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1.
Small Methods ; 5(3): e2001064, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34927823

RESUMO

With the goal of creating single-molecule devices and integrating them into circuits, the emergence of single-molecule electronics provides various techniques for the fabrication of single-molecule junctions and the investigation of charge transport through such junctions. Among the techniques for characterization of charge transport through molecular junctions, electronic noise characterization is an effective strategy with which issues from molecule-electrode interfaces, mechanisms of charge transport, and changes in junction configurations are studied. Electronic noise analysis in single-molecule junctions can be used to identify molecular conformations and even monitor reaction kinetics. This review summarizes the various types of electronic noise that have been characterized during single-molecule electrical detection, including the functions of random telegraph signal (RTS) noise, flicker noise, shot noise, and their corresponding applications, which provide some guidelines for the future application of these techniques to problems of charge transport through single-molecule junctions.

2.
Cell Rep ; 37(6): 109981, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758299

RESUMO

Memory T cells exhibit considerable diversity that determines their ability to be protective. Here, we examine whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell-surface markers, we identify CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5'-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They resemble long-lived, polyfunctional memory cells but are also poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRMs). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that facilitate CD73 expression and regulate TRM differentiation. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival.

3.
Phytomedicine ; 93: 153770, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678528

RESUMO

BACKGROUND: Syringa microphylla Diels is a plant in the family Syringa Linn. For hundreds of years, its flowers and leaves have been used as a folk medicine for the treatment of cough, inflammation, colds, sore throat, acute hepatitis, chronic hepatitis, early liver cirrhosis, fatty liver, and oesophageal cancer. PURPOSE: For the first time, we have comprehensively reviewed information on Syringa microphylla Diels that is not included in the Pharmacopoeia, clarified the pharmacological mechanisms of Syringa microphylla Diels and its active ingredients from a molecular biology perspective, compiled in vivo and in vitro animal experimental data and clinical data, and summarized the toxicology and pharmacokinetics of Syringa microphylla Diels. The progress in toxicology research is expected to provide a theoretical basis for the development of new drugs from Syringa microphylla Diels, a natural source of compounds that are potentially beneficial to human health. METHODS: The PubMed, Google Scholar, China National Knowledge Infrastructure, Web of Science, SciFinder Scholar and Thomson Reuters databases were utilized to conduct a comprehensive search of published literature as of July 2021 to find original literature related to Syringa microphylla Diels and its active ingredients. RESULTS: To date, 72 compounds have been isolated and identified from Syringa microphylla Diels, and oleuropein, verbascoside, isoacteoside, echinacoside, forsythoside B, and eleutheroside B are the main active components. These compounds have antioxidant, antibacterial, anti-inflammatory, and neuroprotective effects, and their safety and effectiveness have been demonstrated in long-term traditional applications. Molecular pharmacology experiments have indicated that the active ingredients of Syringa microphylla Diels exert their pharmacological effects in various ways, primarily by reducing oxidative stress damage via Nrf2/ARE pathway regulation, regulating inflammatory factors and inducing apoptosis through the MAPK and NF-κB pathways. CONCLUSION: This comprehensive review of Syringa microphylla Diels provides new insights into the correlations among molecular mechanisms, the importance of toxicology and pharmacokinetics, and potential ways to address the limitations of current research. As Syringa microphylla Diels is a natural low-toxicity botanical medicine, it is worthy of development and utilization and is an excellent choice for treating various diseases.


Assuntos
Syringa , Animais , Antioxidantes , Etnofarmacologia , Humanos , Medicina Tradicional , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/toxicidade
4.
Nanoscale ; 13(29): 12594-12601, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34259698

RESUMO

The control of single atoms offers fundamental insight into understanding the charge transport through single clusters, and the atomic precision of the clusters provides the opportunity to manipulate the charge transport even at the single-atom level. Herein, we designed and investigated the electrical conductance and thermopower of Anderson-type polyoxometalate (POM) clusters with single-atom variation using the scanning tunneling microscopy break-junction (STM-BJ) technique. Our results show the electrical conductance of single clusters can be changed by an order of magnitude by substituting different center-metal atoms, and the electrical conductance of clusters shows different bias-dependence. Furthermore, the Seebeck coefficients of the POM clusters also can be significantly changed by the center-metal atoms. The non-equilibrium quantum transport calculations reveal that the electrostatic potential profile is non-uniformly dependent on the center-metal atoms. This leads to gating of electrical conductance by bias voltage. This supports the tuning of thermopower and bias dependent transmission spectra. This work provides the fundamental understanding of single-atom control of charge transport in POM single-cluster junctions.

5.
Nanotechnology ; 32(44)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34320474

RESUMO

Ti3C2Txis an important member of the MXenes family. Due to its excellent electrical conductivity, adjustable atomic layer, and modifiable active surface, Ti3C2Txhas attracted great attention in the field of electromagnetic interference (EMI) shielding. This paper introduces the important role of regulating conductive network to improve the EMI shielding performance of materials and summarizes the EMI shielding performance of Ti3C2Txnanohybrids reported in recent years. In addition, Ti3C2Txbased EMI shielding materials towards multifunctional devices are also systematically introduced. After that, the development status of Ti3C2Txnanohybrids in the field of EMI shielding is objectively described, and the main problems and challenges are evaluated. Finally, the prospect of Ti3C2Txnanohybrids for advanced and green EMI shielding materials is forecasted.

6.
J Med Chem ; 64(15): 10557-10580, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34260235

RESUMO

The widespread use of antibiotics has made the problem of bacterial resistance increasingly serious, and the study of new drug-resistant bacteria has become the main direction of antibacterial drug research. Among antibiotics, the fully synthetic oxazolidinone antibacterial drugs linezolid and tedizolid have been successfully marketed and have achieved good clinical treatment effects. Oxazolidinone antibacterial drugs have good pharmacokinetic and pharmacodynamic characteristics and unique antibacterial mechanisms, and resistant bacteria are sensitive to them. This Perspective focuses on reviewing oxazolidinones based on the structural modification of linezolid and new potential oxazolidinone drugs in the past 10 years, mainly describing their structure, antibacterial activity, safety, druggability, and so on, and discusses their structure-activity relationships, providing insight into the reasonable design of safer and more potent oxazolidinone antibacterial drugs.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Oxazolidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/química
8.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060486

RESUMO

With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1-deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a-deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.


Assuntos
COVID-19/imunologia , Senescência Celular/imunologia , Histonas/deficiência , MicroRNAs/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Animais , COVID-19/genética , Senescência Celular/genética , Feminino , Histonas/imunologia , Humanos , Masculino , Camundongos Knockout , MicroRNAs/genética , SARS-CoV-2/genética , Sirtuína 1/genética , Sirtuína 1/imunologia
9.
Sci Immunol ; 6(60)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145066

RESUMO

The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4+ T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4+ Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8+ memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Endossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais/genética , Transferência Adotiva/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas Relacionadas à Autofagia/deficiência , Proteínas Relacionadas à Autofagia/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , COVID-19/virologia , Células Cultivadas , Feminino , Proteína Forkhead Box O1/deficiência , Proteína Forkhead Box O1/genética , Voluntários Saudáveis , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/imunologia , Transfecção , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/genética , Adulto Jovem
10.
Nanomicro Lett ; 13(1): 115, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-34138345

RESUMO

There is an urgent global need for wireless communication utilizing materials that can provide simultaneous flexibility and high conductivity. Avoiding the harmful effects of electromagnetic (EM) radiation from wireless communication is a persistent research hot spot. Two-dimensional (2D) materials are the preferred choice as wireless communication and EM attenuation materials as they are lightweight with high aspect ratios and possess distinguished electronic properties. MXenes, as a novel family of 2D materials, have shown excellent properties in various fields, owing to their excellent electrical conductivity, mechanical stability, high flexibility, and ease of processability. To date, research on the utility of MXenes for wireless communication has been actively pursued. Moreover, MXenes have become the leading materials for EM attenuation. Herein, we systematically review the recent advances in MXene-based materials with different structural designs for wireless communication, electromagnetic interference (EMI) shielding, and EM wave absorption. The relationship governing the structural design and the effectiveness for wireless communication, EMI shielding, and EM wave absorption is clearly revealed. Furthermore, our review mainly focuses on future challenges and guidelines for designing MXene-based materials for industrial application and foundational research.

11.
Eur J Med Chem ; 220: 113451, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33895500

RESUMO

All-trans-retinoic acid (ATRA) is effective for preventing cancer and treating skin diseases and acute promyelocytic leukaemia (APL). These pharmacological effects of ATRA are mainly mediated by retinoid X receptors (RXRs) and retinoic acid receptors (RARs). This article provides a comprehensive overview of the clinical progress on and the molecular mechanisms of ATRA in the treatment of APL. ATRA can promote the transcriptional activation of differentiation-related genes and regulate autophagy by inhibiting mTOR, which results in anti-APL effects. In detail, the structures, pharmacological effects, and clinical studies of 68 types of ATRA analogues are described. These compounds have excellent antitumour therapeutic potential and could be used as lead compounds for further development and research.


Assuntos
Antineoplásicos/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tretinoína/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Serina-Treonina Quinases TOR/metabolismo , Tretinoína/análogos & derivados , Tretinoína/química
12.
Nanoscale ; 13(16): 7600-7605, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33928979

RESUMO

The gating of charge transport through single-molecule junctions is considered a critical step towards molecular circuits but remains challenging. In this work, we report an electrostatic gating method to tune the conductance of single-molecule junctions using the scanning tunneling microscope break junction (STM-BJ) technique incorporated with a back-gated chip as a substrate. We demonstrated that the conductance varied at different applied gating voltages (Vgs). The HOMO-dominated molecules show a decrease in conductance with an increase in Vg, and the LUMO-dominated molecules show the opposite trend. The measured conductance trends with Vg are consistent with the transition voltage spectroscopy measurements. Moreover, the transmission functions simulated from density functional theory (DFT) calculations and the finite element analysis all suggest that Vg changed the energy alignment of the molecular junction. This work provides a simple method for modulating the molecular orbitals' alignment relative to the Fermi energy (Ef) of metal electrodes to explore the charge transport properties at the single-molecule scale.

13.
Eur J Med Chem ; 213: 113201, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33524687

RESUMO

The widespread nature of several viruses is greatly credited to their rapidly altering RNA genomes that enable the infection to persist despite challenges presented by host cells. Within the RNA genome of infections is RNA-dependent RNA polymerase (RdRp), which is an essential enzyme that helps in RNA synthesis by catalysing the RNA template-dependent development of phosphodiester bonds. Therefore, RdRp is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. In this review, we describe the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections. Structurally, nucleoside inhibitors (NIs) bind to the RdRp protein at the enzyme active site, and nonnucleoside inhibitors (NNIs) bind to the RdRp protein at allosteric sites. By reviewing these inhibitors, more precise guidelines for the development of more promising anti-RNA virus drugs should be set, and due to the current health emergency, they will eventually be used for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Animais , Antivirais/química , COVID-19/epidemiologia , Inibidores Enzimáticos/química , Humanos , Nucleosídeos/química , Nucleosídeos/uso terapêutico , Pandemias , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
14.
Biomed Pharmacother ; 137: 111313, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33556871

RESUMO

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CLpro), papain-like protease (PLpro) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.


Assuntos
Antivirais , COVID-19 , Terapia de Alvo Molecular/métodos , SARS-CoV-2 , Antivirais/classificação , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Terapias em Estudo
15.
Luminescence ; 36(2): 316-325, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32845573

RESUMO

Self-activated Ca5 Mg3 Zn(VO4 )6 and Ca5 Mg3 Zn(VO4 )6 :xEu3+ phosphors were synthesized via a high-temperature solid-state reaction route. The crystalline structure and luminescence properties of the phosphors were analyzed using an X-ray diffractometer and a photoluminescence spectrometer. The explored results indicated that by varying calcination temperature and the raw material ratio of Ca2+ /Mg2+ /Zn2+ , the phosphors could be developed with different phases, crystallinity, and various fluorescence performances. The fluorescence spectrum of Ca5 Mg3 Zn(VO4 )6 showed a broad emission band over the range 400-650 nm under an excitation wavelength of 330 nm, as well as green light emission. Furthermore, after introduction of Eu3+ ions in Eu(VO4 )4 , the luminescence intensity of the Eu3+ ions greatly increased as the Eu3+ ion concentration increased at the 393 nm excitation wavelength, showing green-yellow light emission simultaneously. Therefore, the obtained phosphors could be used as a potential green-yellow-emitting luminescent material in a white light-emitting diode device.


Assuntos
Európio , Luminescência , Temperatura , Zinco
16.
Front Physiol ; 11: 791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733280

RESUMO

Hyperglycemia is the main feature of diabetes and may increase the risk of vascular calcification (VC), which is an independent predictor for cardiovascular and cerebrovascular diseases (CCD). Selenium (Se) may decrease the risk of CCD, and previous studies confirmed that Se-containing protein from Se-enriched Spirulina platensis (Se-SP) exhibited novel antioxidant potential. However, the effect of Se-SP against VC has been not investigated. Herein, the protective effect and underlying mechanism of Se-SP against high glucose-induced calcification in mouse aortic vascular smooth muscle cells (MOVAS) were explored. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) results showed time-dependent uptake of Se-SP in MOVAS cells, which significantly inhibited high glucose-induced abnormal proliferation. Se-SP co-treatment also effectively attenuated high glucose-induced calcification of MOVAS cells, followed by decreased activity and expression of alkaline phosphatase (ALP). Further investigation revealed that Se-SP markedly prevented reactive oxygen species (ROS)-mediated DNA damage in glucose-treated MOVAS cells. ROS inhibition by glutathione (GSH) effectively inhibited high glucose-induced calcification, indicating that Se-SP could act as ROS inhibitor to inhibit high glucose-induced DNA damage and calcification. Moreover, Se-SP dramatically attenuated high glucose-induced dysfunction of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase/AKT (PI3K/AKT) pathways. Se-SP after Se addition achieved enhanced potential in inhibiting high glucose-induced calcification, which validated that Se-SP as a new Se species could be a highly effective treatment for human CCD.

17.
Eur J Med Chem ; 206: 112711, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810751

RESUMO

This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.


Assuntos
Antivirais/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/uso terapêutico , Proteases 3C de Coronavírus , Cisteína Endopeptidases , Humanos , Peptidomiméticos , Inibidores de Proteases/uso terapêutico
18.
Nanoscale ; 12(28): 15150-15156, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32658229

RESUMO

Seebeck coefficient measurements provide unique insights into the electronic structure of single-molecule junctions, which underpins their charge and heat transport properties. Since the Seebeck coefficient depends on the slope of the transmission function at the Fermi energy (EF), the sign of the thermoelectric voltage will be determined by the location of the molecular orbital levels relative to EF. Here we investigate thermoelectricity in molecular junctions formed from a series of oligophenylene-ethynylene (OPE) derivatives with biphenylene, naphthalene and anthracene cores and pyridyl or methylthio end-groups. Single-molecule conductance and thermoelectric voltage data were obtained using a home-built scanning tunneling microscope break junction technique. The results show that all the OPE derivatives studied here are dominated by the lowest unoccupied molecular orbital level. The Seebeck coefficients for these molecules follow the same trend as the energy derivatives of their corresponding transmission spectra around the Fermi level. The molecule terminated with pyridyl units has the largest Seebeck coefficient corresponding to the highest slope of the transmission function at EF. Density-functional-theory-based quantum transport calculations support the experimental results.

19.
Adv Mater ; 32(36): e2002112, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32686195

RESUMO

Smart devices, nowadays, are inspiring the infinite vitality and possibilities of intelligent life, such as self-power electromagnetic (EM) nanogenerator and microsensor, smart window, thermally-driven EM absorber, interstellar energy deliverer, and so on. Herein, the latest and most impressive works of 3D nano-micro architectures and their smart EM devices are highly focused on. The most key information, including assembly strategy and mechanism, EM response, and approach-structure-function relationship, is extracted and well-organized with profundity and easy-to-understand approach. The merit and demerit are revealed by comparison. What's more, the brightest and most cutting-edge smart EM devices constructed by 3D nano-micro architectures are reported as highlights, and the device principles are deeply dissected. Finally, a profound and top comment on the fast-growing field as well as challenges are proposed, and the future directions are predicted intelligently.

20.
Sci Adv ; 6(17): eaba1808, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32494657

RESUMO

T cell differentiation involves the dynamic regulation of FOXO1 expression, which rapidly declines after activation and is subsequently restored. Reexpression is impaired in naïve CD4+ T cell responses from older individuals. Here, we show that FOXO1 promotes lysosome function through the induction of the key transcription factor for lysosomal proteins, TFEB. Subdued FOXO1 reexpression in activated CD4+ T cells impairs lysosomal activity, causing an expansion of multivesicular bodies (MVBs). Expansion of the MVB compartment induces the sequestration of glycogen synthase kinase 3ß (GSK3ß), thereby suppressing protein turnover and enhancing glycolytic activity. As a consequence, older activated CD4+ T cells develop features reminiscent of senescent cells. They acquire an increased cell mass, preferentially differentiate into short-lived effector T cells, and secrete exosomes that harm cells in the local environment through the release of granzyme B.

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