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BACKGROUND: Norepinephrine transporter (NET) is encoded by the SLC6A2 gene and is a potential target for studying the pathogenesis of PTSD. To the best of our knowledge, no prior investigations have examined SLC6A2 polymorphism-related neuroimaging abnormalities in PTSD patients. METHODS: In 218 Han Chinese adults who had lost their sole child, we investigated the association between the T-182 C SLC6A2 genotype and gray matter volume (GMV). Participants included 57 PTSD sufferers and 161 non-PTSD sufferers, and each group was further separated into three subgroups based on each participant's SLC6A2 genotype (TT, CT, and CC). All participants received magnetic resonance imaging (MRI) and clinical evaluation. To assess the effects of PTSD diagnosis, genotype, and genotype × diagnosis interaction on GMV, 2 × 3 full factorial designs were used. Pearson's correlations were used to examine the association between GMV and CAPS, HAMD, and HAMA. RESULTS: The SLC6A2 genotype showed significant main effects on GMV of the left superior parietal gyrus (SPG) and the bilateral middle cingulate gyrus (MCG). Additionally, impacts of the SLC6A2 genotype-diagnosis interaction were discovered in the left superior frontal gyrus (SFG). The CAPS, HAMA, and HAMD scores, as well as the genotype main effect and diagnostic SLC6A2 interaction, did not significantly correlate with each other. CONCLUSION: These findings indicate a modulatory effect that the SLC6A2 polymorphism exerts on the SPG and MCG, irrespective of PTSD diagnosis. We found evidence to suggest that the SLC6A2 genotype-diagnosis interaction on SFG may potentially contribute to PTSD pathogenesis in adults who lost their sole child.
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Sustancia Gris , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Trastornos por Estrés Postraumático , Adulto , Niño , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , China , Sustancia Gris/patología , Imagen por Resonancia Magnética/métodos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Corteza Prefrontal , Trastornos por Estrés Postraumático/genéticaRESUMEN
BACKGROUND: Negative conversion of nucleic acid was a key factor in deciding discharge or the end of isolation of asymptomatic or mild COVID-19 patients. We aimed to explore the effect of vaccination on the time to negative conversion after Omicron infection. METHODS: This retrospective cohort study included asymptomatic or mild patients with COVID-19 admitted to Fangcang shelter Hospital from November 10, 2022 to December 2, 2022. The relationship between vaccination status and the time to negative conversion was analyzed by multiple linear regression. RESULTS: A total of 2,104 asymptomatic or mild COVID-19 patients were included in the analysis, of whom 1,963 were vaccinated. The mean time to negative conversion of no vaccination, one dose, two doses, and three doses were 12.57 (5.05), 12.18 (3.46), 11.67 (4.86) and 11.22 (4.02) days, respectively (p = 0.002). Compared with no vaccination, two doses (ß=-0.88, 95% CI: -1.74, -0.02, p = 0.045), and three doses (ß=-1.51, 95% CI: -2.33, -0.70, p < 0.001) were both associated with shorter time to negative conversion. Comparing with two doses, booster dose was associated significantly with shorter time to negative conversion (ß=-0.63, 95% CI: -1.07, -0.20, p = 0.004). Age was positively correlated with the time to negative conversion (ß = 0.04, 95% CI: 0.02, 0.05, p < 0.001). CONCLUSION: Vaccination with inactivated vaccine and booster dose can shorten the time to negative conversion of asymptomatic or mild COVID-19 patients. The significant prolongation of time to negative conversion with increasing age suggests the promotion of vaccination, especially booster dose, particularly in the elderly.
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COVID-19 , Ácidos Nucleicos , Anciano , Humanos , Vacunas contra la COVID-19 , COVID-19/prevención & control , Hospitales Especializados , Estudios Retrospectivos , Unidades Móviles de SaludRESUMEN
COVID-19 has infected 272 million patients and caused 5.33 million deaths around the world, and it remains the main global threat. Previous studies revealed that Chinese traditional medicine is an effective treatment for COVID-19 infection. This study aims to reveal the pharmacological effects of kaempferol, which is the active component of Radix Bupleuri and Tripterygii Radix, and potential mechanisms for the treatment of COVID-19. Here, we employed the bioinformatics methods to filter the anti-COVID-19 candidate genes of kaempferol, which mainly enriched in inflammation (TNF, JUN, etc.) and virus infection (AKT1, JNK, etc.). The Transcription levels of AKT1, JNK and JUN were significantly reduced by kaempferol treatment in the LPS-activated macrophages. In addition, kaempferol reduced the secretion of inflammatory factors by LPS-stimulated macrophages, inhibited MAPK/NF-κB signaling and regulated macrophage polarization to M2 type in vitro, and suppressed endotoxin-induced cytokine storm and improved survival in mice. Molecular docking analysis demonstrated that kaempferol was probable to bind the COVID-19 protein 5R84 and formatted hydrogen bond with the residues, the free binding energy of which was lower than the original ligand. In summary, our current work indicates that kaempferol has anti-COVID-19 potential through the reduction of COVID-19-induced body dysfunction and molecule-protein interaction, and bioinformatics results clarify that some of these key target genes might serve as potential molecular markers for detecting COVID-19.
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COVID-19 , Medicamentos Herbarios Chinos , Animales , Ratones , Síndrome de Liberación de Citoquinas , Quempferoles/farmacología , Quempferoles/uso terapéutico , Lipopolisacáridos , Simulación del Acoplamiento Molecular , Biología Computacional , EndotoxinasRESUMEN
Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N7-methylguanosine (m7G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m7G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m7G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m7G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m7G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.
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Neoplasias Pulmonares , Biosíntesis de Proteínas , Uso de Codones , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Humanos , Neoplasias Pulmonares/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN de Transferencia/genéticaRESUMEN
Macrophage migration inhibitory factor (MIF) inhibition can attenuate pulmonary fibrosis, but the antifibrotic mechanism is unclear. Here we investigated the antifibrotic effect of MIF knockdown in rats with bleomycin (BLM)-induced pulmonary fibrosis. The results showed that MIF inhibition attenuated lung injury and extracellular matrix deposition; significantly reduced the levels of cytokines including transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), hydroxyproline (hyp), fibroblast growth factor 23 (FGF23), and secreted phosphoprotein 1 (Spp1); and inhibited the expression of CD68, F4/80, and α-smooth muscle actin (α-SMA) protein. MIF inhibition is associated with reduction of proinflammatory mediators and macrophage infiltration in lungs. In addition, MIF knockdown in the day 14 group was significantly better than MIF knockdown in day 1 group in terms of the above mentioned cytokines TGF-ß1, IL-17, TNF-α. MIF knockdown in day 14 group showed a better trend than MIF knockdown in day 1 group in inhibition of hyp and α-SMA formation. Furthermore, MIF inhibition downregulated the FGF23, Spp1, anti-integrin alpha 10 (Itga10), laminin subunit alpha 1 (Lama1), thrombospondin 2 (THBS2), and Serpin family B member 5 (SERPINB5) mRNA levels and the p-Smad2/3 protein level. MIF knockdown may inhibit fibrosis through the TGF-ß1/Smads signaling pathway. In addition, MIF inhibition protects against vascular remodeling via Thbs2 and Serpinb5 signaling. In summary, our study showed that knockdown of MIF can significantly inhibit lung inflammation and fibrosis in rats with BLM-induced pulmonary fibrosis. The future development of inhibitors targeting MIF may contribute to the treatment of pulmonary fibrosis.
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Antibióticos Antineoplásicos/toxicidad , Bleomicina/toxicidad , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Fibrosis Pulmonar/prevención & control , Animales , Masculino , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND: Losing one's only child is a major traumatic life event that may lead to post-traumatic stress disorder (PTSD); however, the underlying mechanisms of its psychological consequences remain poorly understood. Here, we investigated subregional hippocampal functional connectivity (FC) networks based on resting-state functional magnetic resonance imaging and the deoxyribonucleic acid methylation of the human glucocorticoid receptor gene (NR3C1) in adults who had lost their only child. METHODS: A total of 144 Han Chinese adults who had lost their only child (51 adults with PTSD and 93 non-PTSD adults [trauma-exposed controls]) and 50 controls without trauma exposure were included in this fMRI study (age: 40-67 years). FCs between hippocampal subdivisions (four regions in each hemisphere: cornu ammonis1 [CA1], CA2, CA3, and dentate gyrus [DG]) and methylation levels of the NR3C1 gene were compared among the three groups. RESULTS: Trauma-exposed adults, regardless of PTSD diagnosis, had weaker positive FC between the left hippocampal CA1, left DG, and the posterior cingulate cortex, and weaker negative FC between the right CA1, right DG, and several frontal gyri, relative to healthy controls. Compared to non-PTSD adults, PTSD adults showed decreased negative FC between the right CA1 region and the right middle/inferior frontal gyri (MFG/IFG), and decreased negative FC between the right DG and the right superior frontal gyrus and left MFG. Both trauma-exposed groups showed lower methylation levels of the NR3C1 gene. CONCLUSIONS: Adults who had lost their only child may experience disrupted hippocampal network connectivity and NR3C1 methylation status, regardless of whether they have developed PTSD.
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Hijo Único , Trastornos por Estrés Postraumático , Adulto , Anciano , Humanos , Persona de Mediana Edad , China , Hipocampo/patología , Imagen por Resonancia Magnética , Metilación , Receptores de Glucocorticoides/genética , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/patologíaRESUMEN
BACKGROUND: The lack of knowledge regarding the pathogenesis and host immune response during SARS-CoV-2 infection has limited the development of effective treatments. Thus, we longitudinally investigated the dynamic changes in peripheral blood lymphocyte subsets and parallel changes in cytokine levels in COVID-19 patients with different disease severities to further address disease pathogenesis. METHODS: A total of 67 patients (10 moderate, 38 severe and 19 critical cases) with COVID-19 admitted to a tertiary care hospital in Wuhan from February 8th to April 6th, 2020 were retrospectively studied. Dynamic data of lymphocyte subsets and inflammatory cytokines were collected. RESULTS: On admission, compared with moderate cases, severe and critical cases showed significantly decreased levels of total lymphocytes, T lymphocytes, CD4+ T cells, CD8+ T cells, B cells and NK cells. IL-6 and IL-10 were significantly higher in the critical group. During the following hospitalization period, most of the lymphocyte subsets in the critical group began to recover to levels comparable to those in the severe group from the fourth week after illness onset, except for NK cells, which recovered after the sixth week. A sustained decrease in the lymphocyte subsets and an increase in IL-6 and IL-10 were observed in the nonsurvivors until death. There was a strong negative correlation between IL-6 and IL-10 and total lymphocytes, T lymphocytes, CD4+ T cells, CD8+ T cells and NK cells. CONCLUSIONS: A sustained decrease in lymphocyte subsets, especially CD4+ T cells and NK cells, interacting with proinflammatory cytokine storms was associated with severe disease and poor prognosis in COVID-19.
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COVID-19/inmunología , Citocinas/sangre , Linfocitos , Adulto , Anciano , Linfocitos B , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos , COVID-19/sangre , Femenino , Humanos , Interleucina-10 , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Subgrupos Linfocitarios , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Different demodulation methods affect the efficiency and accuracy of spatial frequency domain imaging (SFDI). A simple and effective method of sum-to-product identities (STPI) demodulation was proposed in this study. STPI requires one fewer image than conventional three-phase demodulation (TPD) at a spatial frequency. Numerical simulation and phantom experiments were performed. The result proved the feasibility of STPI and showed that STPI combined with subtraction can achieve high-precision demodulation in the low spatial frequency domain. Through extraction of phantom optical properties, STPI had similar accuracy compared with other demodulation methods in extracting optical properties in phantoms. STPI was also used to extract the optical properties of milk, and it had highly consistent results with TPD, which can distinguish milk with different fat content. The demodulation effect of this method in the low spatial frequencies is better than other fast demodulation methods.
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BACKGROUND: Disturbance of the triple network model was recently proposed to be associated with the occurrence of posttraumatic stress disorder (PTSD) symptoms. Based on resting-state dynamic causal modeling (rs-DCM) analysis, we investigated the neurobiological model at a neuronal level along with potential neuroimaging biomarkers for identifying individuals with PTSD. METHODS: We recruited survivors of a devastating typhoon including 27 PTSD patients, 33 trauma-exposed controls (TECs), and 30 healthy controls without trauma exposure. All subjects underwent resting-state functional magnetic resonance imaging. Independent components analysis was used to identify triple networks. Detailed effective connectivity patterns were estimated by rs-DCM analysis. Spearman correlation analysis was performed on aberrant DCM parameters with clinical assessment results relevant to PTSD diagnosis. We also carried out step-wise binary logistic regression and receiver operating characteristic curve (ROC) analysis to confirm the capacity of altered effective connectivity parameters to distinguish PTSD patients. RESULTS: Within the executive control network, enhanced positive connectivity from the left posterior parietal cortex to the left dorsolateral prefrontal cortex was correlated with intrusion symptoms and showed good performance (area under the receiver operating characteristic curve = 0.879) in detecting PTSD patients. In the salience network, we observed a decreased causal flow from the right amygdala to the right insula and a lower transit value for the right amygdala in PTSD patients relative to TECs. CONCLUSION: Altered effective connectivity patterns in the triple network may reflect the occurrence of PTSD symptoms, providing a potential biomarker for detecting patients. Our findings shed new insight into the neural pathophysiology of PTSD.
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Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Imagen por Resonancia Magnética , Modelos Neurológicos , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/fisiopatología , Conectoma , Tormentas Ciclónicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Descanso , Trastornos por Estrés Postraumático/etiología , SobrevivientesRESUMEN
BACKGROUND: The strong invasive and metastatic nature of non-small cell lung cancer (NSCLC) leads to poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) is involved in cell migration, motility and invasion. The object of this study is to investigate the involvement of CTHRC1 in NSCLC invasion and metastasis. METHODS: A proteomic analysis was performed to identify the different expression proteins between NSCLC and normal tissues. Cell lines stably express CTHRC1, MMP7, MMP9 were established. Invasion and migration were determined by scratch and transwell assays respectively. Clinical correlations of CTHRC1 in a cohort of 230 NSCLC patients were analysed. RESULTS: CTHRC1 is overexpressed in NSCLC as measured by proteomic analysis. Additionally, CTHRC1 increases tumour cell migration and invasion in vitro. Furthermore, CTHRC1 expression is significantly correlated with matrix metalloproteinase (MMP)7 and MMP9 expression in sera and tumour tissues from NSCLC. The invasion ability mediated by CTHRC1 were mainly MMP7- and MMP9-dependent. MMP7 or MMP9 depletion significantly eradicated the pro-invasive effects mediated by CTHRC1 on NSCLC cells. Clinically, patients with high CTHRC1 expression had poor survival. CONCLUSIONS: CTHRC1 serves as a pro-metastatic gene that contributes to NSCLC invasion and metastasis, which are mediated by upregulated MMP7 and MMP9 expression. Targeting CTHRC1 may be beneficial for inhibiting NSCLC metastasis.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas de la Matriz Extracelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinasa 7 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/mortalidad , Masculino , Metaloproteinasa 7 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , FN-kappa B/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Proteómica , Proteínas Proto-Oncogénicas c-jun/metabolismo , Transducción de SeñalRESUMEN
Investigating hippocampal subfields may provide new and important insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, no study has examined the hippocampal subfield volume changes in parents with or without PTSD who had lost their only child and could no longer conceive in China. Fifty-seven parents with PTSD (PTSD+), 11 trauma-exposed parents without PTSD (PTSD-), and 39 non-traumatized controls were recruited to examine the hippocampal subfield volumes using magnetic resonance imaging. Correlations of the volumes with the time since trauma and Clinician-Administered PTSD Scale (CAPS) scores were investigated in the PTSD+ group. The volumes of the bilateral cornu ammonis (CA) 2-3, CA4-dentate gyrus (DG), and left subiculum were significantly smaller in the PTSD+ and PTSD- groups than in the controls, but there were no significant differences between the PTSD+ and PTSD- groups. Additionally, the left CA2-3 and CA4-DG volumes reduced more than those on the right side in the PTSD+ and PTSD- groups. The subfield volumes were not related to the time since trauma and the CAPS scores in the PTSD+ group. In conclusion, hippocampal subfield volumes decreased in parents who lost their only child with or without PTSD, and the volumetric reduction may be independent of PTSD and trauma-related. Moreover, the hippocampal volume deficits showed laterality that the left side was affected more than the right, and the hippocampal subfields may show differential vulnerabilities to trauma/PTSD, with the CA2-3 and CA4-DG subfields more sensitive than others.
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Hipocampo/patología , Hijo Único/psicología , Padres/psicología , Trastornos por Estrés Postraumático/patología , Adulto , Anciano , Atrofia , Trastorno Bipolar/patología , Giro Dentado/patología , Femenino , Lateralidad Funcional/fisiología , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/fisiología , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: The volumetry of the hippocampal subregion may provide additional information in the early investigation of amnestic mild cognitive impairment (aMCI) and the T2 signal intensity (T2-SI) of the hippocampal subregion has not been well studied quantitatively by magnetic resonance imaging (MRI) in aMCI. METHODS: Using combined MRI-based hippocampal volumetry and T2-SI at the levels of the whole hippocampus and hippocampal subregion, 18 patients with aMCI and 18 age-matched controls were investigated. RESULTS: Significantly lower left whole hippocampal and hippocampal head volumes and higher T2-SI in the bilateral whole hippocampus and hippocampal head were shown, whereas atrophy of the right whole hippocampus and hippocampal subregion was not significant in aMCI. Additionally, correlations were found among the hippocampal volume, T2-SI and Mini-Mental State Examination (MMSE) scores for aMCI in the whole hippocampus and some hippocampal subregions and an almost perfect correlation was found between T2-SI of the left hippocampal head and MMSE scores regarding aMCI (r = -0.831, P = 0.000). CONCLUSION: Abnormalities of the hippocampal volume and T2-SI were documented in aMCI, whereas T2-SI was implied to be more susceptible than the volume in the pathohistological progression in aMCI. Additionally, T2-SI in the left hippocampal head may be a potential biomarker to facilitate the early diagnosis of aMCI.
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Amnesia/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Amnesia/fisiopatología , Disfunción Cognitiva/fisiopatología , Hipocampo/fisiopatología , HumanosRESUMEN
Growth arrest and DNA-damage-inducible protein 45α (GADD45α) is an important member of the family of growth arrest and DNA damage-inducible (GADD) proteins. The expression patterns and possible roles of GADD45α in Parkinson's disease (PD) are so far less understood. In this study, we found that 1-methyl-4-phenylpyridinium (MPP+) treatment up-regulates the expression of GADD45α in both a time-dependent manner and a dose-dependent manner in human dopamine neuroblastoma M17 cells. The up-regulation of GADD45α was abolished by pretreatment with the c-Jun N-terminal kinases (JNK) inhibitor SP600125 but not the p38 specific inhibitor SB203580. Further study revealed that c-Jun silencing abolished the effects of MPP+ on the expression of GADD45α. Important, ChIP studies verified the ability of c-Jun to bind to the GADD45 promoter. In addition, we found that inhibition of GADD45α by small RNA interference exacerbates the impaired cell viability, LDH release, and apoptosis induced by MPP+. Correspondingly, silence of GADD45 exacerbated Caspase-3 activation induced by MPP+. These data suggested a neuroprotective effect of GADD45α against MPP+ neurotoxicity.
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1-Metil-4-fenilpiridinio/farmacología , Proteínas de Ciclo Celular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Nucleares/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenilpiridinio/uso terapéutico , Análisis de Varianza , Antracenos/farmacología , Western Blotting , Caspasa 3/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular , Inmunoprecipitación de Cromatina , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles , Etiquetado Corte-Fin in Situ , Proteínas Nucleares/antagonistas & inhibidores , Enfermedad de Parkinson/metabolismo , Piridinas , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa , Sales de Tetrazolio , TiazolesRESUMEN
The reduction of hippocampal volume remains controversial in depression because of the variability among individuals in clinical studies. Here, a reliable experimental rat model of depression, established by chronic unpredictable mild stress (CUMS), was used. Thirty rats were randomly divided into two groups (CUMS group and control group). Hippocampal volume was dynamically measured every 2 weeks in a 56-day chronic stress procedure using structural magnetic resonance imaging, and the correlation between the hippocampal volume and the learning and memory changes was investigated. Our results demonstrated that CUMS rats showed significantly smaller volumes of the bilateral hippocampus compared to that of the controls, changing dramatically with the development of CUMS procedure. The left hippocampal volume was reduced earlier and more markedly than the right one from the 2nd week to the 8th week of the CUMS procedure (on the 8th week: left: approximately 15.3 %; right: approximately 8.4 % reduction). Additionally, the hippocampal volume of CUMS rats was significantly negatively correlated with the learning and memory changes. Of note, it showed that the more obviously the hippocampal volume reduced, the more severely the learning and memory damaged. In conclusion, the hippocampal volume decreased gradually and dynamically and was correlated with the impairment of the learning and memory in depression.
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Depresión/patología , Hipocampo/patología , Animales , Modelos Animales de Enfermedad , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
In the realm of acute respiratory infections, coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a global public health challenge. The application of corticosteroids (CSs) in COVID-19 remains a contentious topic among researchers. Accordingly, our team performed a comprehensive meta-analysis of randomized controlled trials (RCTs) to meticulously evaluate the safety and efficacy of CSs in hospitalized COVID-19 patients. To explore efficacy of CSs in the treatment of COVID-19 patients, we meticulously screened RCTs across key databases, including PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, as well as China's CNKI and Wanfang Data. We focused on assessing the 28 days mortality rates. We evaluated the data heterogeneity using the Chi-square test and I2 values, setting significance at 0.1 and 50%. Data from 21 RCTs involving 5721 participants were analyzed. The analysis did not demonstrate a significant association between CSs intervention and the 28 days mortality risk in hospitalized COVID-19 patients (relative risk [RR] = 0.93; 95% confidence interval [95% CI]: 0.84-1.03; P = 0.15). However, subgroup analysis revealed a significant reduction in 28 days mortality among patients with moderate-to-severe COVID-19 (RR at 0.85; 95% CI: 0.76-0.95; P = 0.004). Specifically, short-term CS administration (≤ 3 days) was associated with a substantial improvement in clinical outcomes (RR = 0.24; 95% CI: 0.09-0.63; P = 0.004), as was longer-term use (≥ 8 days) (RR = 0.88; 95% CI: 0.77-0.99; P = 0.04). Additionally, in patients with moderate-to-severe COVID-19, the administration of dexamethasone increased the number of 28 days ventilator-free days (Mean Difference = 1.92; 95% CI: 0.44-3.40; P = 0.01). Methylprednisolone also demonstrated significant benefits in improving clinical outcomes (RR = 0.24; 95% CI: 0.09-0.63; P = 0.004). Our meta-analysis demonstrated that although there is no significant difference in 28 days mortality rates among hospitalized COVID-19 patients, the use of CSs may be beneficial in improving clinical outcomes in moderate or severe COVID-19 patients. There was no significant increase in the occurrence of adverse events associated with the use of CSs. Our meta-analysis provides evidence that while CSs may not be suitable for all COVID-19 patients, they could be effective and safe in severely ill COVID-19 patients. Consequently, it is recommended to administer CSs for personalized treatments in COVID-19 cases to improve the clinical outcomes while minimizing adverse events.
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Tratamiento Farmacológico de COVID-19 , Glucocorticoides , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Humanos , Glucocorticoides/uso terapéutico , Glucocorticoides/efectos adversos , Resultado del Tratamiento , COVID-19/mortalidad , HospitalizaciónRESUMEN
There is increasing evidence that major trauma can adversely affect the brain and cognition. In some cases, trauma may lead to deficits in executive function (EF). The anterior insula may be a causal outflow hub acting to coordinate EF-related brain networks. To clarify the neural underpinnings of EF deficits (EFD) after trauma, we performed a resting-state functional magnetic resonance imaging (rs-fMRI) study of anterior insular subnetworks in adults who have lost their only child. A total of 167 participants completed various psychological and cognitive assessments to assess EF-related deficits. Correlations were computed between abnormal connectivity and cognitive/post-traumatic stress symptoms. The results showed abnormal anterior insular subregion connectivity in the default mode network (DMN), prefrontal lobe, and cerebellum lobe in participants with EFD. No correlation was found between abnormal connectivity and cognitive/post-traumatic stress symptoms in participants with EFD. These results suggest that excessive connections between the insula and DMN could contribute to EFD after trauma. Overall, this study provides novel references into the neural mechanisms of EF status after trauma exposure.
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Disfunción Cognitiva , Imagen por Resonancia Magnética , Adulto , Niño , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Función Ejecutiva , Corteza Prefrontal , Mapeo Encefálico/métodosRESUMEN
Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.
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Ácidos Alcanesulfónicos , Roturas del ADN de Doble Cadena , Translocación Genética , Humanos , Reparación del ADN por Unión de Extremidades , Reparación del ADN/genética , Sistemas CRISPR-CasRESUMEN
Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.
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COVID-19 , Microbioma Gastrointestinal , Trombosis , Humanos , Ratones , Animales , Integrina alfa2beta1/genética , Integrina alfa2beta1/metabolismo , Colágeno/metabolismo , Plaquetas/metabolismo , COVID-19/metabolismoRESUMEN
BACKGROUND: Macrophage migration inhibitory factor (MIF) is important in regulating cell proliferation and apoptosis in both normal and cancerous cells, and may be important in cancer progression and metastasis. In human non-small cell lung cancer (NSCLC), the underlying mechanisms responsible for MIF-dependent regulation of cellular proliferation, and cell death remain poorly appreciated. METHODS: The human H460 lung cancer cell-line was treated with an optimally determined dose of 50 pmol/ml MIF siRNA, following which cell proliferation, cell cycle and apoptosis were analyzed. Additionally, known pathways of apoptosis including expression of Annexin-V, enhanced production of caspases-3 and -4 and expression of the Akt signaling protein were assessed in an attempt to provide insights into the signaling pathways involved in apoptosis following disruption of MIF expression. RESULTS: Specific siRNA sequences markedly decreased MIF expression in H460 cells by 2 to 5-fold as compared with the negative control. Moreover, MIF miRNA dampened not only cellular proliferation, but increased the frequency of apoptotic cells as assessed by cell-surface Annexin-V expression. Entry of cells into apoptosis was partly dependent on enhanced production of caspases -3 and -4 while not affecting the expression of either caspase-8 or the Akt signaling pathway. CONCLUSIONS: In a model of NSCLC, knockdown of MIF mRNA expression dampened H460 proliferation by mechanisms partly dependent on entry of cells into apoptosis and enhanced production of caspase-3 and -4. MIF expression may thus be important in NSCLC progression. Targeting MIF may have clinical utility in the management of human lung cancer.
RESUMEN
Chlorophyll is one of the most important pigments in plants, and the measurement of chlorophyll levels enables real-time monitoring of plant growth, which is of great importance to the vegetation monitoring. Compared with the high cost and time-consuming operation of hyperspectral imaging technique, the spectral reflectance reconstruction technique based on RGB images has the advantages of being inexpensive and fast. In this study, using the example of ginkgo leaves, the spectra were reconstructed from red-green-blue (RGB) images taken by smartphones based on a back propagation (BP) neural network and pseudo-inverse method. Based on a BP neural network, the maximum absolute error between the reconstructed spectra and the reference spectra acquired by the hyperspectral camera was less than 0.038. A partial least squares regression (PLSR) prediction model for chlorophyll content estimation was established using the reconstructed spectra. The R2 and root mean square error (RMSE) of the validation set were 0.8237 and 1.1895%, respectively, there was a high correlation between predicted and measured values. Compared with the pseudo-inverse method, the maximum absolute error of the reconstructed spectra was reduced by 10.9%, the R2 in the chlorophyll prediction results was improved by 12.7%, and the RMSE was reduced by 19.3%. This research showed that reconstructing spectral reflectance based on RGB images can realize real-time measurement of chlorophyll content. It provided a reliable tool for fast and low-cost monitoring of plant physiology and growth conditions.