RESUMO
Microscopy-based spatially resolved omic methods are transforming the life sciences. However, these methods rely on high numerical aperture objectives and cannot resolve crowded molecular targets, limiting the amount of extractable biological information. To overcome these limitations, here we develop Deconwolf, an open-source, user-friendly software for high-performance deconvolution of widefield fluorescence microscopy images, which efficiently runs on laptop computers. Deconwolf enables accurate quantification of crowded diffraction limited fluorescence dots in DNA and RNA fluorescence in situ hybridization images and allows robust detection of individual transcripts in tissue sections imaged with ×20 air objectives. Deconvolution of in situ spatial transcriptomics images with Deconwolf increased the number of transcripts identified more than threefold, while the application of Deconwolf to images obtained by fluorescence in situ sequencing of barcoded Oligopaint probes drastically improved chromosome tracing. Deconwolf greatly facilitates the use of deconvolution in many bioimaging applications.
Assuntos
Processamento de Imagem Assistida por Computador , Hibridização in Situ Fluorescente , Microscopia de Fluorescência , Software , Microscopia de Fluorescência/métodos , Hibridização in Situ Fluorescente/métodos , Processamento de Imagem Assistida por Computador/métodos , Animais , Camundongos , HumanosRESUMO
Thiram is a toxic fungicide extensively used for the management of pathogens in fruits. Although it is known that thiram degrades in plant tissues, the key enzymes involved in this process remain unexplored. In this study, we report that a tau class glutathione S-transferase (GST) from Carica papaya can degrade thiram. This enzyme was easily obtained by heterologous expression in Escherichia coli, showed low promiscuity toward other thiuram disulfides, and catalyzed thiram degradation under physiological reaction conditions. Site-directed mutagenesis indicated that G-site residue S67 shows a key influence for the enzymatic activity toward thiram, while mutation of residue S13, which reduced the GSH oxidase activity, did not significantly affect the thiram-degrading activity. The formation of dimethyl dithiocarbamate, which was subsequently converted into carbon disulfide, and dimethyl dithiocarbamoylsulfenic acid as the thiram degradation products suggested that thiram undergoes an alkaline hydrolysis that involves the rupture of the disulfide bond. Application of the GST selective inhibitor 4-chloro-7-nitro-2,1,3-benzoxadiazole reduced papaya peel thiram-degrading activity by 95%, indicating that this is the main degradation route of thiram in papaya. GST from Carica papaya also catalyzed the degradation of the fungicides chlorothalonil and thiabendazole, with residue S67 showing again a key influence for the enzymatic activity. These results fill an important knowledge gap in understanding the catalytic promiscuity of plant GSTs and reveal new insights into the fate and degradation products of thiram in fruits.
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Carica , Glutationa Transferase , Tiram , Carica/enzimologia , Carica/genética , Fungicidas Industriais/metabolismo , Glutationa Transferase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/química , Mutagênese Sítio-Dirigida , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tiram/metabolismo , Escherichia coli/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
IFN-stimulated genes (ISGs) can act as effector molecules against viral infection and can also regulate pathogenic infection and host immune response. N-Myc and STAT interactor (Nmi) is reported as an ISG in mammals and in fish. In this study, the expression of Nmi was found to be induced significantly by the infection of Siniperca chuatsi rhabdovirus (SCRV), and the induced expression of type I IFNs after SCRV infection was reduced following Nmi overexpression. It is observed that Nmi can interact with IRF3 and IRF7 and promote the autophagy-mediated degradation of these two transcription factors. Furthermore, Nmi was found to be interactive with IFP35 through the CC region to inhibit IFP35 protein degradation, thereby enhancing the negative role in type I IFN expression after viral infection. In turn, IFP35 is also capable of protecting Nmi protein from degradation through its N-terminal domain. It is considered that Nmi and IFP35 in fish can also interact with each other in regulating negatively the expression of type I IFNs, but thus in enhancing the replication of SCRV.
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Interferon Tipo I , Peptídeos e Proteínas de Sinalização Intracelular , Animais , Interferon Tipo I/metabolismo , PeixesRESUMO
The type IV IFN (IFN-υ) is reported in vertebrates from fish to primary mammals with IFN-υR1 and IL-10R2 as receptor subunits. In this study, the proximal promoter of IFN-υ was identified in the amphibian model, Xenopus laevis, with functional IFN-sensitive responsive element and NF-κB sites, which can be transcriptionally activated by transcription factors, such as IFN regulatory factor (IRF)1, IRF3, IRF7, and p65. It was further found that IFN-υ signals through the classical IFN-stimulated gene (ISG) factor 3 (ISGF3) to induce the expression of ISGs. It seems likely that the promoter elements of the IFN-υ gene in amphibians is similar to type III IFN genes, and that the mechanism involved in IFN-υ induction is very much similar to type I and III IFNs. Using recombinant IFN-υ protein and the X. laevis A6 cell line, >400 ISGs were identified in the transcriptome, including ISGs homologous to humans. However, as many as 268 genes were unrelated to human or zebrafish ISGs, and some of these ISGs were expanded families such as the amphibian novel TRIM protein (AMNTR) family. AMNTR50, a member in the family, was found to be induced by type I, III, and IV IFNs through IFN-sensitive responsive element sites of the proximal promoter, and this molecule has a negative role in regulating the expression of type I, III, and IV IFNs. It is considered that the current study contributes to the understanding of transcription, signaling, and functional aspects of type IV IFN at least in amphibians.
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Interferon Tipo I , Interferons , Animais , Humanos , Xenopus laevis , Interferons/genética , Interferons/metabolismo , Peixe-Zebra/metabolismo , Regulação da Expressão Gênica , Transdução de Sinais , Interferon Tipo I/metabolismo , Mamíferos/metabolismoRESUMO
Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.
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Hepatite B Crônica , Hepatite B , Humanos , Hepatite B Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Vírus da Hepatite B/genética , Resultado do Tratamento , Biomarcadores , Antígenos de Superfície da Hepatite B , DNA Viral , Hepatite B/tratamento farmacológicoRESUMO
OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, Pâ =â .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, Pâ =â .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, Pâ =â 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.
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Neoplasias Pulmonares , Tuberculose , Humanos , Masculino , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Tuberculose/induzido quimicamente , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , FemininoRESUMO
The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.
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Dissecação , Fator 6 Nuclear de Hepatócito/metabolismo , Fatores de Transcrição Otx/metabolismo , Retina/crescimento & desenvolvimento , Células Fotorreceptoras Retinianas Cones/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Galinhas , Cromatina , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Fator 6 Nuclear de Hepatócito/genética , Fatores de Transcrição Otx/genética , Retina/metabolismo , Células-TroncoRESUMO
African swine fever virus (ASFV) is a large DNA virus that causes African swine fever (ASF), an acute and hemorrhagic disease in pigs with lethality rates of up to 100%. To date, how ASFV efficiently suppress the innate immune response remains enigmatic. In this study, we identified ASFV cysteine protease pS273R as an antagonist of type I interferon (IFN). Overexpression of pS273R inhibited JAK-STAT signaling triggered by type I IFNs. Mechanistically, pS273R interacted with STAT2 and recruited the E3 ubiquitin ligase DCST1, resulting in K48-linked polyubiquitination at K55 of STAT2 and subsequent proteasome-dependent degradation of STAT2. Furthermore, such a function of pS273R in JAK-STAT signaling is not dependent on its protease activity. These findings suggest that ASFV pS273R is important to evade host innate immunity. IMPORTANCE ASF is an acute disease in domestic pigs caused by infection with ASFV. ASF has become a global threat with devastating economic and ecological consequences. To date, there are no commercially available, safe, and efficacious vaccines to prevent ASFV infection. ASFV has evolved a series of strategies to evade host immune responses, facilitating its replication and transmission. Therefore, understanding the immune evasion mechanism of ASFV is helpful for the development of prevention and control measures for ASF. Here, we identified ASFV cysteine protease pS273R as an antagonist of type I IFNs. ASFV pS273R interacted with STAT2 and mediated degradation of STAT2, a transcription factor downstream of type I IFNs that is responsible for induction of various IFN-stimulated genes. pS273R recruited the E3 ubiquitin ligase DCST1 to enhance K48-linked polyubiquitination of STAT2 at K55 in a manner independent of its protease activity. These findings suggest that pS273R is important for ASFV to escape host innate immunity, which sheds new light on the mechanisms of ASFV immune evasion.
Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Cisteína Proteases , Interferon Tipo I , Animais , Cisteína Proteases/genética , Cisteína Proteases/metabolismo , Imunidade Inata/genética , Interferon Tipo I/metabolismo , Sus scrofa , Suínos , Ubiquitina-Proteína Ligases/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization. RESULTS: Here, we present SIGFRIED, which makes use of existing reference panels with a projection-based approach that simplifies kinship estimation in the admixed populations. We use simulated and real datasets to demonstrate the accuracy and efficiency of kinship estimation. We present a secure federated kinship estimation framework and implement a secure kinship estimator using homomorphic encryption-based primitives for computing relatedness between samples in two different sites while genotype data are kept confidential. Source code and documentation for our methods can be found at https://doi.org/10.5281/zenodo.7053352. CONCLUSIONS: Analysis of relatedness is fundamentally important for identifying relatives, in association studies, and for estimation of population-level estimates of inbreeding. As the awareness of individual and group genomic privacy is growing, privacy-preserving methods for the estimation of relatedness are needed. Presented methods alleviate the ethical and privacy concerns in the analysis of relatedness in admixed, historically isolated and underrepresented populations. SHORT ABSTRACT: Genetic relatedness is a central quantity used for finding relatives in databases, correcting biases in genome wide association studies and for estimating population-level statistics. Methods for estimating genetic relatedness have high computational requirements, and occasionally do not consider individuals from admixed ancestries. Furthermore, the ethical concerns around using genetic data and calculating relatedness are not considered. We present a projection-based approach that can efficiently and accurately estimate kinship. We implement our method using encryption-based techniques that provide provable security guarantees to protect genetic data while kinship statistics are computed among multiple sites.
Assuntos
Estudo de Associação Genômica Ampla , Privacidade , Humanos , Genótipo , Privacidade Genética , GenomaRESUMO
ASFV is a large DNA virus that is highly pathogenic in domestic pigs. How this virus is sensed by the innate immune system as well as why it is so virulent remains enigmatic. In this study, we show that the ASFV genome contains AT-rich regions that are recognized by the DNA-directed RNA polymerase III (Pol-III), leading to viral RNA sensor RIG-I-mediated innate immune responses. We further show that ASFV protein I267L inhibits RNA Pol-III-RIG-I-mediated innate antiviral responses. I267L interacts with the E3 ubiquitin ligase Riplet, disrupts Riplet-RIG-I interaction and impairs Riplet-mediated K63-polyubiquitination and activation of RIG-I. I267L-deficient ASFV induces higher levels of interferon-ß, and displays compromised replication both in primary macrophages and pigs compared with wild-type ASFV. Furthermore, I267L-deficiency attenuates the virulence and pathogenesis of ASFV in pigs. These findings suggest that ASFV I267L is an important virulence factor by impairing innate immune responses mediated by the RNA Pol-III-RIG-I axis.
Assuntos
Vírus da Febre Suína Africana/patogenicidade , Imunidade Inata/imunologia , Fatores de Virulência/imunologia , Virulência/imunologia , Febre Suína Africana/imunologia , Vírus da Febre Suína Africana/imunologia , Animais , RNA Polimerase III/imunologia , Receptores de Superfície Celular/imunologia , SuínosRESUMO
Chronic hepatitis B infection (CHB) affects 300 million people worldwide and is being targeted by the United Nations 2030 Sustainable Development Goals (SDGs) and the World Health Organisation (WHO), working towards elimination of hepatitis B virus (HBV) as a public health threat. In this piece, we explore the evidence and potential impact of peer support to enhance and promote interventions for people living with CHB. Peer support workers (PSWs) are those with lived experience of an infection, condition or situation who work to provide support for others, aiming to improve education, prevention, treatment and other clinical interventions and to reduce the physical, psychological and social impacts of disease. Peer support has been shown to be a valuable tool for improving health outcomes for people living with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), but to date has not been widely available for communities affected by HBV. HBV disproportionately affects vulnerable and marginalised populations, who could benefit from PSWs to help them navigate complicated systems and provide advocacy, tackle stigma, improve education and representation, and optimise access to treatment and continuity of care. The scale up of peer support must provide structured and supportive career pathways for PSWs, account for social and cultural needs of different communities, adapt to differing healthcare systems and provide flexibility in approaches to care. Investment in peer support for people living with CHB could increase diagnosis, improve retention in care, and support design and roll out of interventions that can contribute to global elimination goals.
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Hepatite B Crônica , Grupo Associado , Apoio Social , Humanos , Hepatite B Crônica/terapia , Hepatite B Crônica/psicologiaRESUMO
Abdominal aortic aneurysm (AAA) is a dangerous condition affecting the aorta. Macrophage pyroptosis, phenotypic transformation, and apoptosis of aortic smooth muscle cells (ASMCs) are pivotal mechanisms in AAA pathogenesis. This study explores how Gasdermin B (GSDMB) regulates macrophage non-canonical pyroptosis and its impact on the phenotypic transformation and apoptosis of ASMCs, thereby unveiling the role of GSDMB in AAA pathogenesis. Immunofluorescence analysis was used to assess the expression levels and localization of GSDMB, cysteinyl aspartate-specific protease-4 (Caspase-4), and N-terminal of cleaved GSDMD (N-GSDMD) in AAA tissues. A cell model that mimics macrophage non-canonical pyroptosis was established by treating THP-1 cells with lipopolysaccharide (LPS). THP-1 cells with reduced or increased GSDMB were generated using small interfering RNA (siRNA) or plasmids. Co-culture experiments involving THP-1 cells and HASMCs were conducted to explore the impact of GSDMB on HASMCs. The mitochondrial reactive oxygen species (mtROS) scavenger Mito-TEMPO lowered mtROS levels in THP-1 cells. Our findings revealed that GSDMB was significantly upregulated in AAA macrophages, which was accompanied by robust non-canonical pyroptosis. THP-1 cells showed non-canonical pyroptosis in response to LPS, which was accompanied by an increase in GSDMB. Further research demonstrated that altering GSDMB, either by knockdown or overexpression, can affect macrophage non-canonical pyroptosis as well as the phenotypic transformation and apoptosis of HASMCs. LPS-induced non-canonical pyroptosis in THP-1 cells was associated with an increase in mtROS, whereas Mito-TEMPO effectively decreased non-canonical pyroptosis and the expression of GSDMB. These findings suggest that GSDMB plays a role in AAA macrophage non-canonical pyroptosis, which influences the phenotypic transformation and apoptosis of HASMCs. The mtROS-Dynamin-Related Protein 1 (Drp1) axis is likely to regulate the GSDMB-mediated non-canonical pyroptosis.
Assuntos
Aneurisma da Aorta Abdominal , Macrófagos , Piroptose , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Humanos , Macrófagos/metabolismo , Células THP-1 , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas de Ligação a Fosfato/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Caspases Iniciadoras/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Mitocôndrias/metabolismo , GasderminasRESUMO
Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (P < 0.05). This activation contributed to oxidative stress (P < 0.05), enhanced autophagy (P < 0.05) and cell death (P < 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (P < 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (P < 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (P < 0.05), oxidative stress (P < 0.05), and cell damage (P < 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (P < 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (P < 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (P < 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.
Assuntos
Autofagia , Ferritinas , Coativadores de Receptor Nuclear , Traumatismo por Reperfusão , Coativadores de Receptor Nuclear/metabolismo , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Ferritinas/metabolismo , Camundongos , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológicoRESUMO
Residues of environmental organophosphorus pesticides (OPs) will seriously endanger human health. Most reported OP sensors utilized the restrictions capacity of OPs on the catalytic capacity of acetylcholinesterase (AChE) to acetylthiocholine chloride (ATCh), which suffers from high costs, weak stability, long reaction time, and unrecyclable. Herein, a recyclable strategy was proposed for selective and sensitive detection of glyphosate (Gly). The weak fluorescence of UIO-66-NH2 at 450 nm was enhanced almost 10-fold after reacting with Gly because of the rotation-restricted emission enhancement mechanism. Moreover, inspired by the process of charging and discharging the batteries, we introduced Cu2+ to chelate with Gly. Because of the strong chelation between Cu2+ and Gly, the Gly was removed from UIO-66-NH2, which resulted in the quenching of fluorescence intensity and making UIO-66-NH2 recycle. This method proposed is fast, recyclable, easily conducted, and with a low 0.33 µM LOD in dd H2O based on 3σ/S. The recovery rates of Gly in tap water ranged from 93.07 to 104.35% within a satisfied 7.75% RSD. The Cu2+ LOD is 0.01 mM based on 3σ/S and 94.37-118.34% recovery rates within 6.48% RSD in tap water. We believe that the findings in this work provide a meaningful and promising strategy to detect Gly and Cu2+ in real samples. This sensor first successfully achieves the recycling use of the material in OP fluorescence detection, which greatly decreases the cost of the designed sensor and reduces the possibility of secondary pollution to the environment, broadens a new circulation dimension of fluorescence detection methods in detecting OPs, and has the potential to remove glyphosate from water. It also provides a method to utilize functionalized metal-organic frameworks to establish various sensors.
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PURPOSE: Accurate classification of cancer subgroups is essential for precision medicine, tailoring treatments to individual patients based on their cancer subtypes. In recent years, advances in high-throughput sequencing technologies have enabled the generation of large-scale transcriptomic data from cancer samples. These data have provided opportunities for developing computational methods that can improve cancer subtyping and enable better personalized treatment strategies. METHODS: Here in this study, we evaluated different feature selection schemes in the context of meningioma classification. To integrate interpretable features from the bulk (n = 77 samples) and single-cell profiling (â¼ 10 K cells), we developed an algorithm named CLIPPR which combines the top-performing single-cell models, RNA-inferred copy number variation (CNV) signals, and the initial bulk model to create a meta-model. RESULTS: While the scheme relying solely on bulk transcriptomic data showed good classification accuracy, it exhibited confusion between malignant and benign molecular classes in approximately â¼ 8% of meningioma samples. In contrast, models trained on features learned from meningioma single-cell data accurately resolved the sub-groups confused by bulk-transcriptomic data but showed limited overall accuracy. CLIPPR showed superior overall accuracy and resolved benign-malignant confusion as validated on n = 789 bulk meningioma samples gathered from multiple institutions. Finally, we showed the generalizability of our algorithm using our in-house single-cell (â¼ 200 K cells) and bulk TCGA glioma data (n = 711 samples). CONCLUSION: Overall, our algorithm CLIPPR synergizes the resolution of single-cell data with the depth of bulk sequencing and enables improved cancer sub-group diagnoses and insights into their biology.
Assuntos
Algoritmos , Neoplasias Meníngeas , Meningioma , Análise de Sequência de RNA , Análise de Célula Única , Humanos , Análise de Célula Única/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/classificação , Meningioma/genética , Meningioma/patologia , Meningioma/classificação , Análise de Sequência de RNA/métodos , Variações do Número de Cópias de DNA , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Transcriptoma , Perfilação da Expressão Gênica/métodosRESUMO
The single-step purification of ethylene (C2H4) from a mixture of carbon dioxide (CO2), acetylene (C2H2), ethylene (C2H4), and ethane (C2H6) was achieved through MOF Compound-1, where the aromatic pore surface and carboxylates selectively recognized C2H6 and CO2, respectively, resulting in a reversal of the adsorption orders for both gases (C2H6 > C2H4 and CO2 > C2H4). Breakthrough testing verified that the C2H4 purification ability could be enhanced 2.6 times after adding impure CO2. Grand Canonical Monte Carlo (GCMC) simulations demonstrate that there are interactions between CO2 and C2H6 molecules as well as between CO2 molecules themselves. These interactions contribute to the enhancement of the C2H4 purification ability upon the addition of CO2 and the increased adsorption of CO2.
RESUMO
One-step C2H4 purification from a mixture of C2H2/C2H4/C2H6 could be achieved by metal-organic framework (MOF) NTUniv-70 with an F-functional group. The selectivities of C2H4/C2H6 and C2H4/C2H2 of NTUnvi-70 based on ideal adsorbed solution theory were at least twice that of the original MOF platform, which was in line with the enthalpy of adsorption (Qst) and breakthrough testing. Grand canonical Monte Carlo simulations indicated that the C-H···F interactions played an important role in enhanced C2H4/C2H6 and C2H4/C2H2 adsorption selectivities.
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Single-step ethylene (C2H4) production from acetylene (C2H2), ethylene (C2H4), and ethane (C2H6) mixtures was realized via the strategy of a flow channel with recognition corners in MOF NTUniv-64. Both the uptake amounts and the enthalpy of adsorption (Qst) showed the same order of C2H2 > C2H6 > C2H4. Breakthrough testing also verified the above data and the C2H4 purification ability. Grand Canonical Monte Carlo (GCMC) simulations indicated that uneven corners could precisely detain C2H2 and C2H6, in which the C-H···π interaction distance between C2H2 (2.84 Å) and C2H6 (3.03 Å) and the framework was shorter than that of C2H4 (3.85 Å).
RESUMO
The strategy of flow channel with wrinkles and calcium sites for single-step C2H4 purification from C2 gases and methanol-to-olefins (MTO) products separation was realized in FJI-Y9. The adsorption amounts showed a total reversal order of C3H6 > C2H6 > C2H2 > C2H4 at 298 K. Modeling indicated that the wrinkles and Ca2+ facilitated the full contact of C3H6 and C2H6. Breakthrough experiments illustrated that FJI-Y9 could yield pure C2H4 in a single step with a productivity of 0.78 mmol g-1. In a lone adsorption/desorption cycle for MTO product separation, the productivities of C3H6 and C2H4 were 1.96 and 1.29 mol g-1, standing as the highest recorded values.
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Exploiting a photocatalyst with high stability and excellent activity for Cr(VI) reduction under mild conditions is crucial yet challenging. Herein, the rigid aromatic multicarboxylate ligand with chromophore anthracene was selected to coordinate with multivalent metal ion manganese and to obtain a stable two-dimensional (2D) Mn-based metal-organic framework (MOF), LCUH-120, which can efficiently and quickly convert Cr(VI) into Cr(III) under light without the need for any additional photosensitizer. The efficient photosensitive anthracene group serves as a photosensitizer center and multivalent Mn(II) ion as a photocatalyst center in LCUH-120, and the conversion of Cr(VI) to Cr(III) can be realized completely in just 40 min. Specifically, the rate constant (k) and reduction rate of the Cr(VI) photocatalytic reaction can be high up to 0.134 min-1 and 2.50 mgCr(VI) g-1cata min-1 in an acidic environment (pH = 2), respectively. Compared to our previously reported three-dimensional (3D) Sm-MOF, LCUH-120 exhibits a significantly higher catalytic reaction rate, which might be ascribed to the fact that the photocatalyst center Mn node can improve the rate of electron transfer and promote the separation of holes and photogenerated electrons. In an acidic environment, the reaction mechanism can be verified through various contrast experiments and theoretical simulations.