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In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.
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Proteínas Hedgehog , Células-Tronco Neurais , Animais , Camundongos , Neurônios , Neurogênese , Encéfalo , MamíferosRESUMO
Recently, patients with Mpox breakthrough infection or reinfection were constantly reported. However, the induction, risk factors, and important clinical symptoms of breakthrough infection and reinfection of Mpox virus (MPXV), as well as the factors affecting the effectiveness of Mpox vaccine are not characterized. Herein, a literature review was preformed to summarize the risk factors and important clinical symptoms of patients with Mpox breakthrough infection or reinfection, as well as the factors affecting the effectiveness of smallpox vaccine against Mpox. Results showed that MSM sexual behavior, condomless sexual behavior, multiple sexual partners, close contact, HIV infection, and the presence of comorbidity are important risk factors for Mpox breakthrough infection and reinfection. Genital ulcers, proctitis, and lymphadenopathy are the important clinical symptoms of Mpox breakthrough infection and reinfection. The effectiveness of emergent vaccination of smallpox vaccine for post-exposure of MPXV is associated with smallpox vaccination history, interval between exposure and vaccination, and history of HIV infection. This review provides a better understanding for the risk factors and important clinical symptoms of Mpox breakthrough infection and reinfection, as well as the formulation of Mpox vaccine vaccination strategies.
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Infecções por HIV , Mpox , Vacina Antivariólica , Humanos , Reinfecção/epidemiologia , Reinfecção/prevenção & controle , Infecções Irruptivas , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Antígenos ViraisRESUMO
As sessile organisms, plants need to respond to rapid changes in numerous environmental factors, mainly diurnal changes of light, temperature, and humidity. Maize is the world's most grown crop, and as a C4 plant it exhibits high photosynthesis capacity, reaching the highest rate of net photosynthesis at midday; that is, there is no "midday depression." Revealing the physiological responses to diurnal changes and underlying mechanisms will be of great significance for guiding maize improvement efforts. In this study, we collected maize leaf samples and analyzed the proteome and phosphoproteome at nine time points during a single day/night cycle, quantifying 7424 proteins and 5361 phosphosites. The new phosphosites identified in our study increased the total maize phosphoproteome coverage by 8.5%. Kinase-substrate network analysis indicated that 997 potential substrates were phosphorylated by 20 activated kinases. Through analysis of proteins with significant changes in abundance and phosphorylation, we found that the response to a heat stimulus involves a change in the abundance of numerous proteins. By contrast, the high light at noon and rapidly changing light conditions induced changes in the phosphorylation level of proteins involved in processes such as chloroplast movement, photosynthesis, and C4 pathways. Phosphorylation is involved in regulating the activity of large number of enzymes; for example, phosphorylation of S55 significantly enhanced the activity of maize phosphoenolpyruvate carboxykinase1 (ZmPEPCK1). Overall, the database of dynamic protein abundance and phosphorylation we have generated provides a resource for the improvement of C4 crop plants.
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Plantas , Zea mays , Zea mays/metabolismo , Plantas/metabolismo , Fosforilação , Proteínas de Plantas/metabolismo , Fosfoproteínas/metabolismo , Folhas de Planta/metabolismo , FotossínteseRESUMO
Polarization detection and imaging technologies have attracted significant attention for their extensive applications in remote sensing, biological diagnosis, and beyond. However, previously reported polarimeters heavily relied on polarization-sensitive materials and pre- established mapping relationships between the Stokes parameters and detected light intensities. This dependence, along with fabrication and detection errors, severely constrain the working waveband and detection precision. In this work, we demonstrated a highly precise, stable, and broadband full-Stokes polarimeter based on large-area uniform chiral shells and a post-established mapping relationship. By precisely controlling the geometry through the deposition of Ag on a large-area microsphere monolayer with a uniform lattice, the optical chirality and anisotropy of chiral shells can reach about 0.15 (circular dichroism, CD) and 1.7, respectively. The post-established mapping relationship between the Stokes parameters and detected light intensities is established through training a deep learning algorithm (DLA) or fitting the derived mapping-relationship formula based on the Mueller matrix theory with a large dataset collected from our home-built polarization system. For the detection precision with DLA, the mean squared errors (MSEs) at 710 nm can reach 0.10% (S1), 0.41% (S2), and 0.24% (S3), while for the Mueller matrix theory, the corresponding values are 0.14% (S1), 0.46% (S2), and 0.48% (S3). The in-depth comparative studies indicate that the DLA outperforms the Mueller matrix theory in terms of detection precision and robustness, especially for weak illumination, small optical anisotropy and chirality. The averaged MSEs over a broad waveband ranging from 500 nm to 750 nm are 0.16% (S1), 0.46% (S2), and 0.61% (S3), which are significantly smaller than those derived from the Mueller matrix theory (0.45% (S1), 1% (S2), and 39.8% (S3)). The optical properties of chiral shells, the theory and DLA enabled mapping-relationships, the combination modes of chiral shells, and the MSE spectra have been systematically investigated.
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Aberrant energy metabolism in the brain is a common pathological feature in the preclinical Alzheimer's Disease (AD). Recent studies have reported the early elevations of glycolysis-involved enzymes in AD brain and cerebrospinal fluid according to a large-scale proteomic analysis. It's well-known that astrocytes exhibit strong glycolytic metabolic ability and play a key role in the regulation of brain homeostasis. However, its relationship with glycolytic changes and cognitive deficits in early AD patients is unclear. Here, we investigated the mechanisms by which astrocyte glycolysis is involved in early AD and its potential as a therapeutic target. Our results suggest that Aß-activated microglia can induce glycolytic-enhanced astrocytes in vitro, and that these processes are dependent on the activation of the AKT-mTOR-HIF-1α pathway. In early AD models, the increase in L-lactate produced by enhanced glycolysis of astrocytes leads to spatial cognitive impairment by disrupting synaptic plasticity and accelerating Aß aggregation. Furthermore, we find rapamycin, the mTOR inhibitor, can rescue the impaired spatial memory and Aß burden by inhibiting the glycolysis-derived L-lactate in the early AD models. In conclusion, we highlight that astrocytic glycolysis plays a critical role in the early onset of AD and that the modulation of glycolysis-derived L-lactate by rapamycin provides a new strategy for the treatment of AD.
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In this paper, we present an example of a photoinduced catalyst, halogen-, and base-free TEMPO-mediated interrupted 6π-photocyclization/dehydrogenative aromatization of ortho-biaryl-appended 1,3-dicarbonyl compounds for the preparation of 10-phenanthrenols. The reaction involves rapid photocycloaddition via a 1,2-biradical of 1,3-dicarbonyl compounds, followed by subsequent dehydrogenative aromatization of 1,4-biradical intermediates using TEMPO as the commercially available oxidant rather than trapped by TEMPO to form an alkoxyamine product.
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OBJECTIVE: The study aimed to evaluate the impact of Botulinum toxin A (BoNT/A) on neuropsychiatric symptoms in Parkinson's disease (PD) patients. METHODS: A total of 125 PD patients and an equal number of age- and gender-matched healthy controls were involved. Mental health status was assessed using the Cornell Medical Index (CMI) self-assessment questionnaire. Sixty-four PD patients exhibiting neuropsychiatric symptoms were selected for the controlled study and randomly grouped into treatment and control groups. The treatment group received BoNT/A injections, while the control group received a placebo. The primary outcome measures included depression scores from the CMI and the proportion of patients displaying improvement in neuropsychiatric symptoms at 8 weeks post-treatment. The secondary outcome was other CMI scores at 4, 8, and 12 weeks post-treatment. RESULTS: The outcomes revealed that PD patients had significantly higher scores in various neuropsychiatric factors compared to healthy controls. At 4 weeks post-treatment, the treatment group displayed improvements in depression and tension. At 8 weeks post-treatment, they exhibited significant reductions in depression, anxiety, sensitivity, and tension compared to the control group. Moreover, a notably higher percentage of patients in the treatment group showed improvement in neuropsychiatric symptoms compared to the control group. At 12 weeks post-treatment, the treatment group exhibited significant improvements in somatization, depression, sensitivity, and tension. CONCLUSION: PD patients commonly experience multiple neuropsychiatric symptoms, and BoNT/A has demonstrated efficacy in alleviating these symptoms. Specifically, BoNT/A was found to effectively alleviate somatization, tension, anxiety, depression, and sensitivity in PD patients.
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PURPOSE: The treatment with anti-VEGF for Retinopathy of prematurity (ROP) has already been widely applied in clinics even though there are still many concerns about this treatment. In this project we investigated the clinical outcomes of intra-vitreous conbercept (IVC) and ranibizumab (IVR) injection for treating type 1 prethreshold ROP in Zone II. METHODS: The data of ROP infants receiving IVR or IVC from January 2017 to March 2020 who were followed up for at least 12 months in our hospital was studied in the present retrospective study. Regression, reactivation, complications, and ocular biological parameters were evaluated. RESULTS: One hundred twenty-five eyes (64 infants) in IVC group and 229 eyes (117 infants) in IVR group were observed in the study. All infants showed good response to the two anti-VEGF agents. No eyes deteriorated during the observation. No significant difference was found between the two groups as to the regression within one week and one month, the reactivation rate, and the retreatment interval (p > 0.05) whereas retinal complete vascularization rate at 6 mons after the initial treatment and mean completion time of retinal vascularization after initial injection showed significant difference (p < 0.05). At 12 mons PMA the ocular parameters also presented no statistical difference between the two treated groups (p > 0.05). However, the ocular showed slight myopic tendency with the anti-VEGF treatment when compared to the control group (p < 0.05) whereas there was no statistical difference revealed between the two treated groups (p > 0.05). CONCLUSIONS: Both conbercept and ranibizumab for treating type 1 prethreshold ROP in Zone II are safe and effective. They had little effect on the development of ocular whereas there was a slight tendency of myopia after the treatment.
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Inibidores da Angiogênese , Injeções Intravítreas , Ranibizumab , Proteínas Recombinantes de Fusão , Retinopatia da Prematuridade , Humanos , Ranibizumab/uso terapêutico , Ranibizumab/administração & dosagem , Retinopatia da Prematuridade/tratamento farmacológico , Estudos Retrospectivos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Masculino , Feminino , Recém-Nascido , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Resultado do Tratamento , SeguimentosRESUMO
PURPOSE: We aimed to develop and evaluate a new diagnostic method, the 'chicken-wing muscle up test', to improve the accuracy of diagnosis of glenolabral articular disruption (GLAD) lesions compared to currently used clinical tests for injuries to the labrum. METHODS: Preoperative evaluations were conducted on 85 patients undergoing arthroscopic surgery at a single center between July 2021 to July 2022. The diagnostic performance of the preoperative clinical examinations (chicken-wing muscle up test, O'Brien test, crank test, and O'Driscoll test) were validated against the findings of arthroscopic examinations. RESULTS: 12 of the 85 patients in this study had arthroscopically confirmed GLAD lesions. The chicken-wing muscle up test demonstrated significantly higher sensitivity (83.33%) for GLAD lesions than the O'Brien test (33.33%), but not the crank test (50.00%) or O'Driscoll test (25.00%), and significantly higher specificity (95.89%) than the O'Brien test (75.34%), crank test (82.19%), and O'Driscoll test (71.23%). The chicken-wing muscle up test had the largest area under the receiver operating characteristic curve (AUC = 0.896, P < 0.001; O'Driscoll test AUC = 0.543, P > 0.05; crank test AUC = 0.661, P > 0.05; O'Brien test AUC = 0.481, P > 0.05), indicating significantly better diagnostic efficacy for GLAD lesions than the other three tests. CONCLUSIONS: The chicken-wing muscle up test is a reliable diagnostic method that improves the accuracy of diagnosis of GLAD lesions.
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Artroscopia , Humanos , Feminino , Masculino , Adulto , Artroscopia/métodos , Pessoa de Meia-Idade , Adulto Jovem , Músculo Esquelético , Adolescente , Sensibilidade e Especificidade , Estudos Retrospectivos , Exame Físico/métodosRESUMO
Berberine is a natural isoquinoline alkaloid with low toxicity, which exists in a wide variety of medicinal plants. Berberine has been demonstrated to exhibit potent prevention of indomethacin-induced gastric injury (GI) but the related mechanism remains unclear. In the present study, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied for the first time to investigate the alteration of serum metabolites in the protection of berberine against indomethacin-induced gastric injury in rats. Subsequently, bioinformatics was utilized to analyze the potential metabolic pathway of the anti-GI effect of berberine. The pharmacodynamic data indicated that berberine could ameliorate gastric pathological damage, inhibit the level of proinflammatory factors in serum, and increase the level of antioxidant factors in serum. The LC-MS-based metabolomics analysis conducted in this study demonstrated the presence of 57 differential metabolites in the serum of rats with induced GI caused by indomethacin, which was associated with 29 metabolic pathways. Moreover, the study revealed that berberine showed a significant impact on the differential metabolites, with 45 differential metabolites being reported between the model group and the group treated with berberine. The differential metabolites were associated with 24 metabolic pathways, and berberine administration regulated 14 of the 57 differential metabolites, affecting 14 of the 29 metabolic pathways. The primary metabolic pathways affected were glutathione metabolism and arachidonic acid metabolism. Based on the results, it can be concluded that berberine has a gastroprotective effect on the GI. This study is particularly significant since it is the first to elucidate the mechanism of berberine's action on GI. The results suggest that berberine's action may be related to energy metabolism, oxidative stress, and inflammation regulation. These findings may pave the way for the development of new therapeutic interventions for the prevention and management of NSAID-induced GI disorders.
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Berberina , Gastropatias , Ratos , Animais , Indometacina , Berberina/farmacologia , Espectrometria de Massa com Cromatografia Líquida , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem , Metabolômica/métodos , Gastropatias/tratamento farmacológicoRESUMO
OBJECTIVE: Relational job characteristics include perceived social worth and perceived social influence. Good relational job characteristics mean that nurses have high prosocial behavior. The purpose of this study was to explore the potential profile of nurses' relational job characteristics, influencing factors and their differences in turnover intention and subjective well-being, thus finding the most suitable clinical relationship job characteristics. METHODS: A cross-sectional survey was conducted among 1013 clinical nurses using the general demographic data questionnaire, Relational Job Characteristics scale, Turnover Intention Questionnaire and Campbell index of well-being. A latent profile analysis was performed to explore relational job characteristics latent profiles. Multinomial logistic regression analysis was conducted to examine the predictors of profile membership, and a one-way analysis of variance was applied to compare the turnover intention and subjective well-being in each latent profile. RESULTS: Five latent profiles were identified and labeled 'High prosocial job characteristics' profile (20.7%), 'Moderate prosocial job characteristics' profile (41.7%), 'High social worth-low social impact perceived' profile (6.3%), 'Low social worth-high social impact perceived' profile (18.8%) and 'Low prosocial job characteristics' profile (12.5%). Factors affecting the different types of nurse relationship job characteristics include age, marital status, hospital department, nursing years, professional title and hospital position. Among them, chief nurse, nurses with more than 20 years of nursing experience and obstetrics and gynecology nurses were more likely to be 'high prosocial job characteristics' profile. The turnover intention of nurses in 'high prosocial job characteristics' profile was significantly lower than that of other profiles, and their subjective well-being was significantly higher than that of other profiles. CONCLUSION: Improving nurses' perception of social worth and social impact on clinical work can improve nurses' prosocial behavior and subjective well-being, and reduce their turnover intention. Nursing managers or policy makers can formulate targeted intervention measures according to the influencing factors of potential profiles.
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Carboxylation with carbon dioxide (CO2 ) represents one notable methodology to produce carboxylic acids. In contrast to carbon-heteroatom bonds, carbon-carbon bond cleavage for carboxylation with CO2 is far more challenging due to their inherent and less favorable orbital directionality for interacting with transition metals. Here we report a photocatalytic protocol for the deconstructive carboxylation of alkenes with CO2 to generate carboxylic acids in the absence of transition metals. It is emphasized that our protocol provides carboxylic acids with obviously unchanged carbon numbers when terminal alkenes were used. To show the power of this strategy, a variety of pharmaceutically relevant applications including the modular synthesis of propionate nonsteroidal anti-inflammatory drugs and the late-stage carboxylation of bioactive molecule derivatives are demonstrated.
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OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.
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Displasia Broncopulmonar , Recém-Nascido Prematuro , Gêmeos , Humanos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/epidemiologia , Fatores de Risco , Recém-Nascido , Feminino , Estudos Retrospectivos , Masculino , Idade Gestacional , Peso ao Nascer , Modelos LogísticosRESUMO
MAIN CONCLUSION: OsTST1 affects yield and development and mediates sugar transportation of plants from source to sink in rice, which influences the accumulation of intermediate metabolites from tricarboxylic acid cycle indirectly. Tonoplast sugar transporters (TSTs) are essential for vacuolar sugar accumulation in plants. Carbohydrate transport across tonoplasts maintains the metabolic balance in plant cells, and carbohydrate distribution is crucial to plant growth and productivity. Large plant vacuoles store high concentrations of sugars to meet plant requirements for energy and other biological processes. The abundance of sugar transporter affects crop biomass and reproductive growth. However, it remains unclear whether the rice (Oryza sativa L.) sugar transport protein OsTST1 affects yield and development. In this study, we found that OsTST1 knockout mutants generated via CRISPR/Cas9 exhibited slower development, smaller seeds, and lower yield than wild type (WT) rice plants. Notably, plants overexpressing OsTST1 showed the opposite effects. Changes in rice leaves at 14 days after germination (DAG) and at 10 days after flowering (DAF) suggested that OsTST1 affected the accumulation of intermediate metabolites from the glycolytic pathway and the tricarboxylic acid (TCA) cycle. The modification of the sugar transport between cytosol and vacuole mediated by OsTST1 induces deregulation of several genes including transcription factors (TFs). In summary, no matter the location of sucrose and sink is, these preliminary results revealed that OsTST1 was important for sugar transport from source to sink tissues, thus affecting plant growth and development.
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Oryza , Proteínas de Plantas , Transporte Biológico , Carboidratos , Oryza/genética , Oryza/metabolismo , Açúcares , Vacúolos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
The epidemic of Mpox virus (MPXV) from May 2022 was once declared as a Public Health Emergency of International Concern by the World Health Organization. Vaccines play an important role in prevention of infectious diseases, and mRNA vaccine technology was proved to be a safe and effective platform with successful application in defense of coronavirus disease 2019. In this study, based on A29L, M1R, A35R, and B6R of MPXV, we developed two MPXV mRNA vaccine candidates, designated as MPXfus and MPXmix. The MPXfus was one-component, in which these four antigen proteins were linked in tandem by flexible linker and encoded by an individual mRNA as a fusion protein. The MPXmix was multicomponent containing four mRNA, and each mRNA encoded one antigen protein respectively. Mice were immunized with equal quality of MPXfus or MPXmix, delivered by lipid nanoparticles for evaluation and comparison of the immune responses induced by these two MPXV vaccine candidates. Results of immune response analyses indicated that both MPXfus and MPXmix could elicit high-level of antigen-specific antibodies and robust cellular immune response in mice. Moreover, results of virus neutralization assays suggested that sera from MPXfus- or MPXmix-immunized mice possessed high neutralizing activities against vaccinia virus. In addition, titers of antigen-specific antibody, levels of cellular immune response, and activities of neutralizing antibody against vaccinia virus induced by MPXfus and MPXmix presented no significant difference. In summary, this study provides valuable insights for further clinical development of one-component and multicomponent mRNA vaccine candidates for the prevention of MPXV and other orthomyxoviruses.
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Mpox , Animais , Camundongos , Anticorpos Neutralizantes , Vaccinia virus/genética , Imunidade Celular , RNA Mensageiro/genética , Anticorpos AntiviraisRESUMO
Semi-quantum key distribution (SQKD) protocols are used to distribute secret keys between a quantum party and a classical party. However, existing SQKD protocols rely on two-way communication, and may still be vulnerable to Trojan horse side-channel attacks where Eve sends her own photon into a receiver's apparatus and measures the reflected photon to estimate the key. In this paper, we propose a practical SQKD with one-way key. This requires that the single photons travelling through the one-way channel are used to encode bit information, and the returned photons are used to quantify Eve's information, thus reducing the security analysis of the Trojan horse attack in SQKD. Meanwhile, our protocol with one basis enjoys security advantage in practical SQKD systems when source flaws are taken into account. In particular, the present protocol is secure under practical conditions when weak coherent pulses (WCP) are used. Our simulation results show that the protocol using WCP can distribute secret keys over a distance of 110 km without decoy states.
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Portable fiber optical spectrometers (PFOSs) have been widely used in the contemporary industrial and agricultural production and life due its low cost and small volume. PFOSs mainly combine one fiber to guide light and one optical spectrometer to detect spectra. In this work, we demonstrate that PFOSs can work as a broadband full-Stokes polarimeter through slightly bending the fiber several times and establishing the mapping relationship between the Stokes parameters S^ and the bending-dependent light intensities I^, i.e., S^=f(I^). The different bending geometries bring different birefringence effects and reflection effects that change the polarization state of the out-going light. In the meanwhile, the grating owns a polarization-depended diffraction efficiency especially for the asymmetric illumination geometry that introduces an extrinsic chiroptical effect, which is sensitive to both the linear and spin components of light. The minimum mean squared error (MSE) can reach to smaller than 1% for S1, S2, and S3 at 810â nm, and the averaged MSE in the wave band from 440â nm to 840â nm is smaller than 2.5%, where the working wavelength can be easily extended to arbitrary wave band by applying PFOSs with proper parameters. Our findings provide a convenient and practical method for detecting full-Stokes parameters.
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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , Pneumonia , Camundongos , Humanos , Animais , Leucócitos Mononucleares/metabolismo , Anticorpos Monoclonais/uso terapêutico , Células Endoteliais/metabolismo , Fibrinolisina/metabolismo , Fibrinolisina/farmacologia , Fibrinolisina/uso terapêutico , Pulmão/metabolismo , Fibrose , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pneumonia/metabolismo , Colágeno/metabolismo , Bleomicina/toxicidade , Fibroblastos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Fosfopiruvato Hidratase/farmacologia , Fosfopiruvato Hidratase/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Given the reduced immune response to vaccines in older populations, this study aimed to evaluate the efficacy of COVID-19 vaccinations and its impact on breakthrough infection, hospital admission, and mortality in the elderly. METHODS: We carried out a systemic review and meta-analysis where MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials were queried to identify relevant literature. We included randomized controlled trials (RCTs), non-randomized trials, prospective, observational cohort, and case-control studies assessing breakthrough infection, hospital admission, and mortality after coronavirus 2 (SARS-CoV-2) vaccination in the elderly (≥ 60 years old). RESULTS: Overall, 26 studies were included in this meta-analysis. Compared with the unvaccinated group, the vaccinated group showed a decreased risk of SARS-CoV-2 infection after 28-34 (relative risk [RR] = 0.42, 95% confidence interval [CI] 0.37-0.49) and 35-60 days (RR = 0.49, 95% CI 0.37-0.62). There was a step-wise increase in efficacy with additional doses with the two-dose group experiencing decreased risk of breakthrough infection (RR = 0.37, 95% CI 0.32-0.42), hospital admissions (RR = 0.25, 95% CI 0.14-0.45), disease severity (RR = 0.38, 95% CI 0.20-0.70), and mortality (RR = 0.21, 95% CI 0.14-0.32) compared with those receiving one or no doses. Similarly three-dose and four-dose vaccine groups also showed a decreased risk of breakthrough infection (3-dose: RR = 0.14, 95% CI 0.10-0.20; 4-dose RR = 0.46, 95% CI 0.4-0.53), hospital admissions (3-dose: RR = 0.11, 95% CI 0.07-0.17; 4-dose: RR = 0.42, 95% CI 0.32-0.55), and all-cause mortality (3-dose: RR = 0.10, 95% CI 0.02-0.48; 4-dose: RR = 0.48, 95% CI 0.28-0.84) Subgroup analysis found that protection against mortality for vaccinated vs. unvaccinated groups was similar by age (60-79 years: RR = 0.59; 95% CI, 0.47-0.74; ≥ 80 years: RR = 0.76; 95% CI, 0.59-0.98) and gender (female: RR = 0.66; 95% CI, 0.50-0.87, male: (RR = 0.58; 95% CI, 0.44-0.76), and comorbid cardiovascular disease (CVD) (RR = 0.69; 95% CI, 0.52-0.92) or diabetes (DM) (RR = 0.59; 95% CI, 0.39-0.89. CONCLUSIONS: Our pooled results showed that SARS-CoV-2 vaccines administered to the elderly is effective in preventing prevent breakthrough infection, hospitalization, severity, and death. What's more, increasing number of vaccine doses is becoming increasingly effective.
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A photocatalyst- and additive-free visible-light-induced 6π-photocyclization of ortho-biaryl-appended ß-ketoesters has been developed. Upon irradiation with visible light, substrates undergo 6-endo-trig cyclization/1,5-H shift to 9,10-dihydrophenanthren-9-ols with high efficiency and selectivity. The reaction proceeds via conrotatory ring closure followed by a suprafacial 1,5-hydrogen shift leading to the observed single trans-fused products. Preliminary mechanistic studies reveal the feasibility of both 1,5-H shift and intersystem crossing of the diradical intermediate.