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Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.
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Betacoronavirus/clasificación , Betacoronavirus/genética , Quirópteros/virología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Brotes de Enfermedades , Neumonía Viral/epidemiología , Neumonía Viral/virología , Enzima Convertidora de Angiotensina 2 , Animales , Anticuerpos Antivirales/sangre , Betacoronavirus/metabolismo , Betacoronavirus/ultraestructura , COVID-19 , Línea Celular , China/epidemiología , Chlorocebus aethiops , Femenino , Genoma Viral/genética , Humanos , Masculino , Peptidil-Dipeptidasa A/metabolismo , Filogenia , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/clasificación , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , SARS-CoV-2 , Homología de Secuencia de Ácido Nucleico , Síndrome Respiratorio Agudo Grave , Células VeroRESUMEN
Immune checkpoint inhibitor (ICI) therapy is effectively employed in treating various malignancies. However, the response rate is constrained to 5-30%, which is attributed to differences in immune responses across different tumors. Overcoming all obstacles of multistep immune activation with monotherapy is difficult. Here, maleimide-modified resiquimod (R848) prodrug nanoparticles (MAL-NPs) are reported and combined with radiotherapy (RT) and anti-PD1 to enhance ICI therapy. MAL-NPs can promote antigen endocytosis by dendritic cells and are radio-reduced to produce R848. When combined with RT, MAL-NPs can augment the concentration of nanoparticles at tumor sites and be selectively radio-reduced within the tumor, thereby triggering a potent antitumor immune response. The systemic immune response and long-term memory efficacy induced by MAL-NPs + RT + anti-PD1 significantly inhibit the abscopal tumor growth and prevent tumor recurrence. This strategy can achieve systemic therapy through selective training of the tumor immune microenvironment, offering a new approach to overcome the obstacles of ICI therapy.
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Nanoestructuras , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microambiente Tumoral , Línea Celular Tumoral , InmunoterapiaRESUMEN
The criteria of myelodysplastic syndromes (MDS) with mutated SFB31 (MDS-SFB31) proposed by the 5th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) need validation. We analysed 125 consecutive MDS cases with SFB31 mutation or ring sideroblasts (RS) ≥15% without excess blasts. We found that SFB31-negative MDS with RS had significantly different clinical features and worse prognosis. According to WHO 2022, the detection of ≥15% RS may substitute for SF3B1 mutation and our analyses support this proposal for similar prognosis of two groups after excluding high-risk genetic features referred by WHO 2022. Patients with variant allele frequency (VAF) <10% SFB31 tend to have briefer survival, supporting the VAF 10% threshold of ICC. Patients with multilineage dysplasia (MLD) had significantly shorter OS than those with single lineage dysplasia. MLD is still a powerful morphological marker of worse outcome in WHO 2022 and ICC-defined MDS-SF3B1.
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BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by m6A methylation. METHODS: Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the m6A methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis. RESULTS: LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 m6A modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels. CONCLUSION: WTAP-mediated m6A modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.
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Apoptosis , MicroARNs , Dinámicas Mitocondriales , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Ratones , Apoptosis/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Línea Celular , Masculino , Ratones Endogámicos C57BL , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Especies Reactivas de Oxígeno/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Secuencia de Bases , Metilación , Potencial de la Membrana MitocondrialRESUMEN
Excellent stability is an essential premise for organic diradicals to be used in organic electronic and spintronic devices. We have attached two tris(2,4,6-trichlorophenyl)methyl (TTM) radical building blocks to the two sides of perylene bisimide (PBI) bridges and obtained two regioisomeric diradicals (1,6-TTM-PBI and 1,7-TTM-PBI). Both of the isomers show super stability rather than the monomeric TTM under ambient conditions, due to the increased conjugation and the electron-withdrawing effects of the PBI bridges. The diradicals show distinct and reversible multistep redox processes, and a spectro-electrochemistry investigation revealed the generation of organic mixed-valence (MV) species during reduction processes. The two diradicals have singlet ground states, very small singlet-triplet energy gaps (ΔES-T ) and a pure open-shell character (with diradical character y0 =0.966 for 1,6-TTM-PBI and 0.967 for 1,7-TTM-PBI). This work opens a window to developing very stable diradicals and offers the opportunity of their further application in optical, electronic and magnetic devices.
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BACKGROUND: The study set out to develop an accurate and clinically valuable prognostic nomogram to assess the risk of in-hospital death in patients with acute decompensated chronic heart failure (ADCHF) and diabetes. METHODS: We extracted clinical data of patients diagnosed with ADCHF and diabetes from the Medical Information Mart for Intensive Care III database. Risk variables were selected utilizing least absolute shrinkage and selection operator regression analysis, and were included in multivariate logistic regression and presented in nomogram. bootstrap was used for internal validation. The discriminative power and predictive accuracy of the nomogram were estimated using the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: Among 867 patients with ADCHF and diabetes, In-hospital death occurred in 81 (9.3%) patients. Age, heart rate, systolic blood pressure, red blood cell distribution width, shock, ß-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, assisted ventilation, and blood urea nitrogen were brought into the nomogram model. The calibration curves suggested that the nomogram was well calibrated. The AUC of the nomogram was 0.873 (95% CI: 0.834-0.911), which was higher that of the Simplified Acute Physiology Score II [0.761 (95% CI: 0.711-0.810)] and sequential organ failure assessment score [0.699 (95% CI: 0.642-0.756)], and Guidelines-Heart Failure score [0.782 (95% CI: 0.731-0.835)], indicating that the nomogram had better ability to predict in-hospital mortality. In addition, the internally validated C-index was 0.857 (95% CI: 0.825-0.891), which again verified the validity of this model. CONCLUSIONS: This study constructed a simple and accurate nomogram for predicting in-hospital mortality in patients with ADCHF and diabetes, especially in those who admitted to the intensive care unit for more than 48 hours, which contributed clinicians to assess the risk and individualize the treatment of patients, thereby reducing in-hospital mortality.
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Diabetes Mellitus , Insuficiencia Cardíaca , Humanos , Nomogramas , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Diabetes Mellitus/diagnóstico , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Estudios RetrospectivosRESUMEN
Multiple myeloma (MM) is a B-cell malignancy characterized by the excessive proliferation of bone marrow plasma cells and the production of abnormal immunoglobulins. Despite advances in therapeutic strategies, it remains an incurable disease. Recently, innovative anticancer drugs have been developed and approved, leading to improvements in MM therapy; however, drug resistance continues to be a major obstacle that results in treatment failure. Therefore, the development of novel agents is imperative to achieve superior therapeutic outcomes for relapsed/refractory multiple myeloma (MM) patients. Previously, we identified EP12 as a c-Myc G4 stabilizer that could induce cytotoxicity in MM cells in vitro. However, further investigation is required to elucidate the underlying molecular mechanisms and anti-MM activity of EP12 in vivo. In this study, we have discovered that the compound EP12 effectively inhibits primary myeloma growth in vivo by destabilizing c-Myc and disrupting the canonical nuclear factor-κB (NF-κB) signaling pathway. Overall, our findings suggest that EP12, as a potent c-Myc inhibitor, holds great promise as a therapeutic agent for MM.
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Mieloma Múltiple , FN-kappa B , Humanos , FN-kappa B/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Transducción de Señal , Linfocitos B , Células de la Médula ÓseaRESUMEN
BACKGROUND: Currently, there is no clear consensus on whether medical treatment or endoscopic treatment should be used for peptic ulcer bleeding patients with adherent clot. The aim of this study is to investigate the hemostatic effects of medical treatment, single endoscopic treatment, and combination endoscopic treatment for peptic ulcer bleeding (PUB) patients with adherent clot. METHODS: We retrospectively analyzed PUB patients with adherent clot who underwent endoscopic examination or treatment in our center from March 2014 to January 2023 and received intravenous administration of proton pump inhibitors. Patients were divided into medical treatment (MT) group, single endoscopic treatment (ST) group, and combined endoscopic treatment (CT) group. Subsequently, inverse probability of treatment weighting (IPTW) was performed to calculate the rebleeding rate. RESULTS: A total of 605 eligible patients were included in this study. After IPTW, the rebleeding rate in the MT group on days 3, 7, 14, and 30 were 13.3 (7.3), 14.2 (7.8), 14.5 (7.9), and 14.5 (7.9), respectively; the rebleeding rates in the ST group were 17.4 (5.1), 20.8 (6.1), 20.8 (6.1), and 20.8 (6.1), respectively; the rebleeding rates in the CT group were 0.4 (0.9), 1.7 (3.3), 2.3 (4.5), and 2.3 (4.5), respectively. Although the rebleeding rate in the medical treatment group was higher, there was no significant difference among the three groups on days 3, 7, 14, and 30 (P = 0.132, 0.442, 0.552, and 0.552). CONCLUSIONS: Medical therapy has similar hemostatic efficacy with endoscopic treatment for PUB patients with adherent clot (FIIb ulcers). However, for patients with more risk factors and access to well-equipped endoscopy centers, endoscopic treatment may be considered. The choice of treatment approach should be based on the individual conditions of the patient, as well as other factors such as medical resources available.
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Hemostasis Endoscópica , Hemostáticos , Úlcera Péptica , Humanos , Úlcera/complicaciones , Úlcera/terapia , Estudios Retrospectivos , Úlcera Péptica Hemorrágica/etiología , Endoscopía Gastrointestinal/efectos adversos , Hemostasis Endoscópica/efectos adversos , Úlcera Péptica/complicaciones , RecurrenciaRESUMEN
Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.
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Antineoplásicos , Antígeno B7-H1 , Curcumina , Ginsenósidos , Animales , Curcumina/farmacología , Curcumina/química , Ginsenósidos/química , Ginsenósidos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Femenino , Antígeno B7-H1/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Micelas , Ratones Endogámicos BALB C , Polímeros/química , Polímeros/farmacología , Células Dendríticas/efectos de los fármacos , Nanopartículas/química , Células Madre Neoplásicas/efectos de los fármacos , Portadores de Fármacos/química , Óxidos/química , Óxidos/farmacologíaRESUMEN
Pulmonary hypertension (PH) is a chronic pulmonary vascular disease and causes massive deaths. Here, we intended to investigate the function and mechanism of SOCS5 in PH. We engineered a hypoxia-induced PH model in mice. HE staining were implemented to evaluate pathological alterations in the lung tissues. The potential mechanism of SOCS5 in regulating hypoxia-induced pulmonary artery smooth muscle cell (PASMC) function was explored in vitro. RT-qPCR and western blot revealed that the level of SOCS5 was decreased both in PH mice and hypoxia-induced HPASMCs. Functional assays were performed for confirming the role of SOCS5 in modulating the cell phenotype and JAK2/STAT3 pathway in HPASMCs. Results revealed that overexpression of SOCS5 suppressed proliferation, migration and contraction of HPASMCs and negatively regulated the JAK2/STAT3 signaling pathway in HPASMCs under hypoxia in vitro, while knockdown of SOCS5 accelerated it. As evidenced by mechanism studies, SOCS5 was targeted and regulated by miR-155-5p, hence affecting on HPASMC proliferation, migration and contraction. These outcomes indicated that the decreased level of SOCS5 in hypoxia-induced HPASMCs promoted the cell proliferation, cell migration, and cell contraction through activating JAK2/STAT3 signaling pathway. Moreover, SOCS5 was targeted by miR-155-5p. All in all, our work hinted that miR-155-5p/SOCS5/JAK2/STAT3 axis played a crucial part in PH.
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Hipertensión Pulmonar , MicroARNs , Enfermedades Vasculares , Animales , Ratones , Hipertensión Pulmonar/genética , Hipoxia , MicroARNs/genética , Transducción de SeñalRESUMEN
Objective: The incidence of stroke worldwide is increasing year by year. With the enhancement of public health awareness, people's demand for the quality of stroke rehabilitation is getting higher and higher, so better quality care measures are needed in the treatment of stroke. Based on this, this paper explores the impact of a new type of nursing care measure, the complementary health care model combined with condition tracking, on stroke patients. Methods: 238 stroke patients were randomly divided into a conventional group (n=119) and a combined group (n=119). 238 stroke patients were randomly divided into conventional group (n=119) and combined group (n=119). The conventional group received routine care, in which doctors and nursing carried out their own work without cooperation after the patients were admitted to the hospital; the combined group received a complementary health care model and condition tracking, in which doctors and nurses jointly checked the rooms, discussed cases, jointly formulated treatments and nursing care plans, and jointly formulated the patients' discharge and rehabilitation plans after the patients were admitted to the hospital. Before the intervention, at the time of discharge, and 6 months after discharge, the neurological function of the patients in both groups was assessed using the National Institutes of Health Stroke Scale (NIHSS) and the Fugl-Meyer (FMA) scale, the cognitive function of the patients in both groups was assessed using the Montreal Cognitive Assessment (MoCA) scale and the Measured Mental State Examination (MMSE), and the cognitive function of the patients in both groups was assessed using the General Self-Efficacy Scale (GSS) and the Montreal Cognitive Assessment (MCA) scale. General Self-Efficacy Scale (GSES) to assess self-efficacy, Exercise Adherence Questionnaire (EAQ) to assess adherence to functional exercise and Specific Quality of Life Scale (SSQoL-12) to assess the quality of life of patients in both groups, and the self-developed satisfaction with nursing care to assess patients' satisfaction with the care model. Results: Before the intervention, there was no difference in the National Institutes of Health Stroke Scale (NIHSS), the Fugl-Meyer Assessment (FMA), the Montreal Cognitive Assessment (MoCA), the Mental State Examination (MMSE), the General Self-Efficacy Scale (GSES), the Exercise Adherence Questionnaire (EAQ) and the Stroke-Specific Quality of Life Scale-12 (SSQoL-12) scores between the two groups (P > .05). At discharge and six months later, NIHSS scores continued to decrease in both groups, with the joint group being lower than the conventional group (P < .05); scores for all other items continued to increase, with the joint being higher than the conventional group (P < .05). Satisfaction with care was higher in the combined group than in the conventional group (P < .05). Conclusion: The complementary healthcare model combined with condition tracking can effectively promote the prognosis of rehabilitation of stroke patients, and has a positive effect in promoting the recovery of neurological and cognitive functions, strengthening self-efficacy, and improving the quality of life, which can be promoted in the clinic.
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Growing evidences have shown that the decline in honey bee populations is mainly caused by the combination of multiple stressors. However, the impacts of parasitic Nosema ceranae to host fitness during long-term pesticide exposure-induced stress is largely unknown. In this study, the effects of chronic exposure to a sublethal dose of dinotefuran, in the presence or absence of N. ceranae, was examined in terms of survival, food consumption, detoxification enzyme activities and gut microbial community. The interaction between dinotefuran and Nosema ceranae on the survival of honey bee was synergistic. Co-exposure to dinotefuran and N. ceranae led to less food consumption and greater changes of enzyme activities involved in defenses against oxidative stress. Particularly, N. ceranae and dinotefuran-N. ceranae co-exposure significantly impacted the gut microbiota structure and richness in adult honey bees, while dinotefuran alone did not show significant alternation of core gut microbiota compared to the control group. We herein demonstrated that chronical exposure to dinotefuran decreases honey bee's survival but is not steadily associated with the gut microbiota dysbiosis; by contrast, N. ceranae parasitism plays a dominant role in the combination in influencing the gut microbial community of the host honey bee. Our findings provide a comprehensive understanding of combinatorial effects between biotic and abiotic stressors on one of the most important pollinators, honey bees.
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Microbioma Gastrointestinal , Guanidinas , Nitrocompuestos , Nosema , Abejas , Animales , Neonicotinoides/toxicidad , Nitrocompuestos/toxicidadRESUMEN
Conventionally, the electromechanical system requires the installation of auxiliary displacement sensors and only the amount on the drive part and motion end, which increases volume, cost, and measurement error in the system. This paper presents an integrated measurement method with a sensing head, which takes the equal division characteristics of mechanical structures as part of the sensor, thus, the so-called self-sensing system. Moreover, the displacement is measured by counting the time pulses. The sensing head is integrated with the entire electromechanical system, including the driving, transmitting, and moving parts. Thus, the integration of the sensing part is greatly improved. Taking the rotary table as a special example, and the sensing head embedded into each part of the system, displacement information is obtained by the common processing system and fused by the adaptive weighted average method. The results of the experiment show that the fusion precision of each component is higher than only the motor position information as the feedback. The proposed method is a practical self-sensing technology with significant volume reduction and intelligent control benefits in the industry, especially suitable for extremely small and narrow spaces.
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Despite the great progress of current bacterially based biotherapeutics, their unsatisfying efficacy and underlying safety problems have limited their clinical application. Herein, inspired by probiotic Escherichia coli strain Nissle 1917, probiotic-derived outer membrane vesicles (OMVs) are found to serve as an effective therapeutic platform for the treatment of inflammatory bowel disease (IBD). To further enhance the therapeutic effect, the probiotic-derived OMV-encapsulating manganese dioxide nanozymes are constructed, named nanoprobiotics, which can adhere to inflamed colonic epithelium and eliminate intestinal excess reactive oxygen species in the murine IBD model. Moreover, combined with the anti-inflammatory medicine metformin, nanoprobiotics could further remold the pro-inflammatory microenvironment, improve the overall richness and diversity of the gut microbiota, and exhibit better therapeutic efficacy than commercial IBD chemotherapeutics. Importantly, insignificant overt systemic toxicity in this treatment was observed. By integrating cytokine storm calm with biotherapy, we develop a safe and effective bionanoplatform for the effective treatment of inflammation-mediated intestinal diseases.
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Wilms tumor gene 1 (WT-1 gene) is overexpressed in most patients with acute myeloid leukemia (AML) and is an indicator for minimal residual disease (MRD) monitoring, but because the WT-1 gene has relatively low specificity, further studies of the prognostic value of a combination of the WT-1 and other genes are needed. The aim of this study was to explore the prognostic value of the WT-1 gene combined with recurrent cytogenetic genes in AML. In AML, the transcript expression of the WT-1 gene was closely related to leukemic tumor burden and acted as an accurate molecular indicator for MRD detection. Most patients with low expression levels of the WT-1 gene after induction and consolidation therapy were significantly associated with favorable relapse-free survival (RFS) and overall survival (OS), but 17.6% of patients relapsed and died of primary disease. However, when analyzing the WT-1 gene combined with recurrent cytogenetic genes, none of the patients with low expression levels of the WT-1 gene and recurrent cytogenetic genes negative relapsed and died in the median follow-up time of 19 months (range: 3-94 months). Thus, the combination of the WT-1 gene and recurrent cytogenetic genes is a more accurate indicator for MRD monitoring and prognosis evaluation in AML patients.
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Genes del Tumor de Wilms , Leucemia Mieloide Aguda , Humanos , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Recurrencia , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/patología , Análisis CitogenéticoRESUMEN
Salmonella enterica (S. enterica) has infected humans for a long time, but its evolutionary history and geographic spread across Eurasia is still poorly understood. Here, we screened for pathogen DNA in 14 ancient individuals from the Bronze Age Quanergou cemetery (XBQ), Xinjiang, China. In 6 individuals we detected S. enterica. We reconstructed S. enterica genomes from those individuals, which form a previously undetected phylogenetic branch basal to Paratyphi C, Typhisuis and Choleraesuis-the so-called Para C lineage. Based on pseudogene frequency, our analysis suggests that the ancient S. enterica strains were not host adapted. One genome, however, harbors the Salmonella pathogenicity island 7 (SPI-7), which is thought to be involved in (para)typhoid disease in humans. This offers first evidence that SPI-7 was acquired prior to the emergence of human-adapted Paratyphi C around 1,000 years ago. Altogether, our results show that Salmonella enterica infected humans in Eastern Eurasia at least 3,000 years ago, and provide the first ancient DNA evidence for the spread of a pathogen along the Proto-Silk Road.
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Infecciones por Salmonella/genética , Infecciones por Salmonella/historia , Infecciones por Salmonella/transmisión , Salmonella enterica/genética , China , ADN Antiguo , Evolución Molecular , Historia Antigua , Humanos , Filogenia , Factores de Virulencia/genéticaRESUMEN
Theanine is an important secondary metabolite endowing tea with umami taste and health effects. It is essential to explore the metabolic pathway and regulatory mechanism of theanine to improve tea quality. Here, we demonstrated that the expression patterns of CsGGT2 (γ-glutamyl-transpeptidase), participated in theanine synthesis in vitro in our previous research, are significantly different in the aboveground and underground tissues of tea plants and regulated by light. Light up-regulated the expression of CsHY5, directly binding to the promoter of CsGGT2 and acting as an activator of CsGGT2, with a negative correlation with theanine accumulation. The enzyme activity assays and transient expression in Nicotiana benthamiana showed that CsGGT2, acting as bifunctional protein, synthesize and degrade theanine in vitro and in planta. The results of enzyme kinetics, Surface plasmon resonance (SPR) assays and targeted gene-silencing assays showed that CsGGT2 had a higher substrate affinity of theanine than that of ethylamine, and performed a higher theanine degradation catalytic efficiency. Therefore, light mediates the degradation of theanine in different tissues by regulating the expression of the theanine hydrolase CsGGT2 in tea plants, and these results provide new insights into the degradation of theanine mediated by light in tea plants.
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Camellia sinensis , Regulación de la Expresión Génica de las Plantas , Luz , gamma-Glutamiltransferasa , Camellia sinensis/enzimología , Camellia sinensis/genética , gamma-Glutamiltransferasa/genética , gamma-Glutamiltransferasa/metabolismo , Hidrolasas/genética , Hidrolasas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Proteolisis/efectos de la radiaciónRESUMEN
Many clinical features, besides cytogenetic and molecular abnormalities, can affect the prognosis of the patients with acute myeloid leukemia (AML). Within this context it remains unclear if and how platelet counts affect the outcome of AML patients. In the present study, we examined the platelet counts at diagnosis in 633 newly diagnosed adult patients with AML from January 2010 to April 2021, and divided the cases into the group with low level of platelet counts (≤30×109/L, n=316) and high level of platelet counts (>30×109/L, n=317) according to the median platelet counts. We then validated the prognostic significance and potential mechanism of platelet counts on the relevance of spectral features for diagnostic risk stratification, initial induction therapy response, treatment effect maintenance, long-term survival, leukemia stem cells (LSCs) proportion, immunomodulatory cytokines level and immune cell subsets proportion. The results suggested that AML patients with a high level of platelet counts at diagnosis were associated with a high-risk molecular cytogenetic stratification, low complete remission (CR) rate, poor leukemia free survival (LFS), high proportion of LSCs, high level of transforming growth factor-ß (TGF-ß) and interleukin-1ß (IL-1ß), high proportion of regulatory T cells (Tregs) and monocytic myeloid-derived suppressor cells (M-MDSCs). It was demonstrated that platelet might be an unfavorable prognostic biomarker and was associated with LSCs and immunomodulatory cytokines as well as immune cell subsets in AML.
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Citocinas , Leucemia Mieloide Aguda , Adulto , Humanos , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Biomarcadores , Células MadreRESUMEN
Evidence on joint association of a phthalate mixture with thyroid function among children and its underlying mechanism is largely unknown. We aimed to explore the associations of 10 urinary phthalate metabolites (mPAEs), either as individuals or as a mixture, with thyroid function indicators [free thyroxine, free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH)] in 144 children aged 4-12 years with up to 3 repeated visits across 3 seasons. Significant and positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP), mono-iso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) with TSH, as well as monobenzyl phthalate (MBzP) with FT3 in dose-response manners. The relationship between MEHP and TSH remained robust in multiple-phthalate models. Bayesian kernel machine regression (BKMR) models revealed overall linear associations of the 10 mPAE mixture with higher TSH and FT3 levels, and MEHP and MBzP were major contributors. Meanwhile, MEHP, MiBP, and MnBP were linked to the elevation of multiple cytokines including CCL 27, CCL3, CXCL1, and IL-16. Among them, IL-16 mediated the relationships of MEHP and MiBP with TSH, and the mediated proportions were 24.16% and 24.27%, respectively. Our findings suggested that mPAEs dominated by MEHP were dose-responsively associated with elevated TSH among healthy children and mediated by IL-16.
Asunto(s)
Contaminantes Ambientales , Ácidos Ftálicos , Niño , Humanos , Exposición a Riesgos Ambientales , Glándula Tiroides/metabolismo , Teorema de Bayes , Interleucina-16 , Ácidos Ftálicos/metabolismo , TirotropinaRESUMEN
The rapid deprotonation of GË+ in the DNA strand impedes positive charge (hole) transfer, whereas the slow deprotonation rate of GË+ in the G-tetrad makes it a more suitable carrier for hole conduction. The QM/MM(ABEEM) combined method, which involves the integration of QM and the ABEEM polarizable force field (ABEEM PFF), was developed to investigate the deprotonation of neutral and cation free radicals in the G-tetrad and GGX(8-oxo-G) tetrad (xanthine and 8-oxoguanine dual substituted G-tetrad). By incorporating valence-state electronegativity piecewise functions χ*(r) and implementing charge local conservation conditions, QM/MM(ABEEM) possesses the advantage of accurately simulating charge transfer and polarization effect during deprotonation. The activation energy calculated by the QM method of XË is the lowest among other bases in the GGX(8-oxo-G) tetrad, which is supported by the computation of the average electronegativity calculated by ABEEM PFF. By utilizing QM/MM(ABEEM) with a two-way free energy perturbation method, the deprotonation activation energy of XË in the GGX(8-oxo-G) tetrad is determined to be 33.0 ± 2.1 kJ mol-1, while that of GË+ in the G-tetrad is 20.7 ± 0.6 kJ mol-1, consistent with the experimental measurement of 20 ± 1.0 kJ mol-1. These results manifest that XË in the GGX(8-oxo-G) tetrad exhibits a slower deprotonation rate than GË+ in the G-tetrad, suggesting that the GGX(8-oxo-G) tetrad may serve as a more favorable hole transport carrier. Furthermore, the unequal average electronegativities of bases in the GGX(8-oxo-G) tetrad impede the deprotonation rate. This study provides a potential foundation for investigating the microscopic mechanism of DNA electronic devices.