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The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
Assuntos
Adenocarcinoma de Pulmão , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares , MAP Quinase Quinase Quinases/antagonistas & inibidores , Mutação de Sentido Incorreto , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Substituição de Aminoácidos , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Knockout , Multimerização Proteica/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.
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Quimiocina CCL1/metabolismo , Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Fibroblastos/patologia , Humanos , Camundongos , Miofibroblastos/patologia , Fibrose Pulmonar/patologia , Transdução de Sinais/fisiologiaRESUMO
Break-induced replication (BIR) is a pathway of homology-directed repair that repairs one-ended DNA breaks, such as those formed at broken replication forks or uncapped telomeres. In contrast to conventional S phase DNA synthesis, BIR proceeds by a migrating D-loop and results in conservative synthesis of the nascent strands. DNA polymerase delta (Pol δ) initiates BIR; however, it is not known whether synthesis of the invading strand switches to a different polymerase or how the complementary strand is synthesized. By using alleles of the replicative DNA polymerases that are permissive for ribonucleotide incorporation, thus generating a signature of their action in the genome that can be identified by hydrolytic end sequencing, we show that Pol δ replicates both the invading and the complementary strand during BIR. In support of this conclusion, we show that depletion of Pol δ from cells reduces BIR, whereas depletion of Pol ε has no effect.
Assuntos
Quebras de DNA , DNA Polimerase III/metabolismo , Replicação do DNA , DNA Fúngico/biossíntese , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/metabolismo , DNA Polimerase I/genética , DNA Polimerase I/metabolismo , DNA Polimerase II/genética , DNA Polimerase II/metabolismo , DNA Polimerase III/genética , DNA Fúngico/genética , Células HEK293 , Células HeLa , Humanos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
BigNeuron is an open community bench-testing platform with the goal of setting open standards for accurate and fast automatic neuron tracing. We gathered a diverse set of image volumes across several species that is representative of the data obtained in many neuroscience laboratories interested in neuron tracing. Here, we report generated gold standard manual annotations for a subset of the available imaging datasets and quantified tracing quality for 35 automatic tracing algorithms. The goal of generating such a hand-curated diverse dataset is to advance the development of tracing algorithms and enable generalizable benchmarking. Together with image quality features, we pooled the data in an interactive web application that enables users and developers to perform principal component analysis, t-distributed stochastic neighbor embedding, correlation and clustering, visualization of imaging and tracing data, and benchmarking of automatic tracing algorithms in user-defined data subsets. The image quality metrics explain most of the variance in the data, followed by neuromorphological features related to neuron size. We observed that diverse algorithms can provide complementary information to obtain accurate results and developed a method to iteratively combine methods and generate consensus reconstructions. The consensus trees obtained provide estimates of the neuron structure ground truth that typically outperform single algorithms in noisy datasets. However, specific algorithms may outperform the consensus tree strategy in specific imaging conditions. Finally, to aid users in predicting the most accurate automatic tracing results without manual annotations for comparison, we used support vector machine regression to predict reconstruction quality given an image volume and a set of automatic tracings.
Assuntos
Benchmarking , Microscopia , Microscopia/métodos , Imageamento Tridimensional/métodos , Neurônios/fisiologia , AlgoritmosRESUMO
Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non-CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.
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DNA Helicases/fisiologia , Proteínas de Ligação a DNA/fisiologia , Epigênese Genética , Células-Tronco Neurais/metabolismo , Células Neuroepiteliais/metabolismo , Síndrome CHARGE/genética , Linhagem Celular , Linhagem da Célula/genética , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Haploinsuficiência , Humanos , Crista Neural/metabolismo , Transcrição GênicaRESUMO
Genomic recombination is an important driving force for viral evolution, and recombination events have been reported for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the Coronavirus Disease 2019 pandemic, which significantly alter viral infectivity and transmissibility. However, it is difficult to identify viral recombination, especially for low-divergence viruses such as SARS-CoV-2, since it is hard to distinguish recombination from in situ mutation. Herein, we applied information theory to viral recombination analysis and developed VirusRecom, a program for efficiently screening recombination events on viral genome. In principle, we considered a recombination event as a transmission process of ``information'' and introduced weighted information content (WIC) to quantify the contribution of recombination to a certain region on viral genome; then, we identified the recombination regions by comparing WICs of different regions. In the benchmark using simulated data, VirusRecom showed a good balance between precision and recall compared to two competing tools, RDP5 and 3SEQ. In the detection of SARS-CoV-2 XE, XD and XF recombinants, VirusRecom providing more accurate positions of recombination regions than RDP5 and 3SEQ. In addition, we encapsulated the VirusRecom program into a command-line-interface software for convenient operation by users. In summary, we developed a novel approach based on information theory to identify viral recombination within highly similar sequences, providing a useful tool for monitoring viral evolution and epidemic control.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Teoria da Informação , Filogenia , Recombinação GenéticaRESUMO
Embryonic stem cells (ESCs) exhibit a metabolic preference for glycolysis over oxidative phosphorylation to meet their substantial adenosine triphosphate (ATP) demands during self-renewal. This metabolic choice inherently maintains low mitochondrial activity and minimal reactive oxygen species (ROS) generation. Nonetheless, the intricate molecular mechanisms governing the restraint of ROS production and the mitigation of cellular damage remain incompletely elucidated. In this study, we reveal the pivotal role of RNA-binding motif protein 46 (RBM46) in ESCs, acting as a direct post transcriptional regulator of ROS levels by modulating BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) mRNA expression. Rbm46 knockout lead to diminished mitochondrial autophagy, culminating in elevated ROS within ESCs, disrupting the delicate balance required for healthy self-renewal. These findings provide insights into a novel mechanism governing ROS regulation in ESCs.
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Mitofagia , Células-Tronco Embrionárias Murinas , Animais , Camundongos , Autofagia , Mitocôndrias/metabolismo , Mitofagia/genética , Células-Tronco Embrionárias Murinas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/uso terapêutico , Imunização PassivaRESUMO
Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.
Assuntos
Esôfago de Barrett , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Locos de Características Quantitativas , Humanos , Esôfago de Barrett/genética , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/patologia , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/tratamento farmacológico , Predisposição Genética para Doença , Mapas de Interação de Proteínas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Nonobstructive azoospermia (NOA), the most severe manifestation of male infertility, lacks a comprehensive understanding of its genetic etiology. Here, a bi-allelic loss-of-function variant in REC114 (c.568C > T: p.Gln190*) were identified through whole exome sequencing (WES) in a Chinese NOA patient. Testicular histopathological analysis and meiotic chromosomal spread analysis were conducted to assess the stage of spermatogenesis arrested. Co-immunoprecipitation (Co-IP) and Western blot (WB) were used to investigate the influence of variant in vitro. In addition, our results revealed that the variant resulted in truncated REC114 protein and impaired interaction with MEI4, which was essential for meiotic DNA double-strand break (DSB) formation. As far as we know, this study presents the first report that identifies REC114 as the causative gene for male infertility. Furthermore, our study demonstrated indispensability of the REC114-MEI4 complex in maintaining DSB homoeostasis, and highlighted that the disruption of the complex due to the REC114 variant may underline the mechanism of NOA.
Assuntos
Azoospermia , Infertilidade Masculina , Humanos , Masculino , Azoospermia/genética , Azoospermia/patologia , Perda de Heterozigosidade , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Testículo/patologia , Meiose/genética , Proteínas de Ciclo Celular/genéticaRESUMO
Due to the high cost, low-performance lasers and detectors in the mid-infrared (MIR) band, the development of MIR-integrated devices is very slow. Here, we demonstrate an effective method to characterize the parameters of MIR devices by using frequency conversion technology. We designed and fabricated rib waveguides and the micro-ring resonators (MRRs) on a silicon-on-sapphire platform. The MIR laser for the test is generated by difference frequency generation, and the transmission spectrum of the MIR-MRRs is detected by sum frequency generation. The experimental results show that the waveguide transmission loss is 4.5â dB/cm and the quality factor of the micro-ring reaches 38000, which is in good agreement with the numerical simulations. This work provides a useful method to characterize MIR integrated devices based on the frequency conversion technique, which can boost the development of MIR integrated optics in the future.
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Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.
Assuntos
Esclerose Lateral Amiotrófica , Astrócitos , Proteínas de Ligação a DNA , Proteínas Mitocondriais , Fatores de Transcrição , Feminino , Humanos , Masculino , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Astrócitos/patologia , Astrócitos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Mitocôndrias/patologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: The aim of this multicentre cohort study was to compare the long-term oncological outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with gastric cancer. METHODS: Patients with gastric cancer who underwent radical gastrectomy by robotic or laparoscopic approaches from 1 March 2010 to 31 December 2018 at 10 high-volume centres in China were selected from institutional databases. Patients receiving RG were matched 1 : 1 by propensity score with patients undergoing LG. The primary outcome was 3-year disease-free survival. Secondary outcomes were overall survival and disease recurrence. RESULTS: Some 2055 patients who underwent RG and 4309 patients who had LG were included. The propensity score-matched cohort comprised 2026 RGs and 2026 LGs. Median follow-up was 41 (i.q.r. 39-58) months for the RG group and 39 (38-56) months for the LG group. The 3-year disease-free survival rates were 80.8% in the RG group and 79.5% in the LG group (log rank P = 0.240; HR 0.92, 95% c.i. 0.80 to 1.06; P = 0.242). Three-year OS rates were 83.9 and 81.8% respectively (log rank P = 0.068; HR 0.87, 0.75 to 1.01; P = 0.068) and the cumulative incidence of recurrence over 3 years was 19.3% versus 20.8% (HR 0.95, 0.88 to 1.03; P = 0.219), with no difference between groups. CONCLUSION: RG and LG in patients with gastric cancer are associated with comparable disease-free and overall survival.
Assuntos
Laparoscopia , Levamisol/análogos & derivados , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Humanos , Resultado do Tratamento , Estudos de Coortes , Neoplasias Gástricas/cirurgia , Gastrectomia , Pontuação de Propensão , Estudos Retrospectivos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgiaRESUMO
Tetraparvovirus is an emerging parvovirus infecting a variety of mammals and humans, and associated with human diseases including severe acute respiratory infection and acute encephalitis syndrome. In the present study, a Tetraparvovirus ungulate 1 (formerly known as bovine hokovirus) strain HNU-CBY-2023 was identified and characterized from diseased Chinese Simmental from Hunan province, China. The nearly complete genome of HNU-CBY-2023 is 5346 nt in size and showed genomic identities of 85-95.5% to the known Tetraparvovirus ungulate 1 strains from GenBank, indicating a rather genetic variation. Phylogenetic and genetic divergence analyses indicated that Tetraparvovirus ungulate 1 could be divided into two genotypes (I and II), and HNU-CBY-2023 was clustered into genotype II. This study, for the first time, identified Tetraparvovirus ungulate 1 from domestic cattle from mainland China, which will be helpful to understand the prevalence and genetic diversity of Tetraparvovirus ungulate 1.
Assuntos
Doenças dos Bovinos , Variação Genética , Genoma Viral , Genótipo , Infecções por Parvoviridae , Filogenia , Animais , Bovinos , China , Doenças dos Bovinos/virologia , Doenças dos Bovinos/epidemiologia , Infecções por Parvoviridae/veterinária , Infecções por Parvoviridae/virologia , Infecções por Parvoviridae/epidemiologia , Genoma Viral/genética , Parvovirinae/genética , Parvovirinae/isolamento & purificação , Parvovirinae/classificação , Análise de Sequência de DNA , DNA Viral/genética , População do Leste AsiáticoRESUMO
BACKGROUND AND AIMS: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD-related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. METHODS: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early- and late-stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD-afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. RESULTS: Patients with hepatic WD and mice with WD-related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD-related liver injury. CONCLUSIONS: Individuals and mice with pronounced WD-related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD-related liver injury.
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OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.
Assuntos
Carbazóis , DNA Forma Z , Neoplasias , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Apoptose , PiroptoseRESUMO
In Chinese criminal law, the ages of 12, 14, 16, and 18 years old play a significant role in the determination of criminal responsibility. In this study, we developed an epiphyseal grading system based on magnetic resonance image (MRI) of the hand and wrist for the Chinese Han population and explored the feasibility of employing deep learning techniques for bone age assessment based on MRI of the hand and wrist. This study selected 282 Chinese Han Chinese males aged 6.0-21.0 years old. In the course of our study, we proposed a novel deep learning model for extracting and enhancing MRI hand and wrist bone features to enhance the prediction of target MRI hand and wrist bone age and achieve precise classification of the target MRI and regression of bone age. The evaluation metric for the classification model including precision, specificity, sensitivity, and accuracy, while the evaluation metrics chosen for the regression model are MAE. The epiphyseal grading was used as a supervised method, which effectively solved the problem of unbalanced sample distribution, and the two experts showed strong consistency in the epiphyseal plate grading process. In the classification results, the accuracy in distinguishing between adults and minors was 91.1%, and the lowest accuracy in the three minor classifications (12, 14, and 16 years of age) was 94.6%, 91.1% and 96.4%, respectively. The MAE of the regression results was 1.24 years. In conclusion, the deep learning model proposed enabled the age assessment of hand and wrist bones based on MRI.
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Persons living with HIV (PLWH) and depression or anxiety in the rural South may have suboptimal HIV outcomes. We sought to examine the proportion of PLWH from rural Florida with symptoms of depression or anxiety, the proportion who received depression or anxiety treatment, and the relationship between untreated and treated symptoms of depression or anxiety and HIV outcomes. Cross-sectional survey data collected between 2014 and 2018 were analyzed. Among 187 PLWH residing in rural Florida (median age 49 years, 61.5%, male 45.5% Black), 127 (67.9%) met criteria for symptoms of depression and/or anxiety. Among these 127 participants, 60 (47.2%) were not on depression or anxiety treatment. Participants with untreated symptoms of depression and anxiety (OR 3.2, 95% CI 1.2-9.2, p = 0.03) and treated depression and anxiety with uncontrolled symptoms (OR 1.4, 95% CI 0.5-4.0, p = 0.52) were more likely to have viral non-suppression compared to those without depression or anxiety in an unadjusted bivariate analysis. Only the association between untreated symptoms of depression and anxiety and viral non-suppression was statistically significant, and when adjusting for social and structural confounders the association was attenuated and was no longer statistically significant. This suggests that social and structural barriers impact both mental health and HIV outcomes. Our findings support the need for increased mental health services and resources that address the social and structural barriers to care for PLWH in the rural South.
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Depressão , Infecções por HIV , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Florida/epidemiologia , Depressão/epidemiologia , Depressão/psicologia , Estudos Transversais , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Ansiedade/epidemiologia , Ansiedade/psicologiaRESUMO
The attributes of good solubility and the redox-neutral nature of molten salt fluxes enable them to be useful for the synthesis of novel crystalline actinide compounds. In this work, a flux growth method under an inert atmosphere is proposed to explore the valence diversity of uranium, and a series of five uranium silicate structures, [K3Cl][(UVIO2)(Si4O10)] (1), Cs3[(UVO2)(Si4O10)] (2), K2[UIV(Si2O7)] (3), K8[(UVIO2)(UVO2)2(Si8O22)] (4), and Cs6[UIV(UVO)2(Si12O32)] (5), were synthesized using different metal halide salt and feeding U/Si ratios. Crystal structure analysis reveals that the utilization of argon atmosphere that helps to avoid possible oxidation of low-valence uranium generates a variety of oxidation states of uranium including U(VI), U(V), U(IV), mixed-valence U(V) and U(VI), and mixed-valence U(IV) and U(V). Characterization of physicochemical properties of representative compounds shows that all these uranium silicate compounds have bandgaps among the range of 2.0-3.4 eV, and mixed-valence uranium silicate compounds have relatively narrower bandgaps. Density functional theory calculations on formation enthalpies, lattice energies, and bandgaps of all five compounds were also performed to provide more structural information about these uranium silicates. This work enriches the library of variable-valence uranium silicate compounds and provides a feasible way to produce novel actinide compounds with intriguing properties through the flux growth method that might show potential application in relevant fields such as storage media for nuclear waste.