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1.
Cell ; 187(11): 2855-2874.e19, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657603

RESUMO

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.


Assuntos
Embrião de Mamíferos , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Imageamento Tridimensional , Humanos , Embrião de Mamíferos/metabolismo , Transcriptoma/genética , Gástrula/metabolismo , Gástrula/embriologia , Transdução de Sinais , Linhagem da Célula , Perfilação da Expressão Gênica , Padronização Corporal/genética
2.
Nature ; 598(7879): 76-81, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34616058

RESUMO

Platinum (Pt) has found wide use as an electrocatalyst for sustainable energy conversion systems1-3. The activity of Pt is controlled by its electronic structure (typically, the d-band centre), which depends sensitively on lattice strain4,5. This dependence can be exploited for catalyst design4,6-8, and the use of core-shell structures and elastic substrates has resulted in strain-engineered Pt catalysts with drastically improved electrocatalytic performances7,9-13. However, it is challenging to map in detail the strain-activity correlations in Pt-catalysed conversions, which can involve a number of distinct processes, and to identify the optimal strain modification for specific reactions. Here we show that when ultrathin Pt shells are deposited on palladium-based nanocubes, expansion and shrinkage of the nanocubes through phosphorization and dephosphorization induces strain in the Pt(100) lattice that can be adjusted from -5.1 per cent to 5.9 per cent. We use this strain control to tune the electrocatalytic activity of the Pt shells over a wide range, finding that the strain-activity correlation for the methanol oxidation reaction and hydrogen evolution reaction follows an M-shaped curve and a volcano-shaped curve, respectively. We anticipate that our approach can be used to screen out lattice strain that will optimize the performance of Pt catalysts-and potentially other metal catalysts-for a wide range of reactions.

3.
Blood ; 143(18): 1825-1836, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38211332

RESUMO

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.


Assuntos
Antineoplásicos , Compostos Bicíclicos Heterocíclicos com Pontes , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Animais , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Mutação , Apoptose/efeitos dos fármacos
4.
FASEB J ; 38(1): e23370, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38168496

RESUMO

Aging is acknowledged as the most significant risk factor for cardiovascular disease (CVD). This study sought to identify and validate potential aging-related genes associated with CVD by using bioinformatics. The confluence of the limma test, weighted correlation network analysis (WGCNA), and 2129 aging and senescence-associated genes led to the identification of aging-related differential expression genes (ARDEGs). By using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), potential biological roles and pathways of ARDEGs were identified. To find the significantly different functions between CVD and non-cardiovascular disease (nCVD) and to reckon the processes score, enrichment analysis of all genes was carried out using gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). By using GO and KEGG, potential biological roles and pathways of ARDEGs were identified. To evaluate the immune cell composition of the immune microenvironment, we performed an immune infiltration analysis on the dataset from the training group. We were able to acquire four ARDEGs (PTGS2, MMP9, HBEGF, and FN1). Aging, cellular senescence, and nitric oxide signal transduction were selected for biological function analysis. The diagnostic value of the four ARDEGs in distinguishing CVD from nCVD samples was deemed to be favorable. This research identified four ARDEGs that are associated with CVD. This study provides insight into prospective novel biomarkers for aging-related CVD diagnosis and progression monitoring.


Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Humanos , Doenças Cardiovasculares/genética , Estudos Prospectivos , Senescência Celular , Biologia Computacional
5.
Mol Cell Proteomics ; 22(12): 100672, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37866481

RESUMO

Talaroconvolutin-A (TalaA) is a compound from the endophytic fungus T. convolutispora of the Chinese herbal medicine Panax notoginseng. Whether TalaA exerts anticancer activity in bladder cancer remains unknown. Using CCK8 assay, EdU staining, crystal violet staining, flow cytometry, living/dead cell staining, and Western blotting, we studied the anticancer activity of TalaA in vitro. Moreover, we performed xenograft tumor implantation. The antitumor effects were evaluated through H&E and immunohistochemistry staining. Proteomics was conducted to detect changes in the protein profile; transcriptomics was performed to detect changes in mRNA abundance; phosphoproteomics was used to detect changes in protein phosphorylation. TalaA inhibited tumor cell proliferation, DNA replication, and colony formation in a dose-dependent manner in bladder cancer cells. The IC50 values of TalaA on SW780 and UM-UC-3 cells were 5.7 and 8.2 µM, respectively. TalaA (6.0 mg/kg) significantly repressed the growth of xenografted tumors and did not affect the body weight nor cause obvious hepatorenal toxicity. TalaA arrested the cell cycle by downregulating cyclinA2, cyclinB1, and AURKB and upregulating p21/CIP. TalaA also elevated intracellular reactive oxygen species and upregulated transferrin and heme oxygenase 1 to induce ferroptosis. Moreover, TalaA was able to bind to MAPKs (MAPK1, MAPK8, and MAPK14) to inhibit the phosphorylation of ∗SP∗ motif of transcription regulators. This study revealed that TalaA inhibited bladder cancer by arresting cell cycle to suppress proliferation and triggering ferroptosis to cause cell death. Conclusively, TalaA would be a potential candidate for treating bladder cancer by targeting MAPKs, suppressing the cell cycle, and inducing ferroptosis.


Assuntos
Antineoplásicos , Ferroptose , Neoplasias da Bexiga Urinária , Humanos , Antineoplásicos/farmacologia , Proteômica , Apoptose , Linhagem Celular Tumoral , Ciclo Celular , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Proliferação de Células , Perfilação da Expressão Gênica
6.
Small ; 20(27): e2310250, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38295142

RESUMO

The commercialization of rechargeable Zn-air batteries (ZABs) relies on the material innovation to accelerate the sluggish oxygen electrocatalysis kinetics. Due to the differentiated mechanisms of reverse processes, i.e., oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), rationally integrating dual sites for bifunctional oxygen electrocatalysis is prerequisite yet remains challenging. Herein, multicomponent synergistic active sites within highly graphitic carbon substrate are exquisitely constructed, which is accomplished by fluorine (F) modulation strategy. The incorporation of F dopants facilitates pyridinic N formation for anchoring single metal sites, thus guaranteeing the coexistence of sufficient M-Nx sites and metal nanoparticles toward bifunctional oxygen electrocatalysis. As a result, the optimal catalyst, denoted as F NH2-FeNi-800, outperforms commercial Pt/C+RuO2 with smaller gap between Ej = 10 and E1/2 (ΔE) of 0.63 V (vs 0.7 V for Pt/C+RuO2), demonstrating its superior bifunctionality. Beyond that, its superiority is validated in homemade rechargeable ZABs. ZABs assembled using F NH2-FeNi-800 as the air cathode delivers higher peak power density (123.8 mW cm-2) and long-cycle lifetime (over 660 cycles) in comparison with Pt/C@RuO2 (68.8 mW cm-2; 300 cycles). The finding not only affords a highly promising oxygen electrocatalyst, but also opens an avenue to constructing multifunctional active sites for heterogeneous catalysts.

7.
Phys Rev Lett ; 132(11): 116301, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38563917

RESUMO

Recent theoretical and experimental research suggests that θ-TaN is a semimetal with high thermal conductivity (κ), primarily due to the contribution of phonons (κ_{ph}). By using first-principles calculations, we show a nonmonotonic pressure dependence of the κ of θ-TaN. κ_{ph} first increases until it reaches a maximum at around 60 GPa, and then decreases. This anomalous behavior is a consequence of the competing pressure responses of phonon-phonon and phonon-electron interactions, in contrast to the known materials BAs and BP, where the nonmonotonic pressure dependence is caused by the interplay between different phonon-phonon scattering channels. Although TaN has phonon dispersion features similar to BAs at ambient pressure, its response to pressure is different and an overall stiffening of the phonon branches takes place. Consequently, the relevant phonon-phonon scattering weakens as pressure increases. However, the increased electronic density of states near the Fermi level, and specifically the emergence of additional pockets of the Fermi surface at the high-symmetry L point in the Brillouin zone, leads to a substantial increase in phonon-electron scattering at high pressures, driving a decrease in κ_{ph}. At intermediate pressures (∼20-70 GPa), the κ of TaN surpasses that of BAs. Our Letter provides deeper insight into phonon transport in semimetals and metals where phonon-electron scattering is relevant.

8.
Chemphyschem ; : e202400232, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-39031895

RESUMO

Near-infrared (NIR) light has characteristics of invisibility to human eyes, less background interference, low light scattering, and strong cell penetration. Therefore, NIR luminescent materials have significant applications in imaging, sensing, energy, information storage and display. The development of NIR luminescent materials thus has emerged as a highly dynamic area of research in the realm of contemporary materials. To date, NIR luminescent materials are roughly divided into inorganic materials and organic materials. Compared with inorganic materials, organic NIR luminescent materials have become a hot research topic in recent years due to their rich sources, easy control of structure, simple preparation process, low cost, and good film-forming properties. Among them, iridium(III) [Ir(III)] complexes exhibit excellent properties such as thermal stability, simple synthesis, easy color modulation, short excited state lifetimes, and high brightness, thus becoming one of the ideal luminescent material systems for preparing high-quality organic light-emitting diodes. Therefore, how to obtain Ir(III) complexes with NIR emission and high efficiency through molecular design is a necessary and promising research topic. This work reviews the research progress of representative NIR Ir(III) complexes bearing isoquinoline-, phenazine-, and phthalazine-based ligands reported in recent years and introduces the design strategies and electroluminescent performances of NIR Ir(III) complexes.

9.
Inorg Chem ; 63(6): 2954-2966, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38288974

RESUMO

Carbon dioxide (CO2) cycloaddition not only produces highly valued cyclic carbonate but also utilizes CO2 as C1 resources with 100% atomic efficiency. However, traditional catalytic routes still suffer from inferior catalytic efficiency and harsh reaction conditions. Developing multienergy-field catalytic technology with expected efficiency offers great opportunity for satisfied yield under mild conditions. Herein, Zn3In2S6 with sulfur vacancies (Sv) was fabricated with the assistance of cetyltrimethylammonium bromide (CTAB), which is further employed for photothermally driven CO2 cycloaddition first. Photoluminescence spectroscopy and photoelectrochemical characterization demonstrated its superior separation kinetics of photoinduced carriers induced by defect engineering. The temperature-programmed desorption (TPD) technique indicated its excellent Lewis acidity-basicity characters. Due to the combination of above merits from photocatalysis and thermal catalysis, defective Zn3In2S6-Sv achieved a yield as high as 73.2% for cyclic carbonate at 80 °C under blue LED illumination within 2 h (apparent quantum yield of 0.468% under illumination of 380 nm monochromatic light at 36 mW·cm-2), which is 2.9, 2.0, and 6.9 times higher than that in dark conditions and those of pristine Zn3In2S6 and industrial representative tetrabutylammonium bromide (TBAB) thermal-catalysis process under the same conditions, respectively. The synergistic reaction path of photocatalysis and thermal catalysis was discriminated by theoretical calculation. This work provides new insights into the photothermal synergistic catalysis CO2 cycloaddition with defective ternary metal sulfides.

10.
Environ Res ; 248: 118248, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38278510

RESUMO

CO2-induced ocean acidification and warming pose ecological threats to marine life, especially calcifying species such as echinoderms, who rely on biomineralization for skeleton formation. However, previous studies on echinoderm calcification amid climate change had a strong bias towards heavily calcified echinoderms, with little research on lightly calcified ones, such as sea cucumbers. Here, we analyzed the embryo-larval development and their biomineralization-related gene expression of a lightly calcified echinoderm, the sea cucumber (Apostichopus japonicus), under experimental seawater acidification (OA) and/or warming (OW). Results showed that OA (- 0.37 units) delayed development and decreased body size (8.58-56.25 % and 0.36-19.66 % decreases in stage duration and body length, respectively), whereas OW (+3.1 °C) accelerated development and increased body size (33.99-55.28 % increase in stage duration and 2.44-14.41 % enlargement in body length). OW buffered the negative effects of OA on the development timing and body size of A. japonicus. Additionally, no target genes were expressed in the blastula stage, and only two biomineralization genes (colp3α, cyp2) and five TFs (erg, tgif, foxN2/3, gata1/2/3, and tbr) were expressed throughout the embryo-larval development. Our findings suggest that the low calcification in A. japonicus larvae may be caused by biomineralization genes contraction, and low expression of those genes. Furthermore, this study indicated that seawater acidification and warming affect expression of biomineralization-related genes, and had an effect on body size and development rate during the embryo-larval stage in sea cucumbers. Our study is a first step toward a better understanding of the complexity of high pCO2 on calcification and helpful for revealing the adaptive strategy of less-calcified echinoderms amid climate change.


Assuntos
Acidificação dos Oceanos , Água do Mar , Animais , Biomineralização , Concentração de Íons de Hidrogênio , Larva , Expressão Gênica
11.
Proc Natl Acad Sci U S A ; 118(43)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34663729

RESUMO

The CO electrooxidation is long considered invincible in the proton exchange membrane fuel cell (PEMFC), where even a trace level of CO in H2 seriously poisons the anode catalysts and leads to huge performance decay. Here, we describe a class of atomically dispersed IrRu-N-C anode catalysts capable of oxidizing CO, H2, or a combination of the two. With a small amount of metal (24 µgmetal⋅cm-2) used in the anode, the H2 fuel cell performs its peak power density at 1.43 W⋅cm-2 When operating with pure CO, this catalyst exhibits its maximum current density at 800 mA⋅cm-2, while the Pt/C-based cell ceases to work. We attribute this exceptional catalytic behavior to the interplay between Ir and Ru single-atom centers, where the two sites act in synergy to favorably decompose H2O and to further facilitate CO activation. These findings open up an avenue to conquer the formidable poisoning issue of PEMFCs.

12.
J Shoulder Elbow Surg ; 33(2): 399-408, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37748531

RESUMO

BACKGROUND: The causal relationship between type 2 diabetes (T2D) and frozen shoulder is unclear. This study aims to explore the genetic causal association between T2D and glycemic traits (fasting glucose [FG], fasting insulin [FI], glycated hemoglobin [HbA1c], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder. METHODS: Using 2-sample Mendelian randomization (MR), we analyzed nonconfounded estimates of the effects of T2D and glycemic traits on frozen shoulder. Single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10-8) with exposures from genome-wide association studies (GWAS) were identified. We employed fixed effect mode inverse variance weighting (IVW-FE), random effect mode IVW (IVW-MRE), MR-Egger, and weighted median to assess the association of exposures and outcome. Sensitivity analysis was conducted to test for heterogeneity and multidirectionality bias in MR. RESULTS: We found a significant genetic causal correlation between T2D (IVW-MRE P = .007, odds ratio [OR] 1.093, 95% confidence interval [CI] 1.03-1.16), FG (IVW-FE P < .001, OR 1.455, 95% CI 1.173-1.806), and frozen shoulder, but no evidence for causal correlation between FI, HbA1c, and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions. CONCLUSION: This study supports a genetic causal relationship between T2D and FG and frozen shoulder.


Assuntos
Bursite , Diabetes Mellitus Tipo 2 , Humanos , Análise da Randomização Mendeliana , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Jejum , Insulina , Glucose , Polimorfismo de Nucleotídeo Único
13.
J Asian Nat Prod Res ; 26(3): 320-327, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37455565

RESUMO

Two new quinazoline alkaloids versicomides G-H (1 and 2), together with seven known compounds, were isolated from Aspergillus versicolor HYQZ-215 obtained from the sediment of Qarhan Salt Lake. Their structures were elucidated by NMR, HRESIMS, and quantum chemical ECD calculations data. The antimicrobial activities of these compounds were evaluated against seven agricultural pathogenic fungi and eight clinically drug-resistant bacteria.


Assuntos
Alcaloides , Anti-Infecciosos , Aspergillus , Estrutura Molecular , Quinazolinas/farmacologia , Quinazolinas/química , Alcaloides/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química
14.
Nano Lett ; 23(21): 10044-10050, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37889143

RESUMO

We show that engineering phonon scattering, such as through isotope enrichment and temperature modulation, offers the potential to achieve unconventional radiative heat transfer between two boron arsenide bulks at the nanoscale, which holds promise in applications for nonlinear thermal circuit components. A heat flux regulator is proposed, where the temperature window for stabilized heat flux exhibits a wide tunability through phonon scattering engineering. Additionally, we propose several other nonlinear thermal radiative devices, including a negative differential thermal conductance device, a temperature regulator, and a thermal diode, all benefiting from the design space enabled by isotope and temperature engineering of the phonon linewidth. Our work highlights the capability of temperature and isotope engineering in designing and optimizing nonlinear radiative thermal devices and demonstrates the potential of phonon engineering in thermal radiative transport.

15.
Int J Mol Sci ; 25(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38338806

RESUMO

Solid tumours can universally evade contact inhibition of proliferation (CIP), a mechanism halting cell proliferation when cell-cell contact occurs. Merlin, an ERM-like protein, crucially regulates CIP and is frequently deactivated in various cancers, indicating its significance as a tumour suppressor in cancer biology. Despite extensive investigations into Merlin's role in cancer, its lack of intrinsic catalytic activity and frequent conformation changes have made it notoriously challenging to study. To address this challenge, we harnessed innovative luciferase technologies to create and validate a NanoBiT split-luciferase biosensor system in which Merlin is cloned between two split components (LgBiT and SmBiT) of NanoLuc luciferase. This system enables precise quantification of Merlin's conformation and activity both in vitro and within living cells. This biosensor significantly enhances the study of Merlin's molecular functions, serving as a potent tool for exploring its contributions to CIP and tumorigenesis.


Assuntos
Técnicas Biossensoriais , Neoplasias , Neurofibromina 2 , Humanos , Transformação Celular Neoplásica , Genes Supressores de Tumor , Luciferases , Neurofibromina 2/química , Neurofibromina 2/metabolismo , Técnicas Biossensoriais/métodos
16.
Int J Mol Sci ; 25(2)2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38255762

RESUMO

Far-red light exerts an important regulatory influence on plant growth and development. However, the mechanisms underlying far-red light regulation of morphogenesis and photosynthetic characteristics in blueberry plantlets in vitro have remained elusive. Here, physiological and transcriptomic analyses were conducted on blueberry plantlets in vitro supplemented with far-red light. The results indicated that supplementation with low far-red light, such as 6 µmol m-2 s-1 and 14 µmol m-2 s-1 far-red (6FR and 14FR) light treatments, significantly increased proliferation-related indicators, including shoot length, shoot number, gibberellin A3, and trans-zeatin riboside content. It was found that 6FR and 14 FR significantly reduced chlorophyll content in blueberry plantlets but enhanced electron transport rates. Weighted correlation network analysis (WGCNA) showed the enrichment of iron ion-related genes in modules associated with photosynthesis. Genes such as NAC, ABCG11, GASA1, and Erf74 were significantly enriched within the proliferation-related module. Taken together, we conclude that low far-red light can promote the proliferative capacity of blueberry plantlets in vitro by affecting hormone pathways and the formation of secondary cell walls, concurrently regulating chlorophyll content and iron ion homeostasis to affect photosynthetic capacity.


Assuntos
Mirtilos Azuis (Planta) , Luz Vermelha , Fotossíntese , Clorofila , Ferro , Proliferação de Células
17.
Int J Mol Sci ; 25(7)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38612874

RESUMO

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, that subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer biology and potential therapeutic strategies.


Assuntos
Neoplasias , Monoéster Fosfórico Hidrolases , Via de Sinalização Hippo , Genes Reguladores , Transdução de Sinais , Fatores de Transcrição
18.
Entropy (Basel) ; 26(1)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38275493

RESUMO

Identifying critical links is of great importance for ensuring the safety of the cyber-physical power system. Traditional electrical betweenness only considers power flow distribution on the link itself, while ignoring the local influence of neighborhood links and the coupled reaction of information flow on energy flow. An identification method based on electrical betweenness centrality and neighborhood similarity is proposed to consider the internal power flow dynamic influence existing in multi-neighborhood nodes and the topological structure interdependence between power nodes and communication nodes. Firstly, for the power network, the electrical topological overlap is proposed to quantify the vulnerability of the links. This approach comprehensively considers the local contribution of neighborhood nodes, power transmission characteristics, generator capacity, and load. Secondly, in communication networks, effective distance closeness centrality is defined to evaluate the importance of communication links, simultaneously taking into account factors such as the information equipment function and spatial relationships. Next, under the influence of coupled factors, a comprehensive model is constructed based on the dependency relationships between information flow and energy flow to more accurately assess the critical links in the power network. Finally, the simulation results show the effectiveness of the proposed method under dynamic and static attacks.

19.
Int Ophthalmol ; 44(1): 314, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965086

RESUMO

BACKGROUND: Oxidative stress-induced retinal pigment epithelium (RPE) cell damage is a major factor in age-related macular degeneration (AMD). Vitamin D3 (VD3) is a powerful antioxidant and it has been suggested to have anti-aging properties and potential for treating AMD. This study aimed to investigate the effect of VD3 on RPE cell oxidative apoptosis of RPE cells in order to provide experimental evidence for the treatment of AMD. METHODS: Human retinal pigment epithelial cell 19 (ARPE-19) cells were divided into four groups: blank group (untreated), model group (incubated in medium with 400 µmol/L H2O2 for 1 h), VD3 group (incubated in medium with 100 µmol/L VD3 for 24 h), and treatment group (incubated in medium with 400 µmol/L H2O2 for 1 h and 100 µmol/L VD3 for 24 h). Cell viability, cell senescence, ROS content, expression levels of vitamin D specific receptors, Akt, Sirt1, NAMPT, and JNK mRNA expression levels, SOD activity, and MDA, GSH, and GPX levels were measured. RESULTS: We first established an ARPE-19 cell stress model with H2O2. Our control experiment showed that VD3 treatment had no significant effect on ARPE-19 cell viability within 6-48 h. Treating the stressed ARPE-19 cells with VD3 showed mixed results; caspase-3 expression was decreased, Bcl-2 expression was increased, MDA level of ARPE-19 cells was decreased, GSH-PX, GPX and SOD levels were increased, the relative mRNA expression levels of Akt, Sirt1, NAMPT were increased (P < 0.05), and the relative mRNA expression level of JNK was decreased (P < 0.05). CONCLUSION: VD3 can potentially slow the development of AMD.


Assuntos
Apoptose , Sobrevivência Celular , Estresse Oxidativo , Epitélio Pigmentado da Retina , Humanos , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Degeneração Macular/metabolismo , Vitaminas/farmacologia , Vitamina D/farmacologia , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , Sirtuína 1/metabolismo , Sirtuína 1/genética , Senescência Celular/efeitos dos fármacos , Linhagem Celular , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/toxicidade
20.
Phys Chem Chem Phys ; 25(37): 25838-25849, 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37724577

RESUMO

Novel amorphous compounds which could simultaneously use 25% singlet excitons and 75% triplet excitons as the energy source for light amplification enable the reduction of the threshold current density for electrically pumped organic semiconductor laser diodes (OSLDs); however, there is always a trade-off between the high radiative decay rate of the local excited (LE) state that is required for amplified spontaneous emission (ASE) and high exciton utilization benefiting from the charge-transfer (CT) state during electroluminescence (EL). Herein, we have explored a delicate balance to achieve both low ASE threshold and high EL exciton utilization by adopting a carefully tailored hybridized local and charge-transfer (HLCT) molecular design. A series of donor-π-acceptor (D-π-A) molecules (SBz-1, SBz-2 and SBz-3) are synthesized, and the structural change mainly refers to the spatial distance between D and A which could regulate the excited-state character via adjusting the CT length. Notably, the ASE phenomenon with a low threshold (2.97 µJ cm-2) and a high exciton utilization of 57.6% are achieved at the same time for SBz-2 with an appropriate CT length. The results provide guidance for molecular design toward harvesting triplet excitons in organic laser materials.

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