Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 1.278
Filter
Add more filters

Publication year range
1.
Nat Immunol ; 22(6): 746-756, 2021 06.
Article in English | MEDLINE | ID: mdl-34031618

ABSTRACT

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.


Subject(s)
Immunotherapy, Adoptive/methods , Interleukin-10/pharmacology , Neoplasms/therapy , Oxidative Phosphorylation/drug effects , T-Lymphocytes, Cytotoxic/drug effects , Animals , Anion Transport Proteins/genetics , Anion Transport Proteins/metabolism , Cell Line, Tumor , Combined Modality Therapy/methods , Disease Models, Animal , Drug Synergism , Female , HEK293 Cells , Half-Life , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunoglobulin Fc Fragments/pharmacology , Immunoglobulin Fc Fragments/therapeutic use , Interleukin-10/therapeutic use , Mice , Mice, Transgenic , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Neoplasms/immunology , Neoplasms/pathology , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/metabolism , Receptors, Interleukin-10/metabolism , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/therapeutic use , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism
2.
EMBO J ; 42(8): e111472, 2023 04 17.
Article in English | MEDLINE | ID: mdl-36912149

ABSTRACT

For shade-intolerant plants, changes in light quality through competition from neighbors trigger shade avoidance syndrome (SAS): a series of morphological and physiological adaptations that are ultimately detrimental to plant health and crop yield. Phytochrome-interacting factor 7 (PIF7) is a major transcriptional regulator of SAS in Arabidopsis; however, how it regulates gene expression is not fully understood. Here, we show that PIF7 directly interacts with the histone chaperone anti-silencing factor 1 (ASF1). The ASF1-deprived asf1ab mutant showed defective shade-induced hypocotyl elongation. Histone regulator homolog A (HIRA), which mediates deposition of the H3.3 variant into chromatin, is also involved in SAS. RNA/ChIP-sequencing analyses identified the role of ASF1 in the direct regulation of a subset of PIF7 target genes. Furthermore, shade-elicited gene activation is accompanied by H3.3 enrichment, which is mediated by the PIF7-ASF1-HIRA regulatory module. Collectively, our data reveal that PIF7 recruits ASF1-HIRA to increase H3.3 incorporation into chromatin to promote gene transcription, thus enabling plants to effectively respond to environmental shade.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Phytochrome , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Factor VII/genetics , Phytochrome/genetics , Chromatin/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Plant , DNA-Binding Proteins/metabolism
3.
EMBO J ; 42(19): e112814, 2023 10 04.
Article in English | MEDLINE | ID: mdl-37635626

ABSTRACT

The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.


Subject(s)
Saccharomyces cerevisiae Proteins , Autophagy/physiology , Autophagy-Related Proteins/metabolism , Phagosomes/metabolism , Phosphorylation , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism
4.
Proc Natl Acad Sci U S A ; 121(8): e2317704121, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38346203

ABSTRACT

While modern family-related ideas and behaviors have become more widely accepted in contemporary China, Chinese Muslim minorities continue to hold on to traditional religious practices. Surprisingly, data from our survey conducted in Gansu province in China's northwestern borderlands reveal that Muslims of the Hui and Dongxiang ethnicities reported much higher rates of cohabitation experience than the secular majority Han. Based on follow-up qualitative interviews, we found the answer to lie in the interplay between the highly interventionist Chinese state and the robust cultural resilience of local Islamic communities. While the state maintains a high minimum legal age of marriage, the early marriage norm remains strong in Chinese Muslim communities, where religion constitutes an alternative and often more powerful source of legitimacy-at least in the private sphere of life. Using the 2000 census data, we further show that women in almost all 10 Muslim ethnic groups have higher percentages of underage births and premarital births than Han women, both nationally and in the northwest where most Chinese Muslims live. As the once-outlawed behavior of cohabitation became more socially acceptable during the reform and opening-up era, young Muslim Chinese often found themselves in "arranged cohabitations" as de facto marriages formed at younger-than-legal ages. In doing so, Chinese Muslim communities have reinvented the meaning of cohabitation. Rather than liberal intimate relationship based on individual autonomy, cohabitation has served as a coping strategy by which Islamic patriarchs circumvent the Chinese state's aggressive regulations aimed at "modernizing" the Muslim family.


Subject(s)
Asian People , Culture , Islam , Marriage , Female , Humans , Asian People/statistics & numerical data , China/epidemiology , Ethnicity , Sexual Behavior/ethnology , Sexual Behavior/statistics & numerical data , Marriage/ethnology , Marriage/legislation & jurisprudence , Marriage/statistics & numerical data
5.
Proc Natl Acad Sci U S A ; 121(26): e2401840121, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38900793

ABSTRACT

The recent theory-driven discovery of a class of clathrate hydrides (e.g., CaH6, YH6, YH9, and LaH10) with superconducting critical temperatures (Tc) well above 200 K has opened the prospects for "hot" superconductivity above room temperature under pressure. Recent efforts focus on the search for superconductors among ternary hydrides that accommodate more diverse material types and configurations compared to binary hydrides. Through extensive computational searches, we report the prediction of a unique class of thermodynamically stable clathrate hydrides structures consisting of two previously unreported H24 and H30 hydrogen clathrate cages at megabar pressures. Among these phases, LaSc2H24 shows potential hot superconductivity at the thermodynamically stable pressure range of 167 to 300 GPa, with calculated Tcs up to 331 K at 250 GPa and 316 K at 167 GPa when the important effects of anharmonicity are included. The very high critical temperatures are attributed to an unusually large hydrogen-derived density of states at the Fermi level arising from the newly reported peculiar H30 as well as H24 cages in the structure. Our predicted introduction of Sc in the La-H system is expected to facilitate future design and realization of hot superconductors in ternary clathrate superhydrides.

6.
Proc Natl Acad Sci U S A ; 121(21): e2322920121, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38748587

ABSTRACT

In this paper, we present findings from four separate studies using different data sources and methods to examine Chinese attitudes toward the United States amid the COVID-19 pandemic. The empirical results consistently indicate a marked and significant decline in Chinese attitudes toward the US between late 2019 and the end of 2022. Using a quasi-experimental design and granular survey data that exploit daily variations in public opinion, we offer additional evidence that the decline in Chinese attitudes toward the United States followed a distinct pattern not true for Chinese attitudes toward other countries. Specifically, the rise in Chinese unfavorability toward the United States closely corresponded to the heightened Chinese attention to the pandemic's progression in the United States. These results collectively suggest a causal effect of COVID-19, shedding light on how public health crises, international relations, and media jointly shape the increasing enmity between the two great powers.


Subject(s)
Attitude , COVID-19 , Pandemics , Public Opinion , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/psychology , Humans , United States/epidemiology , China/epidemiology , Surveys and Questionnaires , East Asian People
7.
Proc Natl Acad Sci U S A ; 120(27): e2216248120, 2023 Jul 04.
Article in English | MEDLINE | ID: mdl-37368928

ABSTRACT

The US global leadership in science and technology has greatly benefitted from immigrants from other countries, most notably from China in the recent decades. However, feeling the pressure of potential federal investigations since the 2018 launch of the China Initiative, scientists of Chinese descent in the United States now face higher incentives to leave the United States and lower incentives to apply for federal grants. Analyzing data pertaining to institutional affiliations of more than 200 million scientific papers, we find a steady increase in the return migration of scientists of Chinese descent from the United States to China. We also conducted a survey of scientists of Chinese descent employed by US universities in tenured or tenure-track positions (n = 1,304), with results revealing general feelings of fear and anxiety that lead them to consider leaving the United States and/or stop applying for federal grants. If the situation is not corrected, American science will likely suffer the loss of scientific talent to China and other countries.

8.
Acc Chem Res ; 57(9): 1458-1466, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38654437

ABSTRACT

ConspectusRecent years have witnessed the development of cluster materials as they are atomically precise molecules with uniform size and solution-processability, which are unattainable with traditional nanoparticles or framework materials. The motivation for studying Al(III) chemistry is not only to understand the aggregation process of aluminum in the environment but also to develop novel low-cost materials given its natural abundance. However, the Al-related clusters are underdeveloped compared to the coinage metals, lanthanides, and transition metals. The challenge in isolating crystalline compounds is the lack of an effective method to realize the controllable hydrolysis of Al(III) ions. Compared with the traditional hydrolysis of inorganic Al(III) salts in highly alkaline solutions and hydrolysis of aluminum trialkyl compounds conducted carefully in an inert operating environment, we herein developed an effective way to control the hydrolysis of aluminum isopropanol through an alcoxalation reaction. By solvothermal/low melting point solid melting synthesis and using "ligand aggregation, solvent regulation, and supracluster assembly" strategies, our laboratory has established an organic-inorganic hybrid system of aluminum oxo clusters (AlOCs). The employment of organic ligands promotes the aggregation and slows the hydrolysis of Al(III) ions, which in turn improves the crystallization process. The regulation of the structure types can be achieved through the selection of ligands and the supporting solvents. Compared with the traditional condensed polyoxoaluminates, we successfully isolated a broad range of porous AlOCs, including aluminum molecular rings and Archimedes aluminum oxo cages. By studying ring expansion, structural transformation, and intermolecular supramolecular assembly, we demonstrate unique and unprecedented structural controllability and assembly behavior in cluster science. The advancement of this universal synthetic method is to realize materials customization through modularly oriented supracluster assembly. In this Account, we will provide a clear-cut definition and terminology of "ligand aggregation, solvent regulation, and supracluster assembly". Then we will discuss the discovery in this area by using a strategy, such as aluminum molecular ring, ring size expansion, ring supracluster assembly, etc. Furthermore, given the internal and external pore structures, as well as the solubility and modifiability of the AlOCs, we will demonstrate their potential applications in both the solid and liquid phases, such as iodine capture, the optical limiting responses, and dopant in polymer dielectrics. The strategy herein can be applied to extensive cluster science and promote the research of main group element chemistry. The new synthetic method, fascinating clusters, and unprecedented assembly behaviors we have discovered will advance Al(III) chemistry and will also lay the foundation for functional applications.

9.
EMBO Rep ; 24(5): e56105, 2023 05 04.
Article in English | MEDLINE | ID: mdl-36970931

ABSTRACT

Shade avoidance syndrome (SAS) commonly occurs in plants experiencing vegetative shade, triggering a series of morphological and physiological changes for the plants to reach more light. A number of positive regulators, such as PHYTOCHROME-INTERACTING 7 (PIF7), and negative regulators, such as PHYTOCHROMES, are known to ensure appropriate SAS. Here, we identify 211 shade-regulated long non-coding RNAs (lncRNAs) in Arabidopsis. We further characterize PUAR (PHYA UTR Antisense RNA), a lncRNA produced from the intron of the 5' UTR of the PHYTOCHROME A (PHYA) locus. PUAR is induced by shade and promotes shade-induced hypocotyl elongation. PUAR physically associates with PIF7 and represses the shade-mediated induction of PHYA by blocking the binding of PIF7 to the 5' UTR of PHYA. Our findings highlight a role for lncRNAs in SAS and provide insight into the mechanism of PUAR in regulating PHYA gene expression and SAS.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Phytochrome , RNA, Long Noncoding , 5' Untranslated Regions , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , DNA-Binding Proteins/genetics , Gene Expression Regulation, Plant , Hypocotyl/metabolism , Light , Phytochrome/genetics , Phytochrome/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism
10.
Exp Cell Res ; 437(2): 114009, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38537745

ABSTRACT

Osteoarthritis (OA) is a degenerative disease that affects millions of individuals worldwide. Despite its prevalence, the exact causes and mechanisms behind OA are still not fully understood, resulting in a lack of effective treatments to slow down or halt disease progression. Recent research has discovered that extracellular vesicles (EVs) present in the circulation of young mice have a remarkable ability to activate musculoskeletal stem cells in elderly mice. Conversely, EVs derived from elderly mice do not exhibit the same potential, indicating that EVs obtained from young individuals may hold promise to activate aging cells in degenerative tissue. However, it remains unknown whether EVs derived from young individuals can also address cartilage degeneration caused by aging. In this study, we first evaluated EVs derived from young human plasma (YEVs) and EVs derived from old human plasma (OEVs) in an in vitro experiment using chondrocytes. The results revealed that YEVs effectively stimulated chondrocyte proliferation and migration, while OEVs from old plasma did not exhibit a similar effect. Given that OA represents a more complex inflammatory microenvironment, we further determine whether the benefits of YEVs on chondrocytes can be maintained in this context. Our findings indicate that YEVs have the ability to positively regulate chondrocyte function and protect them against apoptosis induced by IL-1ß and TNF-α in an in vitro OA model. Furthermore, we discovered that lyophilized EVs could be stored under mild conditions without any alterations in their physical characteristics. Considering the exceptional therapeutic effects and the wide availability of EVs from young plasma, they hold significant promise as a potential approach to activate chondrocytes and promote cartilage regeneration in early-stage OA.


Subject(s)
Extracellular Vesicles , Osteoarthritis , Humans , Mice , Animals , Chondrocytes , Tumor Necrosis Factor-alpha/pharmacology , Cartilage , Interleukin-1beta/pharmacology
11.
Proc Natl Acad Sci U S A ; 119(47): e2212183119, 2022 11 22.
Article in English | MEDLINE | ID: mdl-36375070

ABSTRACT

About one in six Asian Americans have fallen victim to anti-Asian racism during the COVID-19 pandemic [J. Lee, K. Ramakrishnan, aapidata.com/blog/discrimination-survey-2022/]. By examining anti-Asian racism in the United States primarily as a domestic issue, most prior studies have overlooked the connections between shifting US-China relations and Americans' prejudices against the Chinese in China and, by extension, East Asian Americans. This study investigates the patterns and perceptual bases of nationality-based prejudices against Chinese amid the COVID-19 pandemic in the United States. Our nationally representative online survey experiment reveals that Americans assess a hypothetical Chinese person in China as inferior in multiple social and psychological characteristics to an otherwise identical Japanese person in Japan or East Asian American. Furthermore, subjects who perceive China as more threatening to America's national interests assess Chinese more negatively, especially in terms of trustworthiness and morality, suggesting that perceived China threats propel Americans' negative stereotypes about Chinese. A contextual analysis further indicates that counties with a higher share of Trump voters in 2016 tend to perceive all East Asian-origin groups similarly as a racial outgroup. By contrast, residents in predominantly Democrat-voting counties tend to perceive Chinese in China more negatively relative to Asian Americans, despite broadly viewing East Asians more favorably. Overall, this study underscores the often-overlooked relationships between the prevailing anti-Asian sentiments in the United States and the US-China geopolitical tensions and America's domestic political polarization.


Subject(s)
COVID-19 , Racism , Humans , United States/epidemiology , COVID-19/epidemiology , Pandemics , Prejudice , Racism/psychology , Asian/psychology , Morals , China
12.
Proc Natl Acad Sci U S A ; 119(7)2022 02 15.
Article in English | MEDLINE | ID: mdl-35145032

ABSTRACT

In this paper, we study long-term trends in social mobility in the People's Republic of China since its inception in 1949, with two operationalizations: 1) intergenerational occupational mobility and 2) intergenerational educational mobility. We draw on an accumulation of administrative and survey data and provide comparable estimates of these measures for birth cohorts born after 1945. To help interpret the results, we compare trends in China to those in the United States for the same birth cohorts. We find an increase in intergenerational occupational mobility in China due to its rapid industrialization in recent decades. Net of industrialization, however, intergenerational occupational mobility has been declining for recent cohorts. Intergenerational educational mobility in China shows a similar declining trend. In addition, mobility patterns have differed greatly by gender, with women in earlier cohorts and from a rural origin particularly disadvantaged. We attribute the general decline in social mobility to market forces that have taken hold since China's economic reform that began in 1978. In contrast, social mobility by both measures has been relatively stable in the United States. However, while social mobility in China has trended downward, it is still higher than that in the United States, except for women's educational mobility.


Subject(s)
Educational Status , Intergenerational Relations , Occupations , Social Mobility/history , Social Mobility/statistics & numerical data , China , Female , History, 20th Century , History, 21st Century , Humans , Male , Rural Population , Time Factors
13.
Emerg Infect Dis ; 30(2): 321-324, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38270156

ABSTRACT

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.


Subject(s)
Mpox (monkeypox) , Smallpox , Humans , Smallpox/prevention & control , Vaccination , Antibodies, Neutralizing , China/epidemiology , Vaccinia virus
14.
Cancer Sci ; 115(6): 1749-1762, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38508217

ABSTRACT

N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.


Subject(s)
Adenosine , B7-H1 Antigen , Colorectal Neoplasms , Humans , Adenosine/analogs & derivatives , Adenosine/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/metabolism , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Animals , Mice , Cell Line, Tumor , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Cell Proliferation , Gene Expression Regulation, Neoplastic , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolism , Female , Tumor Hypoxia/genetics , Cell Cycle Proteins
15.
Cancer Sci ; 2024 May 05.
Article in English | MEDLINE | ID: mdl-38705575

ABSTRACT

Persistent activation of estrogen receptor alpha (ERα)-mediated estrogen signaling plays a pivotal role in driving the progression of estrogen receptor positive (ER+) breast cancer (BC). In the current study, LINC00173, a long non-coding RNA, was found to bind both ERα and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα) factor (LITAF), then cooperatively to inhibit ERα protein degradation by impeding the nuclear export of ERα. Concurrently, LITAF was found to attenuate TNFα transcription after binding to LINC00173, and this attenuating transcriptional effect was quite significant under lipopolysaccharide stimulation. Distinct functional disparities between estrogen subtypes emerge, with estradiol synergistically promoting ER+ BC cell growth with LINC00173, while estrone (E1) facilitated LITAF-transcriptional activation. In terms of therapeutic significance, silencing LINC00173 alongside moderate addition of E1 heightened TNFα and induced apoptosis, effectively inhibiting ER+ BC progression.

16.
Crit Rev Eukaryot Gene Expr ; 34(4): 33-44, 2024.
Article in English | MEDLINE | ID: mdl-38505871

ABSTRACT

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Exploring the pathogenesis of AML is still an important topic in the treatment of AML. The expression levels of miR-26b-5p and USP48 were measured by qRT-PCR. The expression levels of related proteins were detected by Western blot. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Coimmunoprecipitation was used to examine the interaction between USP48 and Wnt5a. Bioinformatics analysis showed that high levels of miR-26b-5p and low levels of USP48 were associated with poor prognosis in AML. miR-26b-5p can negatively regulate the expression of USP48. Downregulation of miR-26b-5p inhibited EMT, cell viability and proliferation of AML cells and accelerated apoptosis. Furthermore, the influence of miR-26b-5p inhibition and USP48 knockdown on AML progression could be reversed by a Wnt/ß-catenin signaling pathway inhibitor. This study revealed that miR-26b-5p regulates AML progression, possibly by targeting the USP48-mediated Wnt/ß-catenin molecular axis to affect AML cell biological behavior.


Subject(s)
Leukemia, Myeloid, Acute , MicroRNAs , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Wnt Signaling Pathway/genetics , beta Catenin/genetics , Blotting, Western , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Cell Proliferation/genetics , Cell Line, Tumor , Apoptosis/genetics , Ubiquitin-Specific Proteases/metabolism
17.
Lancet ; 401(10380): 917-927, 2023 03 18.
Article in English | MEDLINE | ID: mdl-36842439

ABSTRACT

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.


Subject(s)
Nasopharyngeal Neoplasms , Radiotherapy, Intensity-Modulated , Male , Humans , Female , Nasopharyngeal Carcinoma/radiotherapy , Radiotherapy, Intensity-Modulated/adverse effects , Neoplasm Recurrence, Local/radiotherapy , Nasopharyngeal Neoplasms/radiotherapy , Hemorrhage
18.
BMC Plant Biol ; 24(1): 28, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38172675

ABSTRACT

BACKGROUND: Canopy architecture is critical in determining the fruit-zone microclimate and, ultimately, in determining an orchard's success in terms of the quality and quantity of the fruit produced. However, few studies have addressed how the canopy environment leads to metabolomic and transcriptomic alterations in fruits. Designing strategies for improving the quality of pear nutritional components relies on uncovering the related regulatory mechanisms. RESULTS: We performed an in-depth investigation of the impact of canopy architecture from physiological, metabolomic and transcriptomic perspectives by comparing pear fruits grown in a traditional freestanding system (SP) or a flat-type trellis system (DP). Physiological studies revealed relatively greater fruit sizes, soluble solid contents and titratable acidities in pear fruits from DP systems with open canopies. Nontargeted metabolite profiling was used to characterize fruits at the initial ripening stage. Significant differences in fruit metabolites, including carbohydrates, nucleic acids, alkaloids, glycerophospholipids, sterol lipids, and prenol lipids, were observed between the two groups. Transcriptomic analysis indicated that a series of organic substance catabolic processes (e.g., the glycerol-3-phosphate catabolic process, pectin catabolic process and glucan catabolic process) were overrepresented in fruits of the DP system. Moreover, integrative analysis of the metabolome and transcriptome at the pathway level showed that DP pear fruits may respond to the canopy microenvironment by upregulating phenylpropanoid biosynthesis pathway genes such as PpPOD. Transient assays revealed that the contents of malic acid and citric acid were lower in the pear flesh of PpPOD RNAi plants, which was associated with regulating the expression of organic acid metabolism-related genes. CONCLUSIONS: Our results provide fundamental evidence that at the physiological and molecular levels, open-canopy architecture contributes to improving pear fruit quality and is correlated with increased levels of carbohydrates and lipid-like molecules. This study may lead to the development of rational culture practices for enhancing the nutritional traits of pear fruits.


Subject(s)
Pyrus , Fruit , Plant Proteins/genetics , Gene Expression Profiling , Carbohydrates , Lipids , Gene Expression Regulation, Plant
19.
J Med Virol ; 96(2): e29469, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38376919

ABSTRACT

The mpox outbreak has subdued with fewer reported cases at the present in high-income countries. It is known that mpox virus (MPXV) infection has been epidemic for more than 50 years in African countries. The ancestral MPXV strain has changed into multiple clades, indicating the ongoing evolution of MPXV, which reflects the historical neglect of mpox in Africa, especially after smallpox eradication, and bestows the danger of more severe mpox epidemics in the future. It is thus imperative to continue the development of mpox diagnostics and treatments so we can be prepared in the event of a new mpox epidemic. In this study, we have developed an MPXV detection tool that leverages the recombinase-aid amplification assay by integrating lateral flow strips (RAA-LF) and one-step sample DNA preparation, with visible readout, no need of laboratory instrument, and ready for field deployment. The detection limit reaches 10 copies per reaction. The performance of our RAA-FL assay in diagnosing mpox clinical samples is on par with that of the quantitative polymerase chain reaction (PCR) assay. Taken together, we have developed a point-of-care RAA-LF method of high accuracy and sensitivity, readily deployable for field detection of MPXV. This diagnostic tool is expected to improve and accelerate field- and self-diagnosis, allow timely isolation and treatment, reduce the spread of MPXV, thus effectively mitigate MPXV outbreak in the future.


Subject(s)
Monkeypox virus , Mpox (monkeypox) , Humans , Africa , Biological Assay , Disease Outbreaks
20.
Opt Express ; 32(5): 8343-8363, 2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38439492

ABSTRACT

High-resolution solar absorption spectra were continuously collected by a ground-based Fourier transform infrared (FTIR) spectrometer to retrieve the total column of carbon monoxide (CO), hydrogen cyanide (HCN), ethane (C2H6), acetylene (C2H2), and formaldehyde (H2CO). The time series and variation characteristics of these gases were analyzed. The biomass combustion process is identified by using the correlations between the monthly mean deviations of HCN, C2H6, C2H2 and H2CO versus CO and satellite fire point data. The months with high correlation coefficients (R > 0.8) and peaks of fire point number are considered to be with biomass combustion occurrence. The emissions of HCN, C2H6, C2H2 and H2CO in Anhui were estimated using the enhancement ratios of gases to CO in these months when biomass combustion was the main driving factor of gas concentration change. The study proved the ability of FTIR system in inferring the period during biomass combustion and estimating emissions of the trace gases concerning biomass combustion.

SELECTION OF CITATIONS
SEARCH DETAIL