for end-stage ankle arthritis. METHODS: A comprehensive literature search was conducted on data from multiple databases, including PubMed, The Cochrane Library, Construction and Building Materials, Embase, Web of Science, and Scopus for RCTs and prospective cohort studies comparing TAR and AF in patients with end-stage ankle arthritis from inception up to June, 2023. Our primary outcomes of interest included patients' clinical function scores and complications. We employed Review Manager 5.4 and Stata/MP 14.0 software for the meta-analysis. RESULTS: Our analysis incorporated 13 comparative studies, including 11 prospective studies, one pilot RCT, and one RCT. The pooled results revealed no significant difference in postoperative Short Form-36 scores between the TAR and AF groups (MD = -1.19, 95% CI: -3.89 to 1.50, p = .39). However, the postoperative Foot and Ankle Ability Measure scores in the AF group were significantly higher than in the TAR group (MD = 8.30, 95% CI: 1.01-15.60, p = .03). There was no significant difference in postoperative complication rates between the TAR and AF groups (RR = 0.95, 95% CI: 0.59 to 1.54, p = .85). CONCLUSION: Currently available evidence suggests no significant disparity in postoperative outcomes between TAR and AF. In the short term, TAR demonstrates better clinical scores than AF and lower complication rates. Conversely, in the long term, AF exhibits superior clinical scores and lower complication rates, although this difference is not statistically significant.


Assuntos
Artrite , Artroplastia de Substituição do Tornozelo , Humanos , Tornozelo , Estudos Prospectivos , Articulação do Tornozelo/cirurgia , Artrite/cirurgia
2.
J Proteome Res ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565891

RESUMO

Cyanobacteria are the oldest prokaryotic photoautotrophic microorganisms and have evolved complicated post-translational modification (PTM) machinery to respond to environmental stress. Lysine 2-hydroxyisobutyrylation (Khib) is a newly identified PTM that is reported to play important roles in diverse biological processes, however, its distribution and function in cyanobacteria have not been reported. Here, we performed the first systematic studies of Khib in a model cyanobacterium Synechococcus sp. strain PCC 7002 (Syn7002) using peptide prefractionation, pan-Khib antibody enrichment, and high-accuracy mass spectrometry (MS) analysis. A total of 1875 high-confidence Khib sites on 618 proteins were identified, and a large proportion of Khib sites are present on proteins in the cellular metabolism, protein synthesis, and photosynthesis pathways. Using site-directed mutagenesis and functional studies, we showed that Khib of glutaredoxin (Grx) affects the efficiency of the PS II reaction center and H2O2 resistance in Syn7002. Together, this study provides novel insights into the functions of Khib in cyanobacteria and suggests that reversible Khib may influence the stress response and photosynthesis in both cyanobacteria and plants.

3.
Adv Sci (Weinh) ; : e2401889, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38554399

RESUMO

All-solid-state batteries (ASSBs) based on inorganic solid electrolytes fascinate a large body of researchers in terms of overcoming the inferior energy density and safety issues of existing lithium-ion batteries. To date, the cathode designs in the ASSBs achieve remarkable achievements, adding the urgency of scaling up the battery system toward inorganic solid-state pouch cell configuration for the application market. Herein, the recent developments of cathode materials and the design considerations for their application in the pouch cell format are reviewed to straighten out the roadmap of ASSBs. Specifically, the intercalation compounds and the conversion materials with conversion chemistries are highlighted and discussed as two potentially valuable material types. This review focuses on the basic electrochemical mechanisms, mechanical contact issues, and sheet-type structure in inorganic solid-state pouch cells with corresponding perspectives, thus guiding the future research direction. Finally, the benchmarks for manufacturing inorganic solid-state pouch cells to meet practical high energy density targets are provided in this review for the development of commercially viable products.

4.
Sci Data ; 11(1): 323, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548755

RESUMO

Balantidium ctenopharyngodoni is identified as the sole ciliate species that exclusively resides within the hindgut of grass carp with high prevalence and intensity. In this study, the successful cultivation of B. ctenopharyngodoni enabled us to collect enough cells for genome sequencing. Consequently, we acquired a high-quality genome assembly spanning 68.66 Mb, encompassing a total of 22,334 nanochromosomes. Furthermore, we predicted 29,348 protein-coding genes, and 95.5% of them was supported by the RNA-seq data. The trend of GC content in the subtelomeric regions of single-gene chromosomes was similar to other ciliates containing nanochromosomes. A large number of genes encoding carbohydrate-binding modules with affinities for starch and peptidoglycans was identified. The identification of mitochondrion-related organelles (MROs) within genome indicates its well-suited adaptation to the anaerobic conditions in the hindgut environment. In summary, our results will offer resources for understanding the genetic basis and molecular adaptations of balantidia to hindgut of herbivorous fish.


Assuntos
Balantidium , Genoma de Protozoário , Animais , Balantidium/genética , Sequência de Bases , Cromossomos , Filogenia , Carpas
5.
Infect Dis Ther ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483776

RESUMO

INTRODUCTION: The replacement intervals for infusion sets may differ among healthcare institutions, which may have an impact on the occurrence of central line-associated bloodstream infections (CLABSI). Nevertheless, there exists a limited amount of high-quality evidence available to assist clinicians in determining the most suitable replacement intervals for infusion sets. Therefore, the objective of this trial is to compare the efficacy of 24-h and 96-h replacement intervals for infusion sets on CLABSI among critically ill adults who have central venous access devices. METHODS: This is a multicenter, parallel-group randomized controlled trial that will investigate the effect of infusion set replacement intervals on CLABSI in adult patients admitted to intensive care units (ICUs). The study will enroll 1240 participants who meet the inclusion criteria, which includes being 18 years or older, expected to stay in the ICU for longer than 96 h, and in need of central venous access. Participants will be randomly assigned to either a control group receiving a 96-h replacement interval or a treatment group receiving a 24-h replacement interval. PLANNED OUTCOME: The primary outcome of this trial is the rate of CLABSI within 28 days after randomization. CONCLUSION: This is the first randomized controlled trial to investigate the effects of infusion set replacement at 24-h and 96-h intervals on CLABSI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05359601.

6.
Actas Esp Psiquiatr ; 52(1): 28-36, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38454900

RESUMO

BACKGROUND: Depressive disorder is a chronic mental illness characterized by persistent low mood as its primary clinical symptom. Currently, psychotherapy and drug therapy stand as the primary treatment modalities in clinical practice, offering a certain degree of relief from negative emotions for patients. Nevertheless, sole reliance on drug therapy exhibits a delayed impact on neurotransmitters, and long-term usage often results in adverse side effects such as nausea, drowsiness, and constipation, significantly impeding medication adherence. This study aims to investigate the impact of combining transcranial magnetic stimulation with sertraline on the cognitive level, inflammatory response, and neurological function in patients with depressive disorder who engage in non-suicidal self-injury (NSSI) behavior. METHODS: A total of 130 depressive patients NSSI behavior, who were admitted to our hospital from December 2020 to February 2023, were selected as the subjects for this research. The single-group (65 cases) received treatment with oral sertraline hydrochloride tablets, while the combination group (65 cases) underwent repetitive transcranial magnetic stimulation (rTMS) in conjunction with sertraline. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was utilized to assess the depression status and cognitive function levels of both groups. Additionally, the enzyme-linked immunosorbent assay (ELISA) was employed to measure serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Furthermore, serum levels of neurotransmitters (norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT)) and neuro-cytokines (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial fibrillary acidic protein (GFAP)) were assessed. The clinical effects of the interventions on both groups were then evaluated. RESULTS: Following the treatment, the combination group exhibited significantly higher levels of immediate memory, delayed memory, attention, visual function, and language function compared to the single group, with statistically significant differences (p < 0.05). Additionally, the serum levels of TNF-α, IL-1ß, IL-6, and GFAP in the combination group were lower than those in the single group, while the levels of BDNF and NGF were higher in the combination group compared to the single group. These differences were also statistically significant (p < 0.05). Simultaneously, the total clinical effective rate in the combination group reached 95.38%, surpassing the 84.61% observed in the single group, and the disparity between the two groups was statistically significant (p < 0.05). CONCLUSIONS: The combined use of rTMS and sertraline in treating patients with depressive disorder exhibiting NSSI behavior has proven to be effective in enhancing cognitive function, mitigating inflammatory responses, and elevating levels of neurotransmitters and nerve cytokines in the patients.


Assuntos
Transtorno Depressivo , Comportamento Autodestrutivo , Humanos , Sertralina/uso terapêutico , Estimulação Magnética Transcraniana/métodos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Necrose Tumoral alfa , Interleucina-6 , Fator de Crescimento Neural , Citocinas/metabolismo , Cognição , Neurotransmissores
7.
Artigo em Inglês | MEDLINE | ID: mdl-38530594

RESUMO

Peroxiredoxin 6 (PRDX6) is a protective biomarker associated with ferroptosis in heart failure (HF). This study investigated the specific mechanism of PRDX6 on doxorubicin (DOX)-induced ferroptosis in HF. Wistar rats and H9c2 cells were induced by DOX to construct HF models. Pathological changes and collagen deposition in myocardium were investigated using HE and Masson staining. PRDX6 levels, indexes of ferroptosis, and JAK2/STAT1 pathway were detected by qRT-PCR, Western blot, and biochemical kits. DOX promoted heart weight/body weight, increased inflammation and collagen deposition, increased PTGS2 and MDA levels, and decreased SLC7A11, GPX4, FTH1, and PRDX6 levels in myocardium. PRDX6 overexpression reduced PTGS2, MDA, Fe2+, and LDH levels, inhibited JAK2 and STAT1 phosphorylation, and increased SLC7A11, GPX4, and FTH1 levels in DOX-added H9c2 cells. RO8191 and erastin reversed the inhibition of PRDX6 on ferroptosis through the JAK2/STAT1 pathway. Overall, PRDX6 alleviated HF by inhibiting DOX-induced ferroptosis through the JAK2/STAT1 pathway inactivation.

8.
Signal Transduct Target Ther ; 9(1): 62, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448403

RESUMO

Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.


Assuntos
Anticorpos Monoclonais Humanizados , Asparaginase , Linfoma , Células T Matadoras Naturais , Polietilenoglicóis , Humanos , Receptor de Morte Celular Programada 1 , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem
9.
Cell Metab ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38513648

RESUMO

Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.

10.
Small ; : e2312230, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38516959

RESUMO

All inorganic CsPbI2Br perovskite (AIP) has attracted great attention due to its excellent resistance against thermal stress as well as the remarkable capability to deliver high-voltage output. However, CsPbI2Br perovskite solar cells (PeSCs) still encounter critical challenges in attaining both high efficiency and mechanical stability for commercial applications. In this work, formamidine disulfide dihydrochloride (FADD) modified ZnO electron transport layer (ETL) has been developed for fabricating inverted devices on either rigid or flexible substrate. It is found that the FADD modification leads to efficient defects passivation, thereby significantly reducing charge recombination at the AIP/ETL interface. As a result, rigid PeSCs (r-PeSCs) deliver an enhanced efficiency of 16.05% and improved long-term thermal stability. Moreover, the introduced FADD can regulate the Young's modulus (or Derjaguin-Muller-Toporov (DMT) modilus) of ZnO ETL and dissipate stress concentration at the AIP/ETL interface, effectively restraining the crack generation and improving the mechanical stability of PeSCs. The flexible PeSCs (f-PeSCs) exhibit one of the best performances so far reported with excellent stability against 6000 bending cycles at a curvature radius of 5 mm. This work thus provides an effective strategy to simultaneously improve the photovoltaic performance and mechanical stability.

11.
Proc Natl Acad Sci U S A ; 121(13): e2315531121, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38498704

RESUMO

Mating type (sex) plays a crucial role in regulating sexual reproduction in most extant eukaryotes. One of the functions of mating types is ensuring self-incompatibility to some extent, thereby promoting genetic diversity. However, heterothallic mating is not always the best mating strategy. For example, in low-density populations or specific environments, such as parasitic ones, species may need to increase the ratio of potential mating partners. Consequently, many species allow homothallic selfing (i.e., self-fertility or intraclonal mating). Throughout the extensive evolutionary history of species, changes in environmental conditions have influenced mating strategies back and forth. However, the mechanisms through which mating-type recognition regulates sexual reproduction and the dynamics of mating strategy throughout evolution remain poorly understood. In this study, we show that the Cip1 protein is responsible for coupling sexual reproduction initiation to mating-type recognition in the protozoal eukaryote Tetrahymena thermophila. Deletion of the Cip1 protein leads to the loss of the selfing-avoidance function of mating-type recognition, resulting in selfing without mating-type recognition. Further experiments revealed that Cip1 is a regulatory subunit of the Cdk19-Cyc9 complex, which controls the initiation of sexual reproduction. These results reveal a mechanism that regulates the choice between mating and selfing. This mechanism also contributes to the debate about the ancestral state of sexual reproduction.


Assuntos
Fertilidade , Reprodução , Reprodução/genética , Eucariotos/genética , Genes Fúngicos Tipo Acasalamento
13.
Elife ; 132024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38415774

RESUMO

Although most species have two sexes, multisexual (or multi-mating type) species are also widespread. However, it is unclear how mating-type recognition is achieved at the molecular level in multisexual species. The unicellular ciliate Tetrahymena thermophila has seven mating types, which are determined by the MTA and MTB proteins. In this study, we found that both proteins are essential for cells to send or receive complete mating-type information, and transmission of the mating-type signal requires both proteins to be expressed in the same cell. We found that MTA and MTB form a mating-type recognition complex that localizes to the plasma membrane, but not to the cilia. Stimulation experiments showed that the mating-type-specific regions of MTA and MTB mediate both self- and non-self-recognition, indicating that T. thermophila uses a dual approach to achieve mating-type recognition. Our results suggest that MTA and MTB form an elaborate multifunctional protein complex that can identify cells of both self and non-self mating types in order to inhibit or activate mating, respectively.


Assuntos
Comunicação Celular , Reprodução , Membrana Celular , Cílios , Reconhecimento Psicológico
14.
Nat Commun ; 15(1): 1321, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351029

RESUMO

Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1high ovarian cancer.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias Ovarianas , Humanos , Feminino , Proteínas/metabolismo , Neoplasias Ovarianas/genética , Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional , Proteases Específicas de Ubiquitina/metabolismo
15.
Adv Mater ; : e2312880, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38330999

RESUMO

While layered metal oxides remain the dominant cathode materials for the state-of-the-art lithium-ion batteries, conversion-type cathodes such as sulfur present unique opportunities in developing cheaper, safer, and more energy-dense next-generation battery technologies. There has been remarkable progress in advancing the laboratory scale lithium-sulfur (Li-S) coin cells to a high level of performance. However, the relevant strategies cannot be readily translated to practical cell formats such as pouch cells and even battery pack. Here these key technical challenges are addressed by molecular engineering of the Li metal for hydrophobicization, fluorination and thus favorable anode chemistry. The introduced tris(2,4-di-tert-butylphenyl) phosphite (TBP) and tetrabutylammonium fluoride (TBA+ F- ) as well as cellulose membrane by rolling enables the formation of a functional thin layer that eliminates the vulnerability of Li metal towards the already demanding environment required (1.55% relative humidity) for cell production and gives rise to LiF-rich solid electrolyte interphase (SEI) to suppress dendrite growth. As a result, Li-S pouch cells assembled at a pilot production line survive 400 full charge/discharge cycles with an average Coulombic efficiency of 99.55% and impressive rate performance of 1.5 C. A cell-level energy density of 417 Wh kg-1 and power density of 2766 W kg-1 are also delivered via multilayer Li-S pouch cell. The Li-S battery pack can even power an unmanned aerial vehicle of 3 kg for a fairly long flight time. This work represents a big step forward acceleration in Li-S battery marketization for future energy storage featuring improved safety, sustainability, higher energy density as well as reduced cost.

16.
Nat Commun ; 15(1): 1438, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365793

RESUMO

The Tibetan Plateau supplies water to nearly 2 billion people in Asia, but climate change poses threats to its aquatic microbial resources. Here, we construct the Tibetan Plateau Microbial Catalog by sequencing 498 metagenomes from six water ecosystems (saline lakes, freshwater lakes, rivers, hot springs, wetlands and glaciers). Our catalog expands knowledge of regional genomic diversity by presenting 32,355 metagenome-assembled genomes that de-replicated into 10,723 representative genome-based species, of which 88% were unannotated. The catalog contains nearly 300 million non-redundant gene clusters, of which 15% novel, and 73,864 biosynthetic gene clusters, of which 50% novel, thus expanding known functional diversity. Using these data, we investigate the Tibetan Plateau aquatic microbiome's biogeography along a distance of 2,500 km and >5 km in altitude. Microbial compositional similarity and the shared gene count with the Tibetan Plateau microbiome decline along with distance and altitude difference, suggesting a dispersal pattern. The Tibetan Plateau Microbial Catalog stands as a substantial repository for high-altitude aquatic microbiome resources, providing potential for discovering novel lineages and functions, and bridging knowledge gaps in microbiome biogeography.


Assuntos
Microbiota , Humanos , Tibet , Microbiota/genética , Lagos , Rios , Água
17.
Diabetes ; 73(5): 682-700, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38394642

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatics analyses followed by functional testing, we demonstrate that hepatic expression of coagulation factor VII (FVII) decreases in patients and mice with NAFLD/nonalcoholic steatohepatitis (NASH). By using adenovirus-mediated F7-knockdown and hepatocyte-specific F7-knockout mouse models, our mechanistic investigations unveil a noncoagulant function of hepatic FVII in mitigating lipid accumulation and lipotoxicity. This protective effect is achieved through the suppression of fatty acid uptake, orchestrated via the AKT-CD36 pathway. Interestingly, intracellular FVII directly interacts with AKT and PP2A, thereby promoting their association and triggering the dephosphorylation of AKT. Therapeutic intervention through adenovirus-mediated liver-specific overexpression of F7 results in noteworthy improvements in liver steatosis, inflammation, injury, and fibrosis in severely afflicted NAFLD mice. In conclusion, our findings highlight coagulation factor FVII as a critical regulator of hepatic steatosis and a potential target for the treatment of NAFLD and NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator VII/genética , Fator VII/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL
18.
Cancer Res ; 84(8): 1252-1269, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38285760

RESUMO

The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy. SIGNIFICANCE: BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer.


Assuntos
Antineoplásicos , Fatores de Transcrição , Humanos , Animais , Camundongos , Fatores de Transcrição/metabolismo , Proteínas Nucleares/metabolismo , Cromatina , Proteínas de Ciclo Celular , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteínas que Contêm Bromodomínio , Histona Desmetilases
19.
Nucleic Acids Res ; 52(D1): D747-D755, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37930867

RESUMO

Protists, a highly diverse group of microscopic eukaryotic organisms distinct from fungi, animals and plants, exert crucial roles within the earth's biosphere. However, the genomes of only a small fraction of known protist species have been published and made publicly accessible. To address this constraint, the Protist 10 000 Genomes Project (P10K) was initiated, implementing a specialized pipeline for single-cell genome/transcriptome assembly, decontamination and annotation of protists. The resultant P10K database (https://ngdc.cncb.ac.cn/p10k/) serves as a comprehensive platform, collating and disseminating genome sequences and annotations from diverse protist groups. Currently, the P10K database has incorporated 2959 genomes and transcriptomes, including 1101 newly sequenced datasets by P10K and 1858 publicly available datasets. Notably, it covers 45% of the protist orders, with a significant representation (53% coverage) of ciliates, featuring nearly a thousand genomes/transcriptomes. Intriguingly, analysis of the unique codon table usage among ciliates has revealed differences compared to the NCBI taxonomy system, suggesting a need to revise the codon tables used for these species. Collectively, the P10K database serves as a valuable repository of genetic resources for protist research and aims to expand its collection by incorporating more sequenced data and advanced analysis tools to benefit protist studies worldwide.


Assuntos
Bases de Dados Genéticas , Eucariotos , Fungos , Genoma , Animais , Códon , Eucariotos/genética , Fungos/genética , Plantas/genética
20.
Nanoscale ; 16(2): 701-707, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38078838

RESUMO

Fullerene-based micro/nano-architectures (FMNAs) with remarkable photoluminescence (PL) emissions have attracted considerable interest as potential building blocks for optical and biolabeling applications, by virtue of their low toxicity and environmentally friendly nature. Nevertheless, the PL polarization properties of FMNAs have rarely been explored. Herein, we demonstrate the preparation of highly crystalline architectures of C84, which exhibit polymorphism depending on the preparation conditions but possess similar hexagonal close-packed (hcp) structures. The PL data demonstrate that the as-prepared carambola-like hexagonal microprisms (c-HPs) show enhanced red emission compared to regular hexagonal microprisms (r-HPs). More importantly, the linear polarization of the PL emission is verified and estimated through single-prism spectroscopy, which changes from 0.42 (r-HP) to 0.58 (c-HP), comparable to those of traditional rod-like semiconductors. Thus, we demonstrate a significant correlation between the morphology and emission characteristics of C84-based microprisms, highlighting the possibility of controlling the photophysical properties of FMNAs by finely tailoring their external morphologies. This study expands the range of carbon materials with linearly polarized emissions and offers potential for use in polarization-based micro-scale sensors or detectors.

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