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1.
Cell ; 187(9): 2194-2208.e22, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38552625

RESUMO

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.


Assuntos
Quimioinformática , Desenho de Fármacos , Polifarmacologia , Animais , Camundongos , Humanos , Quimioinformática/métodos , Ligantes , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/química , Masculino , Sítios de Ligação
2.
Cell ; 182(6): 1419-1440.e23, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32810438

RESUMO

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Células Mieloides/imunologia , Mielopoese , Pneumonia Viral/imunologia , Adulto , Idoso , Antígenos CD11/genética , Antígenos CD11/metabolismo , COVID-19 , Células Cultivadas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Feminino , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/citologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Proteoma/genética , Proteoma/metabolismo , Proteômica , Análise de Célula Única
3.
Proc Natl Acad Sci U S A ; 121(2): e2309670120, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38170755

RESUMO

Gene transcription is a fundamental cellular process carried out by RNA polymerase (RNAP). Transcription initiation is highly regulated, and in bacteria, transcription initiation is mediated by sigma (σ) factors. σ recruits RNAP to the promoter DNA region, located upstream of the transcription start site (TSS) and facilitates open complex formation, where double-stranded DNA is opened up into a transcription bubble and template strand DNA is positioned inside RNAP for initial RNA synthesis. During initial transcription, RNAP remains bound to σ and upstream DNA, presumably with an enlarging transcription bubble. The release of RNAP from upstream DNA is required for promoter escape and processive transcription elongation. Bacteria sigma factors can be broadly separated into two classes with the majority belonging to the σ70 class, represented by the σ70 that regulates housekeeping genes. σ54 forms a class on its own and regulates stress response genes. Extensive studies on σ70 have revealed the molecular mechanisms of the σ70 dependent process while how σ54 transitions from initial transcription to elongation is currently unknown. Here, we present a series of cryo-electron microscopy structures of the RNAP-σ54 initial transcribing complexes with progressively longer RNA, which reveal structural changes that lead to promoter escape. Our data show that initially, the transcription bubble enlarges, DNA strands scrunch, reducing the interactions between σ54 and DNA strands in the transcription bubble. RNA extension and further DNA scrunching help to release RNAP from σ54 and upstream DNA, enabling the transition to elongation.


Assuntos
Escherichia coli , Transcrição Gênica , Microscopia Crioeletrônica , Escherichia coli/genética , Escherichia coli/metabolismo , Regiões Promotoras Genéticas/genética , RNA Polimerases Dirigidas por DNA/metabolismo , DNA/metabolismo , RNA/metabolismo , Bactérias/metabolismo , Fator sigma/metabolismo , DNA Bacteriano/metabolismo
4.
Nano Lett ; 24(22): 6610-6616, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38780077

RESUMO

In pursuit of higher energy density in lithium-ion batteries, silicon (Si) has been recognized as a promising candidate to replace commercial graphite due to its high theoretical capacity. However, the pulverization issue of Si microparticles during lithiation/delithiation results in electrical contact loss and increased side reactions, significantly limiting its practical applications. Herein, we propose to utilize liquid metal (LM) particles as the bridging agent, which assemble conductive MXene (Ti3C2Tx) sheets via coordination chemistry, forming cage-like structures encapsulating mSi particles as self-healing high-energy anodes. Due to the integration of robust Ti3C2Tx sheets and deformable LM particles as conductive buffering cages, simultaneously high-rate capability and cyclability can be realized. Post-mortem analysis revealed the cage structural integrity and the maintained electrical percolating network after cycling. This work introduces an effective approach to accommodate structural change via a resilient encapsulating cage and offers useful interface design considerations for versatile battery electrodes.

5.
Nano Lett ; 24(5): 1695-1702, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38261789

RESUMO

To meet the growing demands in both energy and power densities of lithium ion batteries, electrode structures must be capable of facile electron and ion transport while minimizing the content of electrochemically inactive components. Herein, binder-free LiFePO4 (LFP) cathodes are fabricated with a multidimensional conductive architecture that allows for fast-charging capability, reaching a specific capacity of 94 mAh g-1 at 4 C. Such multidimensional networks consist of active material particles wrapped by 1D single-walled carbon nanotubes (CNTs) and bound together using 2D MXene (Ti3C2Tx) nanosheets. The CNTs form a porous coating layer and improve local electron transport across the LFP surface, while the Ti3C2Tx nanosheets provide simultaneously high electrode integrity and conductive pathways through the bulk of the electrode. This work highlights the ability of multidimensional conductive fillers to realize simultaneously superior electrochemical and mechanical properties, providing useful insights into future fast-charging electrode designs for scalable electrochemical systems.

6.
Nano Lett ; 24(12): 3759-3767, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38478977

RESUMO

Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.


Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Mitoxantrona , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos
7.
BMC Genomics ; 25(1): 612, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890564

RESUMO

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.


Assuntos
Pressão Sanguínea , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pressão Sanguínea/genética , Perfilação da Expressão Gênica , Hipertensão/genética , Transcriptoma , Polimorfismo de Nucleotídeo Único , Masculino , Medição de Risco , Feminino , Cloreto de Sódio na Dieta/efeitos adversos
8.
Mol Biol Evol ; 40(6): msad121, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37325551

RESUMO

When challenged by similar environmental conditions, phylogenetically distant taxa often independently evolve similar traits (convergent evolution). Meanwhile, adaptation to extreme habitats might lead to divergence between taxa that are otherwise closely related. These processes have long existed in the conceptual sphere, yet molecular evidence, especially for woody perennials, is scarce. The karst endemic Platycarya longipes, and its only congeneric species, P. strobilacea, which is widely distributed in the mountains in East Asia, provide an ideal model for examining the molecular basis of both convergent evolution and speciation. Using chromosome-level genome assemblies of both species, and whole genome resequencing data from 207 individuals spanning their entire distribution range, we demonstrate that P. longipes and P. strobilacea form two species-specific clades, which diverged around 2.09 million years ago. We find an excess of genomic regions exhibiting extreme interspecific differentiation, potentially due to long-term selection in P. longipes, likely contributing to the incipient speciation of the genus Platycarya. Interestingly, our results unveil underlying karst adaptation in both copies of the calcium influx channel gene TPC1 in P. longipes. TPC1 has previously been identified as a selective target in certain karst-endemic herbs, indicating a convergent adaptation to high calcium stress among karst-endemic species. Our study reveals the genic convergence of TPC1 among karst endemics, and the driving forces underneath the incipient speciation of the two Platycarya lineages.


Assuntos
Carbonato de Cálcio , Juglandaceae , Cálcio , Especiação Genética , Genômica
9.
Mol Biol Evol ; 40(6)2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37216901

RESUMO

When challenged by similar environmental conditions, phylogenetically distant taxa often independently evolve similar traits (convergent evolution). Meanwhile, adaptation to extreme habitats might lead to divergence between taxa that are otherwise closely related. These processes have long existed in the conceptual sphere, yet molecular evidence, especially for woody perennials, is scarce. The karst endemic Platycarya longipes and its only congeneric species, Platycarya strobilacea, which is widely distributed in the mountains in East Asia, provide an ideal model for examining the molecular basis of both convergent evolution and speciation. Using chromosome-level genome assemblies of both species, and whole-genome resequencing data from 207 individuals spanning their entire distribution range, we demonstrate that P. longipes and P. strobilacea form two species-specific clades, which diverged around 2.09 million years ago. We find an excess of genomic regions exhibiting extreme interspecific differentiation, potentially due to long-term selection in P. longipes, likely contributing to the incipient speciation of the genus Platycarya. Interestingly, our results unveil underlying karst adaptation in both copies of the calcium influx channel gene TPC1 in P. longipes. TPC1 has previously been identified as a selective target in certain karst-endemic herbs, indicating a convergent adaptation to high calcium stress among karst-endemic species. Our study reveals the genic convergence of TPC1 among karst endemics and the driving forces underneath the incipient speciation of the two Platycarya lineages.


Assuntos
Carbonato de Cálcio , Juglandaceae , Ásia Oriental , Cálcio , Especiação Genética , Genômica , Juglandaceae/genética , Juglandaceae/fisiologia
10.
Anal Chem ; 96(21): 8349-8355, 2024 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-38745349

RESUMO

In contrast to intracellular gene transfer, the direct delivery of expressed proteins is a significantly challenging yet essential technique for elucidating cellular functions, including protein complex structure, liquid-liquid phase separation, therapeutic applications, and reprogramming. In this study, we developed a hybrid nanotube (HyNT) stamp system that physically inserts the HyNTs into adhesive cells, enabling the injection of target molecules through HyNT ducts. This system demonstrates the capability to deliver multiple proteins, such as lactate oxidase (LOx) and ubiquitin (UQ), to approximately 1.8 × 107 adhesive cells with a delivery efficiency of 89.9% and a viability of 97.1%. The delivery of LOx enzyme into HeLa cancer cells induced cell death, while enzyme-delivered healthy cells remained viable. Furthermore, our stamp system can deliver an isotope-labeled UQ into adhesive cells for detection by nuclear magnetic resonance (NMR).


Assuntos
Nanotubos , Ubiquitina , Humanos , Células HeLa , Nanotubos/química , Ubiquitina/metabolismo , Ubiquitina/química , Sobrevivência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Espectroscopia de Ressonância Magnética , Ressonância Magnética Nuclear Biomolecular , Oxigenases de Função Mista
11.
Plant Physiol ; 193(3): 2232-2247, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37534747

RESUMO

Bacterial blight seriously affects the growth and production of cassava (Manihot esculenta Crantz), but disease resistance genes and the underlying molecular mechanism remain unknown. In this study, we found that LESION SIMULATING DISEASE 3 (MeLSD3) is essential for disease resistance in cassava. MeLSD3 physically interacts with SIRTUIN 1 (MeSRT1), inhibiting MeSRT1-mediated deacetylation modification at the acetylation of histone 3 at K9 (H3K9Ac). This leads to increased H3K9Ac levels and transcriptional activation of SUPPRESSOR OF BIR1 (SOBIR1) and FLAGELLIN-SENSITIVE2 (FLS2) in pattern-triggered immunity, resulting in immune responses in cassava. When MeLSD3 was silenced, the release of MeSRT1 directly decreased H3K9Ac levels and inhibited the transcription of SOBIR1 and FLS2, leading to decreased disease resistance. Notably, DELLA protein GIBBERELLIC ACID INSENSITIVE 1 (MeGAI1) also interacted with MeLSD3, which enhanced the interaction between MeLSD3 and MeSRT1 and further strengthened the inhibition of MeSRT1-mediated deacetylation modification at H3K9Ac of defense genes. In summary, this study illustrates the mechanism by which MeLSD3 interacts with MeSRT1 and MeGAI1, thereby mediating the level of H3K9Ac and the transcription of defense genes and immune responses in cassava.


Assuntos
Manihot , Xanthomonas axonopodis , Xanthomonas axonopodis/metabolismo , Manihot/genética , Manihot/metabolismo , Manihot/microbiologia , Histonas/metabolismo , Resistência à Doença/genética , Acetilação , Doenças das Plantas/microbiologia
12.
Rev Cardiovasc Med ; 25(5): 161, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-39076498

RESUMO

Background: This study aimed to explore the association between cardiac fibroblast activation and cardiac magnetic resonance (CMR) imaging parameters in patients with myocarditis following infection with coronavirus 2019 (COVID-19). Methods: In this prospective study, four patients with COVID-19-related myocarditis underwent 99mTc-labeled-hydrazinonicotinamide-fibroblast activation protein inhibitor-04 (99mTc-HFAPi) single photon emission computed tomography/computed tomography (SPECT/CT) and CMR imaging. Segmental 99mTc-HFAPi activity was quantified as the percentage of average segmental myocardial count × global left ventricular target-to-background ratio. T1/T2 values, extracellular volume (ECV), and late gadolinium enhancement (LGE) were analyzed by CMR. The consistency between myocardial 99mTc-HFAPi activity and CMR parameters was explored. Results: In patients with myocarditis, the proportion of segments with abnormal 99mTc-HFAPi activity was significantly higher than in those with abnormal LGE (81.25% vs. 60.93%, p = 0.011), abnormal T2 (81.25% vs. 50.00%, p < 0.001), and abnormal ECV (81.25% vs. 59.38%, p = 0.007); however, they were similar in those with abnormal native T1 (81.25% vs. 73.43%, p = 0.291). Meanwhile, 99mTc-HFAPi imaging exhibited good consistency with native T1 (kappa = 0.69). Conclusions: Increased cardiac 99mTc-HFAPi activity is present in COVID-19-related myocarditis, which is correlated with the native T1 values in CMR.

13.
Opt Lett ; 49(5): 1333-1336, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427006

RESUMO

This Letter proposes a novel, to the best of our knowledge, matrix digitization method for a photonic analog-to-digital converter with phase-shifted optical quantization (PSOQ-ADC). This method overcomes the issues of excessive bit width of the output code and the generation of invalid codes encountered by the traditional direct digitization method. A PSOQ-ADC was fabricated on a lithium niobate on insulator (LNOI) platform, and an experimental platform was built. The results show that RF signals at 1/2/5 GHz, which were sampled by a 50GS/s optical pulse train, were digitized successfully with the matrix digitization method, producing 5-bit codes without invalid codes. In comparison, the direct digitization method yields 10-bit codes, and as the optical signal-to-noise ratio (OSNR) decreases, the ratio of invalid codes increases in the direct digitization method; even with Hamming distance correction, its effective number of bits (ENOB) remains smaller than that of the matrix digitization.

14.
PLoS Biol ; 19(6): e3001297, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34111112

RESUMO

Recent studies have shown that long noncoding RNAs (lncRNAs) are critical regulators in the central nervous system (CNS). However, their roles in the cerebellum are currently unclear. In this work, we identified the isoform 204 of lncRNA Gm2694 (designated as lncRNA-Promoting Methylation (lncRNA-PM)) is highly expressed in the cerebellum and derived from the antisense strand of the upstream region of Cerebellin-1 (Cbln1), a well-known critical cerebellar synaptic organizer. LncRNA-PM exhibits similar spatiotemporal expression pattern as Cbln1 in the postnatal mouse cerebellum and activates the transcription of Cbln1 through Pax6/Mll1-mediated H3K4me3. In mouse cerebellum, lncRNA-PM, Pax6/Mll1, and H3K4me3 are all associated with the regulatory regions of Cbln1. Knockdown of lncRNA-PM in cerebellum causes deficiencies in Cbln1 expression, cerebellar synaptic integrity, and motor function. Together, our work reveals an lncRNA-mediated transcriptional activation of Cbln1 through Pax6-Mll1-H3K4me3 and provides novel insights of the essential roles of lncRNA in the cerebellum.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição PAX6/metabolismo , Precursores de Proteínas/metabolismo , RNA Longo não Codificante/metabolismo , Sinapses/metabolismo , Processamento Alternativo/genética , Cerebelo/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Humanos , Atividade Motora , Proteína de Leucina Linfoide-Mieloide/genética , Neurônios/metabolismo , Terminações Pré-Sinápticas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Longo não Codificante/genética , Ativação Transcricional/genética
15.
J Eukaryot Microbiol ; 71(2): e13012, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37975433

RESUMO

To determine the infection status and assess the zoonotic potential of Blastocystis spp. in Hotan Black chickens in southern Xinjiang, China, fecal samples were collected from 617 chickens on 18 large-scale farms. The presence of Blastocystis spp. was determined using polymerase chain reaction based on the small subunit rRNA (SSU rRNA) locus. The results revealed an overall infection rate of 26.3% (162/617). Samples from Farm 1 in Luopu County showed the highest infection rate (76.3%, 29/38). The highest and lowest infection rates were detected in the <30-day (34.4%, 43/125) and > 90-day age groups (12.4%, 11/89), respectively. The infection rate decreased with increasing age. Statistical analysis showed significant differences in the infection rates of Blastocystis spp. among the different sampling sites (p < 0.05) and age groups (p < 0.05). Four Blastocystis spp. subtypes (ST6, ST7, ST10, and ST23) were identified. The infection rates of the zoonotic subtypes, ST6 and ST7, were 3.2% (20/617) and 22.2% (137/617), respectively. The presence of Blastocystis spp. and zoonotic subtypes provided evidence for the potential transmission of this pathogen between Hotan Black chickens and humans, especially in animal handlers in this area.


Assuntos
Infecções por Blastocystis , Blastocystis , Humanos , Animais , Blastocystis/genética , Infecções por Blastocystis/epidemiologia , Infecções por Blastocystis/veterinária , Galinhas , Variação Genética , Reação em Cadeia da Polimerase , Fezes , Prevalência , Filogenia
16.
Arterioscler Thromb Vasc Biol ; 43(5): 697-712, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36951064

RESUMO

BACKGROUND: The major obstacle for applications of human induced pluripotent stem cells (hiPSCs) is efficient and controlled lineage-specific differentiation. Hence, a deeper understanding of the initial populations of hiPSCs is required to instruct proficient lineage commitment. METHODS: hiPSCs were generated from somatic cells by transduction of 4 human transcription factors (OCT4, SOX2, KLF4, and C-MYC) using Sendai virus vectors. Genome-wide DNA methylation analysis and transcriptional analysis were performed to evaluate the pluripotent capacity and somatic memory state of hiPSCs. Flow cytometric analysis and colony assays were performed to assess the hematopoietic differentiation capacity of hiPSCs. RESULTS: Here, we reveal human umbilical arterial endothelial cell-derived induced pluripotent stem cells (HuA-iPSCs) exhibit indistinguishable pluripotency in comparison with human embryonic stem cells and hiPSCs derived from other tissues of origin (umbilical vein endothelial cells, cord blood, foreskin fibroblasts, and fetal skin fibroblasts). However, HuA-iPSCs retain a transcriptional memory typical of the parental human umbilical cord arterial endothelial cells, together with a strikingly similar DNA methylation signature to umbilical cord blood-derived induced pluripotent stem cells that distinguishes them from other human pluripotent stem cells. Ultimately, HuA-iPSCs are most efficient in targeted differentiation toward hematopoietic lineage among all human pluripotent stem cells based on the functional and quantitative evaluation of both flow cytometric analysis and colony assays. Application of the Rho-kinase activator significantly reduces the effects of preferential hematopoietic differentiation in HuA-iPSCs, reflected in CD34+ cell percentage of day 7, hematopoietic/endothelial-associated gene expression, and even colony-forming unit numbers. CONCLUSIONS: Collectively, our data suggest that somatic cell memory may predispose HuA-iPSCs to differentiate more amenably into hematopoietic fate, bringing us closer to generating hematopoietic cell types in vitro from nonhematopoietic tissue for therapeutic applications.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Endoteliais/metabolismo , Diferenciação Celular/genética , Cordão Umbilical , Reprogramação Celular
17.
Bioorg Med Chem Lett ; 108: 129813, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38788964

RESUMO

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 µg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 µg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 µg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.


Assuntos
Fungicidas Industriais , Simulação de Acoplamento Molecular , Pirazóis , Succinato Desidrogenase , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Humanos , Relação Estrutura-Atividade , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ascomicetos/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Dose-Resposta a Droga , Éteres/química , Éteres/farmacologia , Éteres/síntese química , Rhizoctonia
18.
Inorg Chem ; 63(9): 4168-4175, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38373068

RESUMO

In order to help understand the structural stability of KCoO2-type ternary nitrides AMN2, referring to perovskite structure, a tolerance factor t is proposed to describe the size effect on the phase/symmetry options of the experimentally accessible AMN2 nitrides. This leads to a range of t values above 0.946 for structurally stable KCoO2-type AMN2 nitrides with t values around 0.970 for the orthorhombic and tetragonal phase boundary. In contrast, most of AMN2 nitrides exhibit α-NaFeO2-type structure with t ∼ 0.898-0.946 and cations ordered or disordered rocksalt structure while t below 0.898. Employing the proposed criterion, the structure formation for other ternary AMN2 compositions with lanthanum and alkaline earth cations for the A sites were predicted, which was testified through the synthesis attempts and complemented by formation energy evaluations. The efforts to synthesize the ternary Lanthanide and alkaline earth-based AMN2 nitrides were unsuccessful, which could associate the structural instability with the large formation energies of lanthanide nitrides LaMN2 and the greater tolerance factor of 1.048 for BaTiN2. The experimentally already synthesized AMN2 nitrides could be categorized into three types with different tolerance factors, and scarce AMN2 nitrides with lower formation energies would be accessible using different synthetic routes beyond the traditional solid-state synthesis method.

19.
Nanotechnology ; 35(43)2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39074487

RESUMO

Recently discovered ferroelectricity in fluorite-structure ZrO2thin film has attracted increasing and intense interest due to its lower crystallization temperature and higher content in nature in comparison to hafnium oxide. Here, the effect of HfO2interfacial layer on the ferroelectric properties of ZrO2thin films is investigated systematically by designing four types of interfacial structures. It is revealed that the ferroelectric orthorhombic phase, remanent polarization, and endurance can be improved in ZrO2thin film by inserting both a top- and bottom-HfO2interfacial layer. A maximal ferroelectric remanent polarization (2Pr) of 53.4µC cm-2and an optimal endurance performance of 3 × 107field cycles under frequency of 100 kHz are achieved in Pt/HfO2/ZrO2/HfO2/Pt capacitors, with ferroelectric stacks being crystallized at 450 °C via post-deposition annealing method. X-ray photoelectron spectroscopy analysis confirms that the HfO2bottom-layer plays a very important role in the formation of a higher ratio o-phase, thus enhancing the ferroelectricity. These results suggest that designing appropriate interfaces would help achieve excellent ferroelectric properties in ZrO2films.

20.
Nanotechnology ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39137799

RESUMO

High-quality patterning determines the properties of patterned emerging two-dimensional (2D) conjugated polymers which is essential for potential applications in future electronic nanodevices. However, the suitable patterning method for 2D polymers is yet concluded because it's still challenging to gain comprehensive understanding of their damage mechanisms by visualizing the structural modification during patterning process. Here, the damage mechanisms during patterning of 2D polymers, induced by various patterning methods, are unveiled based on a systematic study of structural damage and edge morphology on an imine-based 2D polymer (polyimine). Patterning using focused electron beam, focused ion beam (FIB) and mechanical carving is evaluated. Focused electron beam successively introduces sputtering effect, knock-on displacement damage and massive radiolysis effect as increasing the electron dose from 9.46×107 e-/nm2 to 1.14×1010 e-/nm2. The successful pattering is enabled by knock-on damage while impeded by carbon contamination when beyond a critical sample thickness. FIB creates current-dependent edge morphologies and extensive damage from the ion implantation caused by the tail of unfocused beam. A precisely controlled tip can tear the polyimine film through grain boundaries and in hence create the patterning edge with suitable edge roughness for certain application senarios when the beam damage is avoided. Taking structural damage and the resulting quantitative edge roughness into consideration, this study provides a detailed instruction on the proper patterning techniques for 2D crystalline polymers and paves the way for tailored intrinsic properties and device fabrication using these novel materials. .

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