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1.
Cell ; 187(12): 2969-2989.e24, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38776919

RESUMO

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.


Assuntos
Fungos , Microbioma Gastrointestinal , Micobioma , Animais , Humanos , Masculino , Camundongos , Fezes/microbiologia , Fungos/genética , Fungos/classificação , Fungos/isolamento & purificação , Genoma Fúngico/genética , Genômica , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genética , Metagenoma , Filogenia , Feminino , Adulto , Pessoa de Meia-Idade
2.
Nat Immunol ; 25(4): 622-632, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38454157

RESUMO

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Coelhos , Anticorpos Neutralizantes , Anticorpos Antivirais , Macaca mulatta , Macrófagos , Nanovacinas , Fagocitose , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico
3.
Immunity ; 53(6): 1315-1330.e9, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33275896

RESUMO

Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.


Assuntos
Proteínas de Bactérias/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Ferritinas/imunologia , Helicobacter pylori/metabolismo , Proteínas Recombinantes de Fusão/imunologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Proteínas de Bactérias/química , Vacinas contra COVID-19/química , Ferritinas/química , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Pandemias , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/química , Vacinação
4.
Cell ; 155(5): 997-1007, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24267886

RESUMO

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.


Assuntos
Encéfalo/metabolismo , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Exoma , Feminino , Feto/metabolismo , Feto/patologia , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Mutação , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Análise de Sequência de DNA
5.
EMBO J ; 42(19): e113639, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37565504

RESUMO

WRKY transcription factors in plants are known to be able to mediate either transcriptional activation or repression, but the mechanism regulating their transcriptional activity is largely unclear. We found that group IId WRKY transcription factors interact with OBERON (OBE) proteins, forming redundant WRKY-OBE complexes in Arabidopsis thaliana. The coiled-coil domain of WRKY transcription factors binds to OBE proteins and is responsible for target gene selection and transcriptional repression. The PHD finger of OBE proteins binds to both histones and WRKY transcription factors. WRKY-OBE complexes repress the transcription of numerous stress-responsive genes and are required for maintaining normal plant growth. Several WRKY and OBE mutants show reduced plant size and increased drought tolerance, accompanied by increased expression of stress-responsive genes. Moreover, expression levels of most of these WRKY and OBE genes are reduced in response to drought stress, revealing a previously uncharacterized regulatory mechanism of the drought stress response. These results suggest that WRKY-OBE complexes repress transcription of stress-responsive genes, and thereby balance plant growth and stress tolerance.


Assuntos
Arabidopsis , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas de Plantas/metabolismo , Estresse Fisiológico , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas , Filogenia
6.
Proc Natl Acad Sci U S A ; 121(23): e2320012121, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38809713

RESUMO

Rechargeable sodium-oxygen (Na-O2) battery is deemed as a promising high-energy storage device due to the abundant sodium resources and high theoretical energy density (1,108 Wh kg-1). A series of quasisolid electrolytes are constantly being designed to restrain the dendrites growth, the volatile and leaking risks of liquid electrolytes due to the open system of Na-O2 batteries. However, the ticklish problem about low operating current density for quasisolid electrolytes still hasn't been conquered. Herein, we report a rechargeable Na-O2 battery with polyvinylidene fluoride-hexafluoropropylene recombination Nafion (PVDF-HFP@Nafion) based quasisolid polymer electrolyte (QPE) and MXene-based Na anode with gradient sodiophilic structure (M-GSS/Na). QPE displays good flame resistance, locking liquid and hydrophobic properties. The introduction of Nafion can lead to a high Na+ migration number (tNa+ = 0.68) by blocking the motion of anion and promote the formation of NaF-rich solid electrolyte interphase, resulting in excellent cycling stability at relatively high current density under quasisolid environment. In the meantime, the M-GSS/Na anode exhibits excellent dendrite inhibition ability and cycling stability. Therefore, with the synergistic effect of QPE and M-GSS/Na, constructed Na-O2 batteries run more stably and exhibit a low potential gap (0.166 V) after an initial 80 cycles at 1,000 mA g-1 and 1,000 mAh g-1. This work provides the reference basis for building quasisolid state Na-O2 batteries with long-term cycling stability.

7.
Proc Natl Acad Sci U S A ; 121(26): e2401840121, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38900793

RESUMO

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.

8.
Nat Methods ; 20(11): 1693-1703, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37770710

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR) screening coupled with single-cell RNA sequencing has emerged as a powerful tool to characterize the effects of genetic perturbations on the whole transcriptome at a single-cell level. However, due to its sparsity and complex structure, analysis of single-cell CRISPR screening data is challenging. In particular, standard differential expression analysis methods are often underpowered to detect genes affected by CRISPR perturbations. We developed a statistical method for such data, called guided sparse factor analysis (GSFA). GSFA infers latent factors that represent coregulated genes or gene modules; by borrowing information from these factors, it infers the effects of genetic perturbations on individual genes. We demonstrated through extensive simulation studies that GSFA detects perturbation effects with much higher power than state-of-the-art methods. Using single-cell CRISPR data from human CD8+ T cells and neural progenitor cells, we showed that GSFA identified biologically relevant gene modules and specific genes affected by CRISPR perturbations, many of which were missed by existing methods, providing new insights into the functions of genes involved in T cell activation and neurodevelopment.


Assuntos
Fenômenos Biológicos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Linfócitos T CD8-Positivos , Teorema de Bayes , Transcriptoma , Sistemas CRISPR-Cas
9.
Nature ; 585(7823): 63-67, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879503

RESUMO

Rechargeable lithium-ion batteries with high energy density that can be safely charged and discharged at high rates are desirable for electrified transportation and other applications1-3. However, the sub-optimal intercalation potentials of current anodes result in a trade-off between energy density, power and safety. Here we report that disordered rock salt4,5 Li3+xV2O5 can be used as a fast-charging anode that can reversibly cycle two lithium ions at an average voltage of about 0.6 volts versus a Li/Li+ reference electrode. The increased potential compared to graphite6,7 reduces the likelihood of lithium metal plating if proper charging controls are used, alleviating a major safety concern (short-circuiting related to Li dendrite growth). In addition, a lithium-ion battery with a disordered rock salt Li3V2O5 anode yields a cell voltage much higher than does a battery using a commercial fast-charging lithium titanate anode or other intercalation anode candidates (Li3VO4 and LiV0.5Ti0.5S2)8,9. Further, disordered rock salt Li3V2O5 can perform over 1,000 charge-discharge cycles with negligible capacity decay and exhibits exceptional rate capability, delivering over 40 per cent of its capacity in 20 seconds. We attribute the low voltage and high rate capability of disordered rock salt Li3V2O5 to a redistributive lithium intercalation mechanism with low energy barriers revealed via ab initio calculations. This low-potential, high-rate intercalation reaction can be used to identify other metal oxide anodes for fast-charging, long-life lithium-ion batteries.

10.
Bioinformatics ; 40(Supplement_1): i539-i547, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940179

RESUMO

MOTIVATION: In drug discovery, it is crucial to assess the drug-target binding affinity (DTA). Although molecular docking is widely used, computational efficiency limits its application in large-scale virtual screening. Deep learning-based methods learn virtual scoring functions from labeled datasets and can quickly predict affinity. However, there are three limitations. First, existing methods only consider the atom-bond graph or one-dimensional sequence representations of compounds, ignoring the information about functional groups (pharmacophores) with specific biological activities. Second, relying on limited labeled datasets fails to learn comprehensive embedding representations of compounds and proteins, resulting in poor generalization performance in complex scenarios. Third, existing feature fusion methods cannot adequately capture contextual interaction information. RESULTS: Therefore, we propose a novel DTA prediction method named HeteroDTA. Specifically, a multi-view compound feature extraction module is constructed to model the atom-bond graph and pharmacophore graph. The residue concat graph and protein sequence are also utilized to model protein structure and function. Moreover, to enhance the generalization capability and reduce the dependence on task-specific labeled data, pre-trained models are utilized to initialize the atomic features of the compounds and the embedding representations of the protein sequence. A context-aware nonlinear feature fusion method is also proposed to learn interaction patterns between compounds and proteins. Experimental results on public benchmark datasets show that HeteroDTA significantly outperforms existing methods. In addition, HeteroDTA shows excellent generalization performance in cold-start experiments and superiority in the representation learning ability of drug-target pairs. Finally, the effectiveness of HeteroDTA is demonstrated in a real-world drug discovery study. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/daydayupzzl/HeteroDTA.


Assuntos
Descoberta de Drogas , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Proteínas/química , Proteínas/metabolismo , Aprendizado Profundo , Farmacóforo
11.
FASEB J ; 38(2): e23401, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38236196

RESUMO

Ferroptosis, a type of iron-catalyzed necrosis, is responsible for vascular smooth muscle cell (VSMC) death and serves as a potential therapeutic target for alleviating aortic aneurysm. Here, our study explored the underlying mechanism of ferroptosis affecting VSMC functions and the resultant formation of AAA using its inhibitor Ferrostatin-1 (Fer-1). Microarray-based gene expression profiling was employed to identify differentially expressed genes related to AAA and ferroptosis. An AAA model was established by angiotensin II (Ang II) induction in apolipoprotein E-knockout (ApoE-/- ) mice, followed by injection of Fer-1 and RSL-3 (ferroptosis inducer). Then, the role of Fer-1 and RSL-3 in the ferroptosis of VSMCs and AAA formation was analyzed in Ang II-induced mice. Primary mouse VSMCs were cultured in vitro and treated with Ang II, Fer-1, sh-SLC7A11, or sh-GPX4 to assess the effect of Fer-1 via the SLC7A11/GPX axis. Bioinformatics analysis revealed that GPX4 was involved in the fibrosis formation of AAA, and there was an interaction between SLC7A11 and GPX4. In vitro assays showed that Fer-1 alleviated Ang II-induced ferroptosis of VSMCs and retard the consequent AAA formation. The mechanism was associated with activation of the SLC7A11/GPX4 pathway. Silencing of SLC7A11 or GPX4 could inhibit the ameliorating effect of Fer-1 on the ferroptosis of VSMCs. In vivo animal studies further demonstrated that Fer-1 inhibited Ang II-induced ferroptosis and vessel wall structural abnormalities in AAA mouse through activation of the SLC7A11/GPX4 pathway. Fer-1 may prevent AAA formation through activation of the SLC7A11/GPX4 pathway.


Assuntos
Aneurisma da Aorta Abdominal , Ferroptose , Hormônios Peptídicos , Fenilenodiaminas , Animais , Camundongos , Músculo Liso Vascular , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/prevenção & controle , Cicloexilaminas/farmacologia , Angiotensina II/farmacologia
12.
Nucleic Acids Res ; 51(D1): D1263-D1275, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36243960

RESUMO

Widespread drug resistance has become the key issue in global healthcare. Extensive efforts have been made to reveal not only diverse diseases experiencing drug resistance, but also the six distinct types of molecular mechanisms underlying this resistance. A database that describes a comprehensive list of diseases with drug resistance (not just cancers/infections) and all types of resistance mechanisms is now urgently needed. However, no such database has been available to date. In this study, a comprehensive database describing drug resistance information named 'DRESIS' was therefore developed. It was introduced to (i) systematically provide, for the first time, all existing types of molecular mechanisms underlying drug resistance, (ii) extensively cover the widest range of diseases among all existing databases and (iii) explicitly describe the clinically/experimentally verified resistance data for the largest number of drugs. Since drug resistance has become an ever-increasing clinical issue, DRESIS is expected to have great implications for future new drug discovery and clinical treatment optimization. It is now publicly accessible without any login requirement at: https://idrblab.org/dresis/.


Assuntos
Descoberta de Drogas , Bases de Dados Factuais , Resistência a Medicamentos
13.
BMC Biol ; 22(1): 92, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654264

RESUMO

BACKGROUND: Transposable elements (TEs) have a profound influence on the trajectory of plant evolution, driving genome expansion and catalyzing phenotypic diversification. The pangenome, a comprehensive genetic pool encompassing all variations within a species, serves as an invaluable tool, unaffected by the confounding factors of intraspecific diversity. This allows for a more nuanced exploration of plant TE evolution. RESULTS: Here, we constructed a pangenome for diploid A-genome cotton using 344 accessions from representative geographical regions, including 223 from China as the main component. We found 511 Mb of non-reference sequences (NRSs) and revealed the presence of 5479 previously undiscovered protein-coding genes. Our comprehensive approach enabled us to decipher the genetic underpinnings of the distinct geographic distributions of cotton. Notably, we identified 3301 presence-absence variations (PAVs) that are closely tied to gene expression patterns within the pangenome, among which 2342 novel expression quantitative trait loci (eQTLs) were found residing in NRSs. Our investigation also unveiled contrasting patterns of transposon proliferation between diploid and tetraploid cotton, with long terminal repeat (LTR) retrotransposons exhibiting a synchronized surge in polyploids. Furthermore, the invasion of LTR retrotransposons from the A subgenome to the D subgenome triggered a substantial expansion of the latter following polyploidization. In addition, we found that TE insertions were responsible for the loss of 36.2% of species-specific genes, as well as the generation of entirely new species-specific genes. CONCLUSIONS: Our pangenome analyses provide new insights into cotton genomics and subgenome dynamics after polyploidization and demonstrate the power of pangenome approaches for elucidating transposon impacts and genome evolution.


Assuntos
Elementos de DNA Transponíveis , Evolução Molecular , Genoma de Planta , Gossypium , Gossypium/genética , Elementos de DNA Transponíveis/genética , Locos de Características Quantitativas
14.
Chem Soc Rev ; 53(1): 9-24, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37982289

RESUMO

Lithium metal anodes are an appealing choice for rechargeable batteries due to their exceptionally high theoretical capacity of about 3860 mA h g-1. However, the uneven plating/stripping of lithium metal anodes leads to serious dendrite growth and low coulombic efficiency, curtailing their practical applications. The 3D scaffold/host strategy emerges as a promising approach that concurrently mitigates volume changes and dendrite growth. This review provides an overview of the regulating mechanisms behind scaffold/host materials for dendrite-free applications, tracing their historical development and recent progress across five key stages: material texture selection, lithiophilic modification, structural design, multi-strategy integration, and practical implementation. Additionally, scaffold/host materials are categorized based on their material texture, with a thorough examination of their respective advantages and drawbacks. Furthermore, this tutorial outlines the obstacles and complexities associated with implementing scaffold/host strategies. Finally, the determining factors that affect the electrochemical performances of scaffold/host materials are discussed, along with possible design criteria and future development prospects. This tutorial aims to provide guidance for researchers on the design of advanced scaffold/host materials for advanced Li metal anodes for batteries.

15.
Nano Lett ; 24(22): 6545-6552, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38781416

RESUMO

Extracting interior photoinduced species to the surface before their recombination is of great importance in pursuing high-efficiency semiconductor-based photocatalysis. Traditional strategies toward charge-carrier extraction, mostly relying on the construction of an electric field gradient, would be invalid toward the neutral-exciton counterpart in low-dimensional systems. In this work, by taking bismuth oxybromide (BiOBr) as an example, we manipulate interior exciton extraction to the surface by implementing iodine doping at the edges of BiOBr plates. Spatial- and time-resolved spectroscopic analyses verified the accumulation of excitons and charge carriers at the edges of iodine-doped BiOBr (BiOBr-I) plates. This phenomenon could be associated with interior exciton extraction, driven by an energy-level gradient between interior and edge exciton states, and the following exciton dissociation processes. As such, BiOBr-I shows remarkable performance in photocatalytic C-H fluorination, mediated by both energy- and charge-transfer processes. This work uncovers the importance of spatial regulation of excitonic properties in low-dimensional semiconductor-based photocatalysis.

16.
Nano Lett ; 24(5): 1635-1641, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38277778

RESUMO

We present an on-chip filter with a broad tailorable working wavelength and a single-mode operation. This is realized through the application of topological photonic crystal nanobeam filters employing synthesis parameter dimensions. By introducing the translation of air holes as a new synthetic parameter dimension, we obtained nanobeams with tunable Zak phases. Leveraging the bulk-edge correspondence, we identify the existence of topological cavity modes and establish a correlation between the cavity's interface morphology and working wavelength. Through experiments, we demonstrate filters with adjustable filtering wavelengths ranging from 1301 to 1570 nm. Our work illustrates the use of the synthetic translation dimension in the design of on-chip filters, and it holds potential for applications in other devices such as microcavities.

17.
Genes Chromosomes Cancer ; 63(1): e23210, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37870859

RESUMO

COL1A1::PDGFB fusion uterine sarcoma is a rare uterine mesenchymal tumor with some clinicopathological features that overlap with those of soft tissue dermatofibrosarcoma protuberans. However, the varied clinicopathologic and genetic characteristics have not been fully revealed, which may be a potential pitfall for diagnosis. Here, we present a case of COL1A1::PDGFB fusion-positive uterine sarcoma in a 49-years-old female. Histologically, the tumor from the initial marginal excision predominantly exhibited high-grade fibrosarcomatous and myxofibrosarcoma-like appearances, while a low-grade focal area displaying storiform growth was identified in the residual tumor after subsequently extended resection. Immunohistochemically, the high-grade components mainly exhibited focal positivity for CD34 and mutated-type p53 immunoreactivity, whereas the low-grade component showed diffuse positivity for CD34 and wild-type p53 staining. The COL1A1::PDGFB fusion was confirmed by fluorescence in situ hybridization and next-generation sequencing. In addition, the TERT-124 C > T mutation was further identified in this lesion's fibrosarcomatous and classic storiform components. To the best of our knowledge, this is the first described case of COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation, which might be a novel genetic finding associated with tumorigenesis of this rare tumor.


Assuntos
Dermatofibrossarcoma , Fibrossarcoma , Neoplasias Pélvicas , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Telomerase , Neoplasias Uterinas , Feminino , Humanos , Pessoa de Meia-Idade , Dermatofibrossarcoma/genética , Fibrossarcoma/genética , Hibridização in Situ Fluorescente , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Neoplasias Cutâneas/genética , Telomerase/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirurgia
18.
J Am Chem Soc ; 146(20): 13797-13804, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38722223

RESUMO

Hydrides are promising candidates for achieving room-temperature superconductivity, but a formidable challenge remains in reducing the stabilization pressure below a megabar. In this study, we successfully synthesized a ternary lanthanum borohydride by introducing the nonmetallic element B into the La-H system, forming robust B-H covalent bonds that lower the pressure required to stabilize the superconducting phase. Electrical transport measurements confirm the presence of superconductivity with a critical temperature (Tc) of up to 106 K at 90 GPa, as evidenced by zero resistance and Tc shift under an external magnetic field. X-ray diffraction and transport measurements identify the superconducting compound as LaB2H8, a nonclathrate hydride, whose crystal structure remains stable at pressures as low as ∼ half megabar (59 GPa). Stabilizing superconductive stoichiometric LaB2H8 in a submegabar pressure regime marks a substantial advancement in the quest for high-Tc superconductivity in polynary hydrides, bringing us closer to the ambient pressure conditions.

19.
J Hepatol ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38960374

RESUMO

BACKGROUND & AIMS: Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the cellular receptor for hepatitis B virus (HBV). However, hepatocytes expressing NTCP exhibit varying susceptibilities to HBV infection. This study aimed to investigate whether other host factors modulate the process of HBV infection. METHODS: Liver biopsy samples obtained from children with hepatitis B were used for single-cell sequencing and susceptibility analysis. Primary human hepatocytes, HepG2-NTCP cells, and human liver chimeric mice were used to analyze the effect of candidate host factors on HBV infection. RESULTS: Single-cell sequencing and susceptibility analysis revealed a positive correlation between neuropilin-1 (NRP1) expression and HBV infection. In the HBV-infected cell model, NRP1 overexpression before HBV inoculation significantly enhanced viral attachment and internalization, and promoted viral infection in the presence of NTCP. Mechanistic studies indicated that NRP1 formed a complex with LHBs and NTCP. The NRP1 b domain mediated its interaction with conserved arginine residues at positions 88 and 92 in the preS1 domain of the HBV envelope protein LHBs. This NRP1-preS1 interaction subsequently promoted the binding of preS1 to NTCP, facilitating viral infection. Moreover, disruption of the NRP1-preS1 interaction by the NRP1 antagonist EG00229 significantly attenuated the binding affinity between NTCP and preS1, thereby inhibiting HBV infection both in vitro and in vivo. CONCLUSIONS: Our findings indicate that NRP1 is a novel host factor for HBV infection, which interacts with preS1 and NTCP to modulate HBV entry into hepatocytes. IMPACT AND IMPLICATIONS: HBV infection is a global public health problem, but the understanding of the early infection process of HBV remains limited. Through single-cell sequencing, we identified a novel host factor, NRP1, which modulates HBV entry by interacting with HBV preS1 and NTCP. Moreover, antagonists targeting NRP1 can inhibit HBV infection both in vitro and in vivo. This study could further advance our comprehension of the early infection process of HBV.

20.
EMBO J ; 39(7): e102008, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32115743

RESUMO

Deposition of H2A.Z in chromatin is known to be mediated by a conserved SWR1 chromatin-remodeling complex in eukaryotes. However, little is known about whether and how the SWR1 complex cooperates with other chromatin regulators. Using immunoprecipitation followed by mass spectrometry, we found all known components of the Arabidopsis thaliana SWR1 complex and additionally identified the following three classes of previously uncharacterized plant-specific SWR1 components: MBD9, a methyl-CpG-binding domain-containing protein; CHR11 and CHR17 (CHR11/17), ISWI chromatin remodelers responsible for nucleosome sliding; and TRA1a and TRA1b, accessory subunits of the conserved NuA4 histone acetyltransferase complex. MBD9 directly interacts with CHR11/17 and the SWR1 catalytic subunit PIE1, and is responsible for the association of CHR11/17 with the SWR1 complex. MBD9, TRA1a, and TRA1b function as canonical components of the SWR1 complex to mediate H2A.Z deposition. CHR11/17 are not only responsible for nucleosome sliding but also involved in H2A.Z deposition. These results indicate that the association of the SWR1 complex with CHR11/17 may facilitate the coupling of H2A.Z deposition with nucleosome sliding, thereby co-regulating gene expression, development, and flowering time.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Adenosina Trifosfatases/metabolismo , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Histona Acetiltransferases/metabolismo , Nucleossomos/metabolismo , Mapas de Interação de Proteínas , Fatores de Transcrição/metabolismo
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