RESUMEN
The live attenuated hepatitis A virus vaccine H2 strain was developed by passaging a wild- type H2w isolate in cell cultures. Currently, the mechanism underlying its attenuation phenotype remain largely unknown. In this study, we generated a full-length infectious cDNA clone of the H2 strain using in-fusion techniques. The recovered H2 strain (H2ic) from the cDNA clone exhibited an efficient replication in both the hepatoma cell line Huh7.5.1 and the 2BS cell line used for vaccine production, similar to the parental H2 strain. Additionally, H2ic did not cause disease in Ifnar1-/- C57 mice, consistent with the H2 strain. To explore the cell-adaptive mutations of the H2 strain, chimeric viruses were generated by replacing its non-structural proteins with corresponding regions from H2w using the infectious cDNA clone as a genetic backbone. The chimeric viruses carrying the 3C or 3D proteins from H2w showed decreased replication in Huh7.5.1 and 2BS cell lines compared to H2ic. Other chimeric viruses containing the 2B, 2C, or 3A proteins from H2w failed to be recovered. Furthermore, there were no significant differences in disease manifestation in mice between H2ic and the recovered chimeric viruses. These results demonstrate that adaptive mutations in the 2B, 2C, and 3A proteins are essential for efficient replication of the H2 strain in cell cultures. Mutations in the 3C and 3D proteins contribute to enhanced replication in cell cultures but did not influence the attenuated phenotypes in mice. Together, this study presents the first reverse genetic system of the H2 strain and identifies viral proteins essential for adaptation to cell cultures.
RESUMEN
Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases. Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease (ALD) pathology. Rab GTPases play critical roles in regulating vesicular transport. In this study we investigated the role of Rab11b in ALD, aiming to identify effective therapeutic targets. Here, we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice. Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation, injury and steatosis. We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages (BMDM) cells. Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization. Rab11b overexpression in BMDMs inhibited autophagic flux, leading to the suppression of LC3B-mediated NLRP3 degradation. We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.
RESUMEN
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17ß-estradiol (E2) reduces peptide expression but increases Vglut2 mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When TRPC5 channels in Kiss1ARH neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1ARH neuron, suggesting that E2 modifies ionic conductances in Kiss1ARH neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
RESUMEN
Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Artritis Reumatoide , Quimioterapia Combinada , Interleucina-2 , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Interleucina-2/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.
Asunto(s)
Densidad Ósea , Diabetes Mellitus Tipo 1 , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoporosis , Polimorfismo de Nucleótido Simple , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/complicaciones , Osteoporosis/genética , Densidad Ósea/genética , Factores de Riesgo , Femenino , Masculino , Cuello Femoral/diagnóstico por imagen , Predisposición Genética a la Enfermedad , Vértebras Lumbares , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , AntebrazoRESUMEN
In this study, we developed a multi-site acylation strategy to improve the lipophilicity and cellular uptake of troxerutin, a natural flavonoid with many health-promoting bioactivities. By clarifying the acylation properties of troxerutin catalyzed by lipases from different sources, a series of troxerutin ester derivatives acylated at different sites was synthesized, including troxerutin dipropyl (TDP), tripropyl (TTP), tetrapropyl (TEP), dibutyl (TDB), monohexyl (TMH), monooctyl (TMO) and monodecyl (TMD) esters. Interestingly, the troxerutin esters acylated at multiple sites with shorter fatty chains (TDP, TTP and TEP) had similar lipophilicity to the mono-acylated esters bearing longer fatty chains (TMH, TMO and TMD, respectively) and meanwhile demonstrated surprisingly lower cytotoxicity than that of the long fatty-chain mono-esters. In particular, the multi-acylated esters with shorter fatty chains showed remarkably higher cellular uptake than the mono-esters with long fatty chains. In vitro gastrointestinal digestion suggested that the multi-acylated esters of troxerutin were more resistant to gastrointestinal degradation than the mono-esters. These results indicated that multi-site acylation with short fatty chains could be an effective alternative to introducing one-site mono-acylation for the modification of troxerutin and other flavonoid compounds.
Asunto(s)
Hidroxietilrutósido , Lipasa , Acilación , Humanos , Hidroxietilrutósido/análogos & derivados , Hidroxietilrutósido/farmacología , Hidroxietilrutósido/química , Hidroxietilrutósido/metabolismo , Lipasa/metabolismo , Lipasa/química , AnimalesRESUMEN
Auxin regulates plant growth and development through downstream signaling pathways, including the best-known SCFTIR1/AFB-Aux/IAA-ARF pathway and several other less characterized "noncanonical" pathways. Recently, one SCFTIR1/AFB-independent noncanonical pathway, mediated by Transmembrane Kinase 1 (TMK1), was discovered through the analyses of its functions in Arabidopsis apical hook development. Asymmetric accumulation of auxin on the concave side of the apical hook triggers DAR1-catalyzed release of the C-terminal of TMK1, which migrates into the nucleus, where it phosphorylates and stabilizes IAA32/34 to inhibit cell elongation, which is essential for full apical hook formation. However, the molecular factors mediating IAA32/34 degradation have not been identified. Here, we show that proteins in the CYTOKININ INDUCED ROOT WAVING 1 (CKRW1)/WAVY GROWTH 3 (WAV3) subfamily act as E3 ubiquitin ligases to target IAA32/34 for ubiquitination and degradation, which is inhibited by TMK1c-mediated phosphorylation. This antagonistic interaction between TMK1c and CKRW1/WAV3 subfamily E3 ubiquitin ligases regulates IAA32/34 levels to control differential cell elongation along opposite sides of the apical hook.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas F-Box , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , Transducción de Señal , Ubiquitinas/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas F-Box/genética , Proteínas F-Box/metabolismoRESUMEN
Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1ß, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1ß, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.
Asunto(s)
Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Helicobacter , Neoplasias Gástricas , Humanos , Citocinas/metabolismo , Helicobacter pylori/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Helicobacter/metabolismo , Interleucina-8/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Gastritis/patología , Interleucina-12/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/metabolismo , Mucosa Gástrica/metabolismoRESUMEN
Guaico Culex virus (GCXV) is a newly identified segmented Jingmenvirus from Culex spp. mosquitoes in Central and South America. The genome of GCXV is composed of four or five single-stranded positive RNA segments. However, the infection kinetics and transmission capability of GCXV in mosquitoes remain unknown. In this study, we used reverse genetics to rescue two GCXVs (4S and 5S) that contained four and five RNA segments, respectively, in C6/36 âcells. Further in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics, protein expression and viral titers. Importantly, GCXV RNAs were detected in the bodies, salivary glands, midguts and ovaries of Culex quinquefasciatus at 4-10 days after oral infection. In addition, two GCXVs can colonize Cx. quinquefasciatus eggs, resulting in positive rates of 15%-35% for the second gonotrophic cycle. In conclusion, our results demonstrated that GCXVs with four or five RNA segments can be detected in Cx. quinquefasciatus eggs during the first and second gonotrophic cycles after oral infection.
Asunto(s)
Culex , Mosquitos Vectores , ARN Viral , Replicación Viral , Animales , Culex/virología , Mosquitos Vectores/virología , ARN Viral/genética , Femenino , Línea Celular , Flavivirus/genética , Flavivirus/fisiología , Flavivirus/aislamiento & purificación , Cinética , Carga Viral , Genoma Viral , Glándulas Salivales/virologíaRESUMEN
Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.
Asunto(s)
Hormona Luteinizante , Quinolinas , Receptores de Neuroquinina-3 , Transducción de Señal , Estrés Psicológico , Sustancia P/análogos & derivados , Animales , Femenino , Receptores de Neuroquinina-3/metabolismo , Receptores de Neuroquinina-3/antagonistas & inhibidores , Receptores de Neuroquinina-3/agonistas , Hormona Luteinizante/metabolismo , Estrés Psicológico/metabolismo , Ratones , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Complejo Nuclear Corticomedial/metabolismo , Complejo Nuclear Corticomedial/efectos de los fármacos , Complejo Nuclear Corticomedial/fisiología , Fragmentos de Péptidos/farmacología , Hormona Liberadora de Gonadotropina/metabolismo , Ratones Endogámicos C57BL , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/efectos de los fármacosRESUMEN
BACKGROUND: A growing number of clinical examples suggest that coronavirus disease 2019 (COVID-19) appears to have an impact on the treatment of patients with liver cancer compared to the normal population, and the prevalence of COVID-19 is significantly higher in patients with liver cancer. However, this mechanism of action has not been clarified. AIM: To investigate the disease relevance of COVID-19 in liver cancer. METHODS: Gene sets for COVID-19 (GSE180226) and liver cancer (GSE87630) were obtained from the Gene Expression Omnibus database. After identifying the common differentially expressed genes (DEGs) of COVID-19 and liver cancer, functional enrichment analysis, protein-protein interaction network construction and screening and analysis of hub genes were performed. Subsequently, the validation of the differential expression of hub genes in the disease was performed and the regulatory network of transcription factors and hub genes was constructed. RESULTS: Of 518 common DEGs were obtained by screening for functional analysis. Fifteen hub genes including aurora kinase B, cyclin B2, cell division cycle 20, cell division cycle associated 8, nucleolar and spindle associated protein 1, etc., were further identified from DEGs using the "cytoHubba" plugin. Functional enrichment analysis of hub genes showed that these hub genes are associated with P53 signalling pathway regulation, cell cycle and other functions, and they may serve as potential molecular markers for COVID-19 and liver cancer. Finally, we selected 10 of the hub genes for in vitro expression validation in liver cancer cells. CONCLUSION: Our study reveals a common pathogenesis of liver cancer and COVID-19. These common pathways and key genes may provide new ideas for further mechanistic studies.
RESUMEN
BACKGROUND: Transarterial chemoembolization (TACE) combined with microwave ablation (MWA) is an effective treatment strategy for patients with advanced gastric cancer and liver metastasis. However, it may cause severe postoperative pain and inflammatory responses. The paravertebral block (PVB) is a regional anesthetic technique that provides analgesia to the thoracic and abdominal regions. AIM: To evaluate the effect of PVB on postoperative analgesia and inflammatory response in patients undergoing TACE combined with MWA for advanced gastric cancer and liver metastasis. METHODS: Sixty patients were randomly divided into PVB and control groups. The PVB group received ultrasound-guided PVB with 0.375% ropivacaine preoperatively, whereas the control group received intravenous analgesia with sufentanil. The primary outcome was the visual analog scale (VAS) score for pain at 6 h, 12 h, 24 h, and 48 h after the procedure. Secondary outcomes were the dose of sufentanil used, incidence of adverse events, and levels of inflammatory markers (white blood cell count, neutrophil percentage, C-reactive protein, and procalcitonin) before and after the procedure. RESULTS: The PVB group had significantly lower VAS scores at 6 h, 12 h, 24 h, and 48 h after the procedure compared with the control group (P < 0.05). The PVB group also had a significantly lower consumption of sufentanil and a lower incidence of nausea, vomiting, and respiratory depression than did the control group (P < 0.05). Compared with the control group, the PVB group had significantly lower levels of inflammatory markers 24 h and 48 h after the procedure (P < 0.05). CONCLUSION: PVB can effectively reduce postoperative pain and inflammatory responses and improve postoperative comfort and recovery in patients with advanced gastric cancer and liver metastasis treated with TACE combined with MWA.
RESUMEN
In hepatic fibrosis (HF), hepatic stellate cells (HSCs) form the extracellular matrix (ECM), and the pathological accumulation of ECM in the liver leads to inflammation. Our previous research found that miR-324-3p was down-regulated in culture-activated human HSCs. However, the precise effect of miR-324-3p on HF has not been elucidated. In this study, the HF mouse models were induced through directly injecting carbon tetrachloride (CCl4) into mice; the HF cell models were constructed using TGF-ß1-treated LX-2 cells. Next, real-time-quantitative polymerase chain reaction (RT-qPCR), western blot (WB) and immunohistochemistry (IHC) were applied to assess the expression levels of miR-324-3p, α-smooth muscle actin (α-SMA), Vimentin or SMAD4; hematoxylin and eosin (H&E), Masson' s trichrome and Sirius red staining to evaluate the liver injury; luciferase reporter assay to verify the targeting relationship between miR-324-3p and SMAD4; enzyme-linked immunosorbent assay (ELISA) to determine the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and cell counting kit-8 (CCK-8) and flow cytometry to evaluate the effects of miR-324-3p on cell proliferation and cycle/apoptosis, respectively. The experimental results showed a reduction in miR-324-3p level in CCl4-induced HF mice as well as transforming growth factor (TGF)-ß1-activated HSCs. Interestingly, the miR-324-3p level was rescued following the HF recovery process. In HF mice induced by CCl4, miR-324-3p overexpression inhibited liver tissue damage, decreased serum ALT and AST levels, and inhibited fibrosis-related biomarkers (α-SMA, Vimentin) expression, thereby inhibiting HF. Similarly, miR-324-3p overexpression up-regulated α-SMA and Vimentin levels in HF cells, while knockdown of miR-324-3p had the opposite effect. Besides, miR-324-3p played an antifibrotic role through inhibiting the proliferation of hepatocytes. Further experiments confirmed that miR-324-3p targeted and down-regulated SMAD4 expression. SMAD4 was highly expressed in HF cells, and silencing SMAD4 significantly decreased the α-SMA and Vimentin levels in HF cells. Collectively, the miR-324-3p may suppress the activation of HSCs and HF by targeting SMAD4. Therefore, miR-324-3p is identified as a potential and novel therapeutic target for HF.
RESUMEN
Usutu virus (USUV) is an emerging arthropod-borne flavivirus that has expanded into multiple European countries during the past several decades. USUV infection in human has been linked to severe neurological complications, and no vaccine is now available against USUV. In this work, we develop a live-attenuated chimeric USUV vaccine (termed ChinUSUV) based on the full-length infectious cDNA clone of the licensed Japanese encephalitis virus (JEV) vaccine strain SA14-14-2. In vitro studies demonstrate that ChinUSUV replicates efficiently and maintains its genetic stability. Remarkably, ChinUSUV exhibits a significant attenuation phenotype in multiple mouse models even compared with the licensed JEV vaccine. A single immunization with ChinUSUV elicits potent IgG and neutralizing antibody responses as well as T cell response. Passive transfer of sera from ChinUSUV-immunized mice confers significant protection against lethal homologous challenge in suckling mice. Taken together, our results suggest that ChinUSUV represents a potential USUV vaccine candidate that merits further development.
Asunto(s)
Virus de la Encefalitis Japonesa (Especie) , Encefalitis Japonesa , Flavivirus , Vacunas contra la Encefalitis Japonesa , Humanos , Animales , Ratones , Vacunas Atenuadas , Encefalitis Japonesa/prevención & controlRESUMEN
Spread Through Air Spaces (STAS) is involved in lung adenocarcinoma (LUAD) recurrence, where cancer cells spread into adjacent lung tissue, impacting surgical planning and prognosis assessment. Radiomics-based models show promise in predicting STAS preoperatively, enhancing surgical precision and prognostic evaluations. The present study performed network meta-analysis to assess the predictive efficacy of imaging models for STAS in LUAD. Data were systematically sourced from PubMed, Embase, Scopus, Wiley and Web of Science, according to the Cochrane Handbook for Systematic Reviews of Interventions) and A Measurement Tool to Assess systematic Reviews 2. Using Stata software v17.0 for meta-analysis, surface under the cumulative ranking area (SUCRA) was applied to identify the most effective diagnostic method. Quality assessments were performed using Cochrane Collaboration's risk-of-bias tool and publication bias was assessed using Deeks' funnel plot. The analysis encompassed 14 articles, involving 3,734 patients, and assessed 17 predictive models for STAS in LUAD. According to comprehensive analysis of SUCRA, the machine learning (ML)_Peri_tumour model had the highest accuracy (56.5), the Features_computed tomography (CT) model had the highest sensitivity (51.9) and the positron emission tomography (pet)_CT model had the highest specificity (53.9). ML_Peri_tumour model had the highest predictive performance. The accuracy was as follows: ML_Peri_tumour vs. Features_CT [relative risk (RR)=1.14; 95% confidence interval (CI), 0.99-1.32]; ML_Peri_tumour vs. ML_Tumour (RR=1.04; 95% CI, 0.83-1.30) and ML_Peri_tumour vs. pet_CT (RR=1.04; 95% CI, 0.84-1.29). Comparative analyses revealed heightened predictive accuracy of the ML_Peri_tumour compared with other models. Nonetheless, the field of radiological feature analysis for STAS prediction remains nascent, necessitating improvements in technical reproducibility and comprehensive model evaluation.
RESUMEN
The purpose of this research was to characterize the microbiota of patients with psoriatic arthritis (PsA) and to compare the relationship between the microbiota and peripheral lymphocyte subsets and cytokines. We collected stool samples from 13 PsA patients and 26 sex- and age-matched healthy controls (HCs) and researched the gut microbiota by sequencing the V3-V4 variable region of the bacterial 16S rRNA gene with the Illumina Miseq PE300 system. Flow cytometry was used to assess the peripheral lymphocyte subsets in these participants. Record measures of disease activity such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Alpha and beta diversity were assessed using results from QIIME2. Panel demonstrated the average relative abundance of the different genera in PsA and HCs. Correlation between clinical parameters and the relative abundance of the genus in samples was assessed by the Pearson correlation analysis using R (version 4.0.1). Compared with HC, the abundance of gut microbiota (Chao 1 and ACE) decreased in patients with PsA, and the diversity of bacteria (Shannon and Simpson indices) also decreased in PsA (Fig. 1a). ß Diversity analysis indicated differences in microbial communities between PsA and HC (Fig. 1b, r = 0.039, p = 0.264, ANOSIM). Furthermore, 18 bacterial groups were significantly different at the genus level in PsA compared to HCs (p < 0.05) (Fig. 2).In the phylum and genus, lymphocyte subsets and cytokines are associated with the microbiota. The gut microbiota of patients with PsA differs from HC, which was closely related to lymphocyte subsets.
RESUMEN
During the life cycle of mosquito-borne flaviviruses, substantial subgenomic flaviviral RNA (sfRNA) is produced via incomplete degradation of viral genomic RNA by host XRN1. Zika virus (ZIKV) sfRNA has been detected in mosquito and mammalian somatic cells. Human neural progenitor cells (hNPCs) in the developing brain are the major target cells of ZIKV, and antiviral RNA interference (RNAi) plays a critical role in hNPCs. However, whether ZIKV sfRNA was produced in ZIKV-infected hNPCs as well as its function remains not known. In this study, we demonstrate that abundant sfRNA was produced in ZIKV-infected hNPCs. RNA pulldown and mass spectrum assays showed ZIKV sfRNA interacted with host proteins RHA and PACT, both of which are RNA-induced silencing complex (RISC) components. Functionally, ZIKV sfRNA can antagonize RNAi by outcompeting small interfering RNAs (siRNAs) in binding to RHA and PACT. Furthermore, the 3' stem loop (3'SL) of sfRNA was responsible for RISC components binding and RNAi inhibition, and 3'SL can enhance the replication of a viral suppressor of RNAi (VSR)-deficient virus in a RHA- and PACT-dependent manner. More importantly, the ability of binding to RISC components is conversed among multiple flaviviral 3'SLs. Together, our results identified flavivirus 3'SL as a potent VSR in RNA format, highlighting the complexity in virus-host interaction during flavivirus infection.IMPORTANCEZika virus (ZIKV) infection mainly targets human neural progenitor cells (hNPCs) and induces cell death and dysregulated cell-cycle progression, leading to microcephaly and other central nervous system abnormalities. RNA interference (RNAi) plays critical roles during ZIKV infections in hNPCs, and ZIKV has evolved to encode specific viral proteins to antagonize RNAi. Herein, we first show that abundant sfRNA was produced in ZIKV-infected hNPCs in a similar pattern to that in other cells. Importantly, ZIKV sfRNA acts as a potent viral suppressor of RNAi (VSR) by competing with siRNAs for binding RISC components, RHA and PACT. The 3'SL of sfRNA is responsible for binding RISC components, which is a conserved feature among mosquito-borne flaviviruses. As most known VSRs are viral proteins, our findings highlight the importance of viral non-coding RNAs during the antagonism of host RNAi-based antiviral innate immunity.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Humanos , Mamíferos/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Viral/genética , ARN Viral/metabolismo , Complejo Silenciador Inducido por ARN/metabolismo , ARN Subgenómico , Proteínas Virales/metabolismo , Replicación Viral , Virus Zika/fisiología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virologíaRESUMEN
BACKGROUND: The consolidation tumor ratio (CTR) is a predictor of invasiveness in peripheral T1N0M0 lung adenocarcinoma. However, its association with spread through air spaces (STAS) remains largely unexplored. We aimed to explore the correlation between the CTR of primary tumors and STAS in peripheral T1N0M0 lung adenocarcinoma. METHODS: We collected data from patients who underwent surgery for malignant lung neoplasms between January and November 2022. Univariate and multivariate analyses following propensity-score matching with sex, age, BMI, were performed to identify the independent risk factors for STAS. The incidence of STAS was compared based on pulmonary nodule type. A smooth fitting curve between CTR and STAS was produced by the generalized additive model (GAM) and a multiple regression model was established using CTR and STAS to determine the dose-response relationship and calculate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: 17 (14.5%) were diagnosed with STAS. The univariate analysis demonstrated that the history of the diabetes, size of solid components, spiculation, pleural indentation, pulmonary nodule type, consolidation/tumor ratio of the primary tumor were statistically significant between the STAS-positive and STAS-negative groups following propensity-score matching(p = 0.047, 0.049, 0.030, 0.006, 0.026, and < 0.001, respectively), and multivariate analysis showed that the pleural indentation was independent risk factors for STAS (with p-value and 95% CI of 0.043, (8.543-68.222)). Moreover, the incidence of STAS in the partially solid nodule was significantly different from that in the solid nodule and ground-glass nodule (Pearson Chi-Square = 7.49, p = 0.024). Finally, the smooth fitting curve showed that CTR tended to be linearly associated with STAS by GAM, and the multivariate regression model based on CTR showed an OR value of 1.24 and a p-value of 0.015. CONCLUSIONS: In peripheral stage IA lung adenocarcinoma, the risk of STAS was increased with the solid component of the primary tumor. The pleural indentation of the primary tumor could be used as a predictor in evaluating the risk of the STAS.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Puntaje de Propensión , Radiografía , Análisis MultivarianteRESUMEN
PURPOSE: To establish a multivariate linear equation to predict the diameter (outer diameter) of the acetabular prosthesis used in total hip arthroplasty. METHODS: A cohort of 258 individuals who underwent THA at our medical facility were included in this study. The independent variables encompassed the patients' height, weight, foot length, gender, age, and surgical access. The dependent variable in this study was the diameter of the acetabular prosthesis utilized during the surgical procedure. The entire cohort dataset was randomly partitioned into a training cohort and a validation cohort, with a ratio of 7:3, employing the SPSS 26.0 software. Pearson correlation analysis was conducted to examine the relationships between the patients' height, weight, foot length, gender, age, surgical access, and the diameter of the acetabular prosthesis in the training cohort. Additionally, a multiple linear regression equation was developed using the independent variables from the training cohort and the diameter of the acetabular prosthesis as the dependent variable. This equation aimed to predict the diameter of the acetabular prosthesis based on the patients' characteristics. The accuracy of the equation was evaluated by substituting the data of the validation cohort into the multiple linear equation. The predicted acetabular prosthesis diameters were then compared with the actual diameters used in the operation. RESULTS: The correlation analysis conducted on the training cohort revealed that surgical access (r = 0.054) and age (r = -0.120) exhibited no significant correlation with the diameter of the acetabular prosthesis utilized during the intraoperative procedure. Conversely, height (r = 0.687), weight (r = 0.654), foot length (r = 0.687), and sex (r = 0.354) demonstrated a significant correlation with the diameter of the acetabular prosthesis used intraoperatively. Furthermore, a predictive equation, denoted as Y (acetabular prosthesis diameter in mm) = 20.592 + 0.548 × foot length (cm) + 0.083 × height (cm) + 0.077 × weight (kg), was derived. This equation accurately predicted the diameter within one size with an accuracy rate of 64.94% and within two sizes with an accuracy rate of 94.81%. CONCLUSION: Anthropometric data can accurately predict the diameter of acetabular prosthesis during total hip arthroplasty.
Asunto(s)
Artroplastia de Reemplazo de Cadera , Prótesis de Cadera , Humanos , Modelos Lineales , Estudios Retrospectivos , Acetábulo/diagnóstico por imagen , Acetábulo/cirugíaRESUMEN
BACKGROUND: The pyruvate dehydrogenase E1 subunit ß (PDHB) gene which regulates energy metabolism is located in mitochondria. However, few studies have elucidated the role and mechanism of PDHB in different cancers. AIM: To comprehensive pan-cancer analysis of PDHB was performed based on bioinformatics approaches to explore its tumor diagnostic and prognostic value and tumor immune relevance in cancer. In vitro experiments were performed to examine the biological regulation of PDHB in liver cancer. METHODS: Pan-cancer data related to PDHB were obtained from the Cancer Genome Atlas (TCGA) database. Analysis of the gene expression profiles of PDHB was based on TCGA and Genotype Tissue Expression Dataset databases. Cox regression analysis and Kaplan-Meier methods were used to assess the correlation between PDHB expression and survival prognosis in cancer patients. The correlation between PDHB and receiver operating characteristic diagnostic curve, clinicopathological staging, somatic mutation, tumor mutation burden (TMB), microsatellite instability (MSI), DNA methylation, and drug susceptibility in pan-cancer was also analyzed. Various algorithms were used to analyze the correlation between PDHB and immune cell infiltration and tumor chemotaxis environment, as well as the co-expression analysis of PDHB and immune checkpoint (ICP) genes. The expression and functional phenotype of PDHB in single tumor cells were studied by single-cell sequencing, and the functional enrichment analysis of PDHB-related genes was performed. The study also validated the level of mRNA or protein expression of PDHB in several cancers. Finally, in vitro experiments verified the regulatory effect of PDHB on the proliferation, migration, and invasion of liver cancer. RESULTS: PDHB was significantly and differently expressed in most cancers. PDHB was significantly associated with prognosis in patients with a wide range of cancers, including kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, breast invasive carcinoma, and brain lower grade glioma. In some cancers, PDHB expression was clearly associated with gene mutations, clinicopathological stages, and expression of TMB, MSI, and ICP genes. The expression of PDHB was closely related to the infiltration of multiple immune cells in the immune microenvironment and the regulation of tumor chemotaxis environment. In addition, single-cell sequencing results showed that PDHB correlated with different biological phenotypes of multiple cancer single cells. This study further demonstrated that down-regulation of PDHB expression inhibited the proliferation, migration, and invasion functions of hepatoma cells. CONCLUSION: As a member of pan-cancer, PDHB may be a novel cancer marker with potential value in diagnosing cancer, predicting prognosis, and in targeted therapy.