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The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.
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AIMS: Disease activity assessment and treatment outcome prediction are crucial in the patient management of ulcerative colitis (UC); yet the significance of platelet-to-lymphocyte percentage ratio (PLpR) remains unknown, which was investigated in this study. METHODS: We used data from three clinical trials: ACT 1, PURSUIT, and UNIFI. In total, 7,614 endoscopic procedures and 1,365 patients were included for assessing severity and predicting outcome, respectively. The primary outcome was endoscopic remission, defined as a Mayo endoscopic score of 0. The diagnostic capacity of PLpR was evaluated by the area under the receiver operating characteristic curve (AUC) while multivariable logistic regression was employed to assess the prognostic power of PLpR. RESULTS: PLpR showed higher AUCs than C-reactive protein in identifying endoscopic remission (P < 0.001) and improvement (P < 0.001). Besides, combining PLpR with fecal calprotectin enhanced the power to distinguish disease activity. In therapeutic outcome analyses, higher PLpR level indicated worse long-term outcomes. PLpR ≥ 1016.7 predicted a lower likelihood of endoscopic remission (OR: 0.50 [95 % CI: 0.39-0.65]; P < 0.001), endoscopic improvement (OR: 0.45 [95 % CI: 0.36-0.57]; P < 0.001), clinical remission (OR: 0.50 [95 % CI: 0.39-0.62]; P < 0.001), histologic improvement (OR: 0.50 [95 % CI: 0.31-0.79]; P = 0.004), and histologic-endoscopic mucosal improvement (OR: 0.42 [95 % CI: 0.27-0.66]; P < 0.001). Moreover, PLpR added the prognostic value to C-reactive protein, fecal calprotectin, clinical and endoscopic scores to predict long-term outcomes. CONCLUSION: PLpR could be a promising biomarker for monitoring disease activity and predicting long-term therapeutic outcomes in UC.
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Plaquetas , Colitis Ulcerosa , Humanos , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Linfocitos , Pronóstico , Índice de Severidad de la Enfermedad , Heces/química , Complejo de Antígeno L1 de Leucocito/metabolismo , Inducción de Remisión , Recuento de Plaquetas , Proteína C-Reactiva/análisis , BiomarcadoresRESUMEN
Improving quality is an essential goal of rice breeding and production. However, rice quality is not solely determined by genotype, but is also influenced by the environment. Phenotype plasticity refers to the ability of a given genotype to produce different phenotypes under different environmental conditions, which can be a representation of the stability of traits. Seven quality traits of 141 hybrid combinations, deriving from the test-crossing of 7 thermosensitive genic male sterile (TGMS) and 25 restorer lines, were evaluated at 5 trial sites with intermittent sowing of three to five in Southern China. In the Yangtze River Basin, it was observed that delaying the sowing time of hybrid rice combinations leads to an improvement in their overall quality. Twelve parents were identified to have lower plasticity general combing ability (GCA) values with increased ability to produce hybrids with a more stable quality. The parents with superior quality tend to exhibit lower GCA values for plasticity. The genome-wide association study (GWAS) identified 13 and 15 quantitative trait loci (QTLs) associated with phenotype plasticity and BLUP measurement, respectively. Notably, seven QTLs simultaneously affected both phenotype plasticity and BLUP measurement. Two cloned rice quality genes, ALK and GL7, may be involved in controlling the plasticity of quality traits in hybrid rice. The direction of the genetic effect of the QTL6 (ALK) on alkali spreading value (ASV) plasticity varies in different cropping environments. This study provides novel insights into the dynamic genetic basis of quality traits in response to different cropping regions, cultivation practices, and changing climates. These findings establish a foundation for precise breeding and production of stable and high-quality rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01442-3.
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BACKGROUND: Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better outcomes remains unclear. OBJECTIVES: We aimed to explore the associations between the timing of CR and therapeutic outcomes in UC. METHODS: This study included UC patients from the UNIFI trial. Week-2 CR and time to CR were the major variables of interest. Endoscopic remission (ER) at week 52 was the primary outcome. Multivariate logistic regression was performed to evaluate the association between variables and outcomes. RESULTS: Week-2 CR was associated with ER (aOR: 2.37 [95% CI: 1.28, 4.37], p = 0.006) and Histological remission (HR) (aOR: 2.87 [95% CI: 1.42, 5.72], p = 0.003) at week 52. Moreover, C-reactive protein (CRP) remission could further stratify patients without CR and predict week-52 outcomes. Patients with clinical activity + CRP remission (aOR: 0.49 [95% CI: 0.26, 0.93], p = 0.039) and clinical activity + CRP activity (aOR: 0.24 [95% CI: 0.11, 0.52], p < 0.001) had gradually decreased likelihood of achieving ER, when compared to those with CR. For time to CR, we found that the earlier to CR, the better endoscopic and histological outcomes patients would attain. Patients achieving CR at weeks 2, 4/8, 12/16 and >16 had gradually reduced proportions of ER (51.9% vs. 40.8% vs. 31.6% vs. 8.8%, p < 0.001) and HR (37.0% vs. 19.8% vs. 17.1% vs. 6.1%, p < 0.001) at week 52. Compared with week 2, achieving CR at weeks 4/8, 12/16 and >16 had 39%, 55% and 92% lower likelihoods of week-52 ER, respectively. CONCLUSIONS: Week-2 CR indicates better outcomes in UC patients receiving ustekinumab. Moreover, achieving CR more rapidly is associated with higher probability of ER and HR.
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Proteína C-Reactiva , Colitis Ulcerosa , Colonoscopía , Inducción de Remisión , Humanos , Colitis Ulcerosa/patología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/diagnóstico , Masculino , Femenino , Adulto , Resultado del Tratamiento , Proteína C-Reactiva/análisis , Persona de Mediana Edad , Factores de Tiempo , Ustekinumab/uso terapéuticoRESUMEN
Objectives: To investigate the characteristics and prognostic value of fecal lactoferrin trajectories in ulcerative colitis (UC). Methods: This study used data from the UNIFI trial (ClinicalTrials.gov, NCT02407236) and included patients who received ustekinumab during induction for trajectory modeling (n = 637). Patients who received ustekinumab during maintenance therapy were used for 1-year outcome analyses (n = 403). The levels of fecal lactoferrin, fecal calprotectin, and serum C-reactive protein were measured at weeks 0, 2, 4, and 8. The trajectories of these biomarkers were developed using a latent class growth mixed model. Results: The trajectories of fecal lactoferrin, fecal calprotectin, and serum C-reactive protein were distinct, but all were associated with prior exposure to anti-tumor necrosis factor agents and vedolizumab. Furthermore, the fecal lactoferrin trajectory was the most valuable predictor of endoscopic, clinical, and histological remission. Compared to the high/moderate-rapid decrease trajectory group, the moderate-slow decrease, high-slow decrease, and high-stable groups had adjusted odds ratios (95% confidence interval) of 0.38 (0.18, 0.78; P = 0.010), 0.47 (0.23, 0.93; P = 0.032), and 0.33 (0.17, 0.63; P = 0.001), respectively, of 1-year endoscopic remission. Patients with high/moderate-rapid decrease trajectories also had the highest likelihood of achieving clinical and histological remission. Finally, we developed a patient-stratification scheme based on fecal lactoferrin trajectories and concentrations. Patients with good, moderate, and poor prognoses in the scheme had a distinct probability of achieving 1-year endoscopic remission (52.7%, 30.9%, and 12.8%, respectively). Conclusions: The trajectory of fecal lactoferrin is a valuable prognostic factor for 1-year remission in UC.
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Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease of the gastrointestinal tract. In addition to digestive symptoms, patients with IBD may also develop extra-intestinal manifestations (EIMs), the etiology of which remains undefined. The gut microbiota has been reported to exert a critical role in the pathogenesis of IBD, with a similar pattern of gut dysbiosis observed between patients with IBD and those with EIMs. Therefore, it is hypothesized that the gut microbiota is also involved in the pathogenesis of EIMs. The potential mechanisms are presented in this review, including: 1) impaired gut barrier: dysbiosis induces pore formation in the intestinal epithelium, and activates pattern recognition receptors to promote local inflammation; 2) microbial translocation: intestinal pathogens, antigens, and toxins translocate via the impaired gut barrier into extra-intestinal sites; 3) molecular mimicry: certain microbial antigens share similar epitopes with self-antigens, inducing inflammatory responses targeting extra-intestinal tissues; 4) microbiota-related metabolites: dysbiosis results in the dysregulation of microbiota-related metabolites, which could modulate the differentiation of lymphocytes and cytokine production; 5) immunocytes and cytokines: immunocytes are over-activated and pro-inflammatory cytokines are excessively released. Additionally, we summarize microbiota-related therapies, including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation, to promote better clinical management of IBD-associated EIMs.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Microbiota , Humanos , Microbioma Gastrointestinal/fisiología , Disbiosis/terapia , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/diagnóstico , Trasplante de Microbiota Fecal , CitocinasRESUMEN
Butyrate, produced by gut microbe during dietary fiber fermentation, has anti-inflammatory and antioxidant effects on chronic inflammation diseases, yet it remains to be explored whether butyrate has protective effects against viral infections. Here, we demonstrated that butyrate alleviated tissue injury in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected golden hamsters supplemented with butyrate before and during the infection. Butyrate-treated hamsters showed augmentation of type I interferon (IFN) response and activation of endothelial cells without exaggerated inflammation. In addition, butyrate regulated redox homeostasis by enhancing the activity of superoxide dismutase (SOD) to inhibit excessive apoptotic cell death. Therefore, butyrate exhibited effective prevention against SARS-CoV-2 by upregulating antiviral immune responses and promoting cell survival.
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Background and Aims: Prophylaxis of postoperative recurrence is an intractable problem for clinicians and patients with Crohn's disease. Prognostic models are effective tools for patient stratification and personalised management. This systematic review aimed to provide an overview and critically appraise the existing models for predicting postoperative recurrence of Crohn's disease. Methods: Systematic retrieval was performed using PubMed and Web of Science in January 2022. Original articles on prognostic models for predicting postoperative recurrence of Crohn's disease were included in the analysis. The risk of bias was assessed using the Prediction Model Risk of Bias Assessment (PROBAST) tool. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; number CRD42022311737). Results: In total, 1948 articles were screened, of which 15 were ultimately considered. Twelve studies developed 15 new prognostic models for Crohn's disease and the other three validated the performance of three existing models. Seven models utilised regression algorithms, six utilised scoring indices, and five utilised machine learning. The area under the receiver operating characteristic curve of the models ranged from 0.51 to 0.97. Six models showed good discrimination, with an area under the receiver operating characteristic curve of >0.80. All models were determined to have a high risk of bias in modelling or analysis, while they were at low risk of applicability concerns. Conclusions: Prognostic models have great potential for facilitating the assessment of postoperative recurrence risk in patients with Crohn's disease. Existing prognostic models require further validation regarding their reliability and applicability. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311737.
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Enfermedad de Crohn , Humanos , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/tratamiento farmacológico , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Fecal lactoferrin (FL) is associated with disease activity and relapse in ulcerative colitis. However, whether FL could early predict long-term outcomes in ulcerative colitis is poorly understood. METHODS: This post-hoc analysis included participants who received biologics and had available data of FL concentration at week 4 from the UNIFI and PURSUIT trials (n = 1063). Therapeutic outcomes, including clinical remission, endoscopic improvement and remission, and histological improvement and remission, were evaluated at the end of maintenance therapy. The incidence of colectomy was observed from week 0 to maximum week 228 in the PURSUIT trial (n = 667). Multivariate logistic and Cox proportional-hazard regression were conducted to evaluate the associations between FL and therapeutic outcomes and colectomy, respectively. RESULTS: A high FL level at week 4 was associated with poor long-term clinical, endoscopic and histologic outcomes. FL >84.5 µg/mL predicted a low likelihood of clinical (OR [95% CI]: 0.43 [0.32, 0.57]; p < 0.001), endoscopic (OR [95% CI]: 0.40 [0.29, 0.56]; p < 0.001), and histological (OR [95% CI]: 0.27 [0.14, 0.53]; p < 0.001) remission. Moreover, week-4 FL could add prognostic value to fecal calprotectin and clinical and endoscopic scores for informing long-term therapeutic outcomes. For the risk of colectomy, patients with week-4 FL <20.1 and ≥20.1 µg/mL had an incidence rate of 1.10% and 6.39%, respectively. Patients with FL ≥20.1 µg/mL had a 995% higher risk of colectomy (HR [95% CI], 10.95 [1.45, 82.74]). CONCLUSION: FL could be a promising prognostic biomarker for long-term therapeutic outcomes and risk of colectomy in patient of ulcerative colitis.
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Colitis Ulcerosa , Humanos , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/cirugía , Lactoferrina/análisis , Lactoferrina/uso terapéutico , Biomarcadores/análisis , Pronóstico , Inducción de RemisiónRESUMEN
Although influenza A viruses of several subtypes have occasionally infected humans, to date only those of the H1, H2, and H3 subtypes have led to pandemics and become established in humans. The detection of two human infections by avian H3N8 viruses in April and May of 2022 raised pandemic concerns. Recent studies have shown the H3N8 viruses were introduced into humans from poultry, although their genesis, prevalence, and transmissibility in mammals have not been fully elucidated. Findings generated from our systematic influenza surveillance showed that this H3N8 influenza virus was first detected in chickens in July 2021 and then disseminated and became established in chickens over wider regions of China. Phylogenetic analyses revealed that the H3 HA and N8 NA were derived from avian viruses prevalent in domestic ducks in the Guangxi-Guangdong region, while all internal genes were from enzootic poultry H9N2 viruses. The novel H3N8 viruses form independent lineages in the glycoprotein gene trees, but their internal genes are mixed with those of H9N2 viruses, indicating continuous gene exchange among these viruses. Experimental infection of ferrets with three chicken H3N8 viruses showed transmission through direct contact and inefficient transmission by airborne exposure. Examination of contemporary human sera detected only very limited antibody cross-reaction to these viruses. The continuing evolution of these viruses in poultry could pose an ongoing pandemic threat. IMPORTANCE A novel H3N8 virus with demonstrated zoonotic potential has emerged and disseminated in chickens in China. It was generated by reassortment between avian H3 and N8 virus(es) and long-term enzootic H9N2 viruses present in southern China. This H3N8 virus has maintained independent H3 and N8 gene lineages but continues to exchange internal genes with other H9N2 viruses to form novel variants. Our experimental studies showed that these H3N8 viruses were transmissible in ferrets, and serological data suggest that the human population lacks effective immunological protection against it. With its wide geographical distribution and continuing evolution in chickens, other spillovers to humans can be expected and might lead to more efficient transmission in humans.
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Subtipo H3N8 del Virus de la Influenza A , Subtipo H9N2 del Virus de la Influenza A , Gripe Aviar , Gripe Humana , Animales , Humanos , Gripe Humana/epidemiología , Pollos , Salud Pública , Subtipo H9N2 del Virus de la Influenza A/genética , Filogenia , Hurones , China/epidemiología , Aves de CorralRESUMEN
Inflammatory bowel diseases (IBD) is featured by gastrointestinal inflammation and a disease course with alternating recurrence and remission. The global burden caused by IBD has significantly boosted in recent years, necessitating treatment optimization. Serum amyloid A (SAA) is a class of 104 amino acid conservative acute-phase proteins, which is essential in immune-mediated inflammatory processes, like IBD. The SAA monomeric structure is composed of four α-helical regions and a C-terminal amorphous tail. Its disordered structure enables multiple bindings to different ligands and permits multiple functions. It has been proven that SAA has dual roles in the inflammatory process. SAA stimulates the pro-inflammatory cytokine expression and promotes the pathogenic differentiation of TH17 cells. In addition, SAA can remove toxic lipids produced during inflammatory responses and membrane debris from dead cells, redirect HDL, and recycle cholesterol for tissue repair. In IBD, SAA acts on gut epithelium barriers, induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Owing to the tight connection between SAA and IBD, several clinical studies have taken SAA for a biomarker for diagnosis, assessing disease activity, and predicting prognosis in IBD. Furthermore, 5-MER peptide, a drug specifically targeting SAA, has shown anti-inflammatory effects in some SAA-dependent animal models, providing novel insights into the therapeutic targets of IBD.
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Background: Patients with isolated anastomotic lesions (iAL) are common in postoperative Crohn's disease (CD) and have heterogeneous prognosis. Objectives: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in CD patients with iAL. Design: A bicenter retrospective cohort study. Methods: CD patients who received ileocolonic resection from 2013 and 2020 and had a modified Rutgeerts score of i2a were recruited. NLR was determined within 1 week around the initial endoscopy after ileocolectomy. The primary outcome was clinical recurrence. Kaplan-Meier method and Cox hazard regression analysis were utilized to assess the association between candidate variables and outcomes of interest. Results: In total, 411 postoperative CD patients were preliminarily reviewed and 83 patients were eligible. In total, 36 (48.6%) patients experienced clinical recurrence with a median follow-up time of 16.3 (interquartile range, 9.7-26.3) months. NLR > 2.45 and age at surgery >45 years had higher cumulative incidence of clinical recurrence in the Kaplan-Meier analysis. After adjusted for potential confounders, NLR > 2.45 was the only independent risk factor for clinical recurrence, with an adjusted hazard ratio (HR) of 2.88 [95% confidence interval (CI), 1.39-6.00; p = 0.005]. Furthermore, a risk score based on NLR and age at surgery were built to further stratify patients. Compared to those who scored 0, patients with a score of 1 and 2 had an adjusted HR of 2.48 (95% CI, 1.22-5.02) and 6.97 (95% CI, 2.19-22.16) for developing clinical recurrence, respectively. Conclusions: NLR is a promising prognostic biomarker for CD patients with iAL. The utilization of NLR and the risk score to stratify patients may facilitate the personalized management in patients with iAL.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.
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COVID-19 , Receptores Quiméricos de Antígenos , Humanos , SARS-CoV-2/metabolismo , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Caspofungina , Felodipino , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Inflamación , Citocinas/metabolismoRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is becoming a dominant circulator and has several mutations in the spike glycoprotein, which may cause shifts of immunogenicity, so as to result in immune escape and breakthrough infection among the already infected or vaccinated populations. It is unclear whether infection with Omicron could generate adequate cross-variant protection. To investigate this possibility, we used Syrian hamsters as an animal model for infection of SARS-CoV-2. The serum from Omicron BA.1 variant-infected hamsters showed a significantly lower neutralization effect against infection of the same or different SARS-CoV-2 variants than the serum from Beta variant-infected hamsters. Furthermore, the serum from Omicron BA.1 variant-infected hamsters were insufficient to protect against rechallenge of SARS-CoV-2 Prototype, Beta and Delta variants and itself. Importantly, we found that rechallenge with different SARS-CoV-2 lineages elevated cross-variant serum neutralization titers. Overall, our findings indicate a weakened immunogenicity feature of Omicron BA.1 variant that can be overcome by rechallenge of a different SARS-CoV-2 lineages. Our results may lead to a new guideline in generation and use of the vaccinations to combat the pandemic of SARS-CoV-2 Omicron variant and possible new variants. IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant causes breakthrough infections among convalescent patients and vaccinated populations. However, Omicron does not generate robust cross-protective responses. Here, we investigate whether heterologous SARS-CoV-2 challenge is able to enhance antibody response in a sensitive animal model, namely, Syrian hamster. Of note, a heterologous challenge of Beta and Omicron BA.1 variant significantly broadens the breadth of SARS-CoV-2 neutralizing responses against the prototype, Beta, Delta, and Omicron BA.1 variants. Our findings confirm that vaccination strategy with heterologous antigens might be a good option to protect against the evolving SARS-CoV-2.
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COVID-19 , SARS-CoV-2 , Animales , Cricetinae , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Antígenos Heterófilos/inmunología , Infección Irruptiva , COVID-19/prevención & control , Mesocricetus , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Inmunogenicidad VacunalRESUMEN
Recently, a new variant lineage of SARS-CoV-2, namely Omicron, became the dominant global circulating strain. The multiple antigenic mutations of Omicron largely decrease the efficiency of current vaccines and neutralizing antibodies, which highlights the need for more potent and reachable medical countermeasures. Here, we hypothesize that direct viral clearance by nasal irrigation might be a convenient and alternative option, and perform proof-of-concept experiments in the Syrian hamster model. Interestingly, Omicron shows a different dynamic in the changes of viral RNA, viral titers, and proinflammatory cytokines in nasal rinsing samples when compared with the prototype. Meanwhile, the levels of viral load and proinflammatory cytokines in nasal rinsing samples can indicate the severity of lung injury. Of note, daily nasal irrigation efficiently attenuates inflammation and lung injury in Omicron-infected hamsters by decreasing the viral loads in the respiratory tract organs. Moreover, daily nasal irrigation effectively suppresses viral transmission by close contact.
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The new predominant circulating SARS-CoV-2 variant, Omicron, can robustly escape current vaccines and neutralizing antibodies. Although Omicron has been reported to have milder replication and disease manifestations than some earlier variants, its pathogenicity in different age groups has not been well elucidated. Here, we report that the SARS-CoV-2 Omicron BA.1 sublineage causes elevated infection and lung pathogenesis in juvenile and aged hamsters, with more body weight loss, respiratory tract viral burden, and lung injury in these hamsters than in adult hamsters. Juvenile hamsters show a reduced interferon response against Omicron BA.1 infection, whereas aged hamsters show excessive proinflammatory cytokine expression, delayed viral clearance, and aggravated lung injury. Early inhaled IFN-α2b treatment suppresses Omicron BA.1 infection and lung pathogenesis in juvenile and adult hamsters. Overall, the data suggest that the diverse patterns of the innate immune response affect the disease outcomes of Omicron BA.1 infection in different age groups.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Interferón-alfa , Lesión Pulmonar , Animales , Cricetinae , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales , Antivirales , COVID-19/patología , Interferón-alfa/uso terapéutico , Lesión Pulmonar/virología , Mesocricetus , SARS-CoV-2RESUMEN
Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 d after single-dose vaccination or 9 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants, especially for the latest Omicron variant. In addition, this vaccine also provides cross-protection against H1N1 and H5N1 influenza viruses. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to the fight against the ongoing coronavirus disease 2019 pandemic and influenza infection, compensating limitations of current intramuscular vaccines.
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Inflammatory bowel disease (IBD) is a chronic recurrent gastrointestinal inflammatory disease that poses a heavy burden to the global healthcare system. However, the current paucity of mechanistic understanding of IBD pathogenesis hampers the development of aetiology-directed therapies. Novel therapeutic options based on IBD pathogenesis are urgently needed for attaining better long-term prognosis for IBD patients. The tripartite motif (TRIM) family is a large protein family including more than 70 structurally conservative members, typically characterized by their RBCC structure, which primarily function as E3 ubiquitin ligases in post-translational modification. They have emerged as regulators of a broad range of cellular mechanisms, including proliferation, differentiation, transcription and immune regulation. TRIM family proteins are involved in multiple diseases, such as viral infection, cancer and autoimmune disorders, including inflammatory bowel disease. This review provides a comprehensive perspective on TRIM proteins' involvement in the pathophysiology and progression of IBD, in particular, on intestinal mucosal barriers, gene susceptibility and opportunistic infections, thus providing novel therapeutic targets for this complicated disease. However, the exact mechanisms of TRIM proteins in IBD pathogenesis and IBD-related carcinogenesis are still unknown, and more studies are warranted to explore potential therapeutic targets of TRIM proteins in IBD.
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Enfermedades Inflamatorias del Intestino , Neoplasias , Humanos , Enfermedades Inflamatorias del Intestino/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Background: Endoscopic recurrence is common in postoperative patients with Crohn's disease (CD). Monitoring endoscopic recurrence is important for selecting an appropriate treatment to prevent the development of postoperative disease. The aim of this study was to develop and validate a diagnostic model to identify endoscopic recurrence. Methods: This was a retrospective cohort study recruiting postoperative CD patients who underwent endoscopy at the First Affiliated Hospital, Sun Yat-sen University from January 2016 to June 2020. Endoscopic recurrence was defined as Rutgeerts score > i1. Thirty non-invasive biomarkers, including C-reactive protein, erythrocyte sedimentation rate, vitamin D, complete blood count, and biochemical blood indices, were used as candidate predictors to build a multivariate logistic regression diagnostic model. The predictive ability of the diagnostic models was assessed by receiving the area under the characteristic curve (AUC) and calibration plots, and internal validation was performed by the bootstrap method. Results: Two hundred and nineteen eligible patients were included in this study, and 135 (61.6%) patients had a postoperative endoscopic recurrence. The final diagnostic model included eight biomarkers with an AUC (95% confidence interval (CI)) of 0.796 (0.737-0.855) to identify endoscopic recurrence. The AUC, sensitivity, and specificity of this diagnostic model were 0.781 (0.780-0.782), 0.647 (0.643-0.651) and 0.811 (0.807-0.815), respectively, by internal validation. In addition, the diagnostic model exhibited good calibrability with calibration slope, calibration-in-the-large ('mean calibration') and Brier scores of 1.00, 0.00, and 0.175, respectively. Conclusion: This non-invasive biomarker-based diagnostic model has an excellent ability to identify endoscopic recurrence in patients with CD. Application of the model to clinical practice to monitor postoperative patients may be helpful for patient management.