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BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet-fed ApoE-/- mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet-fed ApoE-/- mice, as shown by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and diminished levels of osteogenic markers (Runx2 and Osterix) in aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Using unbiased protein-RNA screening and molecular validation, we found that AVCAPIR directly interacts with FTO (fat mass and obesity-associated protein), subsequently blocking its N6-methyladenosine demethylase activity. Further transcriptomic and N6-methyladenosine modification epitranscriptomic screening followed by molecular validation confirmed that AVCAPIR hindered FTO-mediated demethylation of CD36 mRNA transcripts, thus enhancing CD36 mRNA stability through the N6-methyladenosine reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1). In turn, the AVCAPIR-dependent increase in CD36 stabilizes its binding partner PCSK9 (proprotein convertase subtilisin/kexin type 9), a procalcific gene, at the protein level, which accelerates the progression of AVC. CONCLUSIONS: We identified a novel piRNA that induced AVC through an RNA epigenetic mechanism and provide novel insights into piRNA-directed theranostics in CAVD.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , ARN Interferente Pequeño , Animales , Calcinosis/metabolismo , Calcinosis/genética , Calcinosis/patología , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Válvula Aórtica/anomalías , Humanos , Ratones , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Masculino , Osteogénesis , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales de Enfermedad , Enfermedad de la Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica/genética , Enfermedad de la Válvula Aórtica/patología , ARN de Interacción con PiwiRESUMEN
BACKGROUND: Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported. METHODS: Here, we took glycogen synthetase kinase 3ß (GSK3ß) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment. RESULTS: NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF. CONCLUSION: Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF.
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Fibrosis , Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Ratones , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Miofibroblastos/metabolismo , Glucógeno/metabolismo , Calcio/metabolismo , Lisosomas/metabolismo , Fibroblastos/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
Hyperspectral imaging is a critical tool for gathering spatial-spectral information in various scientific research fields. As a result of improvements in spectral reconstruction algorithms, significant progress has been made in reconstructing hyperspectral images from commonly acquired RGB images. However, due to the limited input, reconstructing spectral information from RGB images is ill-posed. Furthermore, conventional camera color filter arrays (CFA) are designed for human perception and are not optimal for spectral reconstruction. To increase the diversity of wavelength encoding, we propose to place broadband encoding filters in front of the RGB camera. In this condition, the spectral sensitivity of the imaging system is determined by the filters and the camera itself. To achieve an optimal encoding scheme, we use an end-to-end optimization framework to automatically design the filters' transmittance functions and optimize the weights of the spectral reconstruction network. Simulation experiments show that our proposed spectral reconstruction network has excellent spectral mapping capabilities. Additionally, our novel joint wavelength encoding imaging framework is superior to traditional RGB imaging systems. We develop the deeply learned filter and conduct actual shooting experiments. The spectral reconstruction results have an attractive spatial resolution and spectral accuracy.
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INTRODUCTION: Studies on the relationship between environmental tobacco smoke (ETS) and gestational diabetes mellitus (GDM) are limited. In this study, we aimed to clarify the association between ETS at different trimesters of pregnancy and the risk of GDM among non-smoking pregnant women. METHODS: A total of 16,893 non-smoking mothers from the Southwest Birth Cohort, China, were included in the final analyses. Exposure and outcome measures included self-reported ETS status at different trimesters of pregnancy and GDM diagnosis. Multivariable logistic regression models were constructed to estimate the association between ETS and GDM. RESULTS: The prevalence of ETS exposure was 25.7%. Compared with no ETS, ever ETS had an increased risk of GDM, with an adjusted odds ratio (95% confidence intervals) of 1.21 (1.09, 1.33). The association remained consistent at different trimesters of pregnancy ETS exposure. In the last trimester and with continuous ETS exposure, the risk of GDM increased significantly with the increase in the duration of the exposure. The risk of GDM associated with ever ETS during pregnancy significantly increased in mothers over 30 years old and pre-pregnancy overweight (P for interaction <0.05). CONCLUSIONS: ETS exposure at different trimesters of pregnancy was associated with an increased risk of GDM among non-smoking pregnant women. These findings emphasise the importance of preventing ETS exposure during pregnancy.
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Diabetes Gestacional , Contaminación por Humo de Tabaco , Embarazo , Humanos , Femenino , Adulto , Diabetes Gestacional/epidemiología , Diabetes Gestacional/etiología , Contaminación por Humo de Tabaco/efectos adversos , Estudios de Cohortes , Tercer Trimestre del Embarazo , Sobrepeso , China/epidemiologíaRESUMEN
Coronaviruses employ various strategies for survival, among which the activation of endogenous or exogenous apoptosis stands out, with viral proteins playing a pivotal role. Notably, highly pathogenic coronaviruses such as SARS-CoV-2, SARS-CoV, and MERS-CoV exhibit a greater array of non-structural proteins compared to low-pathogenic strains, facilitating their ability to induce apoptosis via multiple pathways. Moreover, these viral proteins are adept at dampening host immune responses, thereby bolstering viral replication and persistence. This review delves into the intricate interplay between highly pathogenic coronaviruses and apoptosis, systematically elucidating the molecular mechanisms underpinning apoptosis induction by viral proteins. Furthermore, it explores the potential therapeutic avenues stemming from apoptosis inhibition as antiviral agents and the utilization of apoptosis-inducing viral proteins as therapeutic modalities. These insights not only shed light on viral pathogenesis but also offer novel perspectives for cancer therapy.
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Apoptosis , SARS-CoV-2 , Humanos , SARS-CoV-2/fisiología , Proteínas Virales/metabolismo , Proteínas Virales/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , COVID-19/virologíaRESUMEN
The practical, sensitive, and real-time detection of heavy metal ions is an essential and difficult problem. This study presents the design of a unique magnetic electrochemical detection system that can achieve real-time field detection. To enhance the electrochemical performance of the sensor, Fe2O3@C-800, Co/CoO@/C-600, and CoFe2O4@C-600 magnetic composites were synthesized using three MOFs precursors by the solvothermal method. And the morphology structure and electrochemical properties of as-prepared magnetic composites were researched by X-ray diffraction (XRD), Scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS), vibrating sample magnetometer (VSM), specific surface area and porosity analyzer (BET) and differential pulse voltammetry (DPV). The results shown that these composites improve conductivity and stability while preserving the MOFs basic frame structure. Compared with the monometallic MOFs-derived composites, the synergistic effect of the bimetallic composite CoFe2O4@C-600 can significantly enhance the electrochemical performance of the sensor. The linear range for the detection of lead ions was 0.001-60 µM, and the detection limit was 0.0043 µM with a sensitivity of 22.22 µA µM·cm-2 by differential pulse voltammetry. The sensor has good selectivity, stability, reproducibility and can be used for actual sample testing.
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Cobalto , Técnicas Electroquímicas , Plomo , Plomo/análisis , Plomo/química , Cobalto/química , Cobalto/análisis , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Límite de Detección , Hierro/química , Hierro/análisis , Estructuras Metalorgánicas/químicaRESUMEN
BACKGROUND: Focal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation. The diagnosis of FCD is challenging. We generated a radiomics nomogram based on multiparametric magnetic resonance imaging (MRI) to diagnose FCD and identify laterality early. METHODS: Forty-three patients treated between July 2017 and May 2022 with histopathologically confirmed FCD were retrospectively enrolled. The contralateral unaffected hemispheres were included as the control group. Therefore, 86 ROIs were finally included. Using January 2021 as the time cutoff, those admitted after January 2021 were included in the hold-out set (n = 20). The remaining patients were separated randomly (8:2 ratio) into training (n = 55) and validation (n = 11) sets. All preoperative and postoperative MR images, including T1-weighted (T1w), T2-weighted (T2w), fluid-attenuated inversion recovery (FLAIR), and combined (T1w + T2w + FLAIR) images, were included. The least absolute shrinkage and selection operator (LASSO) was used to select features. Multivariable logistic regression analysis was used to develop the diagnosis model. The performance of the radiomic nomogram was evaluated with an area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration and clinical utility. RESULTS: The model-based radiomics features that were selected from combined sequences (T1w + T2w + FLAIR) had the highest performances in all models and showed better diagnostic performance than inexperienced radiologists in the training (AUCs: 0.847 VS. 0.664, p = 0.008), validation (AUC: 0.857 VS. 0.521, p = 0.155), and hold-out sets (AUCs: 0.828 VS. 0.571, p = 0.080). The positive values of NRI (0.402, 0.607, 0.424) and IDI (0.158, 0.264, 0.264) in the three sets indicated that the diagnostic performance of Model-Combined improved significantly. The radiomics nomogram fit well in calibration curves (p > 0.05), and decision curve analysis further confirmed the clinical usefulness of the nomogram. Additionally, the contrast (the radiomics feature) of the FCD lesions not only played a crucial role in the classifier but also had a significant correlation (r = -0.319, p < 0.05) with the duration of FCD. CONCLUSION: The radiomics nomogram generated by logistic regression model-based multiparametric MRI represents an important advancement in FCD diagnosis and treatment.
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Displasia Cortical Focal , Imágenes de Resonancia Magnética Multiparamétrica , Nomogramas , Radiómica , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Displasia Cortical Focal/diagnóstico por imagen , Lateralidad Funcional , Imágenes de Resonancia Magnética Multiparamétrica/métodos , Estudios RetrospectivosRESUMEN
Straw incorporation has been considered as an effective environmental management application to improve soil erosion resistance (SER) and organic carbon sequestration. SER is useful to evaluate soil erosion subjected to concentrated flow. Nevertheless, few studies have been performed to examine how SER varied with the amount of straw incorporation on sloping croplands in high latitude and cool regions. In the current study, the fixed bed scouring tests were conducted in a large hydraulic flume using undisturbed soil samples taken from Hebei small watershed in the black soil region of Northeast China. The response of SER to different straw incorporation amounts (0, 1.125, 2.25, 4.5, 6.75, 9.0 and 13.5 t ha-1) was quantified after three months of straw decomposition. The major influencing factors and the corresponding mechanisms were determined. The findings demonstrated that rill erodibility firstly decreased exponentially with straw incorporation amount (R2 = 0.93), while it slightly increased when straw incorporation amount was more than 9.0 t ha-1. Critical shear stress firstly increased logarithmically (R2 = 0.90) and then slightly decreased when the amount exceeded 9.0 t ha-1. Compared to the treatment of 0 t ha-1, rill erodibility reduced by 17.0%-92.8% and critical shear stress increased by 59.6%-127.2% across different treatments of straw incorporation. Rill erodibility had significant and negative correlations with soil organic matter content, aggregate stability, cohesion, root mass density, straw mass density and straw decomposition amount. The key mechanisms for promoting SER were derived by the direct and indirect effects of straw incorporation and its decomposition on soil physicochemical properties and crop roots. The amount of 9.0 t ha-1 was recommended as the optimum amount of straw incorporation in croplands in Northeast China. These findings are useful to understand how soil erosion resistance responds to the amount of straw incorporation and make rational environmental management policy for semi-humid and cool regions.
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Erosión del Suelo , Suelo , Suelo/química , China , Secuestro de Carbono , PolíticasRESUMEN
Mycotoxin contamination of food crops is a global challenge due to their unpredictable occurrence and severe adverse health effects on humans. Therefore, it is of great importance to develop effective tools to prevent the accumulation of mycotoxins through the food chain. The use of magnetic nanoparticle (MNP)-assisted biosensors for detecting mycotoxin in complex foodstuffs has garnered great interest due to the significantly enhanced sensitivity and accuracy. Within such a context, this review includes the fundamentals and recent advances (2020-2023) in the area of mycotoxin monitoring in food matrices using MNP-based aptasensors and immunosensors. In this review, we start by providing a comprehensive introduction to the design of immunosensors (natural antibody or nanobody, random or site-oriented immobilization) and aptasensors (techniques for aptamer selection, characterization, and truncation). Meanwhile, special attention is paid to the multifunctionalities of MNPs (recoverable adsorbent, versatile carrier, and signal indicator) in preparing mycotoxin-specific biosensors. Further, the contribution of MNPs to the multiplexing determination of various mycotoxins is summarized. Finally, challenges and future perspectives for the practical applications of MNP-assisted biosensors are also discussed. The progress and updates of MNP-based biosensors shown in this review are expected to offer readers valuable insights about the design of MNP-based tools for the effective detection of mycotoxins in practical applications.
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Técnicas Biosensibles , Nanopartículas de Magnetita , Micotoxinas , Humanos , Micotoxinas/análisis , Técnicas Biosensibles/métodos , Inmunoensayo/métodos , Productos AgrícolasRESUMEN
The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.
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Neoplasias , Quinolinas , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias/tratamiento farmacológico , Indoles/efectos adversos , Quinolinas/efectos adversosRESUMEN
Serum samples were collected from 54 hepatitis B e antigen (HBeAg)-positive Chinese patients infected with hepatitis B virus (HBV) subgenotype B2 or C2. They were compared for transmission efficiency using same volume of samples or infectivity using same genome copy number. Adding polyethylene glycol (PEG) during inoculation did not increase infectivity of fresh samples but markedly increased infectivity following prolonged sample storage. Differentiated HepaRG cells infected without PEG produced more hepatitis B surface antigen (HBsAg) and higher HBsAg/HBeAg ratio than sodium taurocholate cotransporting polypeptide (NTCP)-reconstituted HepG2 cells infected with PEG. They better supported replication of core promoter mutant in contrast to wild-type (WT) virus by HepG2/NTCP cells. Overall, subgenotype C2 samples had higher viral load than B2 samples, and in general produced more HBeAg, HBsAg, and replicative DNA following same-volume inoculation. Precore mutant was more prevalent in subgenotype B2 and had reduced transmission efficiency. When same genome copy number of viral particles was inoculated, viral signals were not necessarily higher for three WT C2 isolates than four WT B2 isolates. Using viral particles generated from cloned HBV genome, three WT C2 isolates showed slightly reduced infectivity than three B2 isolates. In conclusion, subgenotype C2 serum samples had higher transmission efficiency than B2 isolates in association with higher viral load and lower prevalence of precore mutant, but not necessarily higher infectivity. PEG-independent infection by HBV viremic serum samples is probably attributed to a labile host factor.
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Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B , Humanos , Genotipo , Antígenos e de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Polietilenglicoles , Pueblos del Este de Asia , Hepatitis B/transmisión , Hepatitis B/virología , Células Hep G2RESUMEN
Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS-STING-mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS-CoV-2 infection, responsible for the COVID-19 pandemic, triggers cGAS-STING activation. cGAS-STING activation can trigger IRF3-Type I interferon (IFN) and autophagy-mediated antiviral activity. Although viral evasion of STING-triggered IFN-mediated antiviral function has been well studied, studies concerning viral evasion of STING-triggered autophagy-mediated antiviral function are scarce. In the present study, we have discovered that SARS-CoV-2 ORF3a is a unique viral protein that can interact with STING and disrupt the STING-LC3 interaction, thus blocking cGAS-STING-induced autophagy but not IRF3-Type I IFN induction. This novel function of ORF3a, distinct from targeting autophagosome-lysosome fusion, is a selective inhibition of STING-triggered autophagy to facilitate viral replication. We have also found that activation of bat STING can induce autophagy and antiviral activity despite its defect in IFN induction. Furthermore, ORF3a from bat coronaviruses can block bat STING-triggered autophagy and antiviral function. Interestingly, the ability to inhibit STING-induced autophagy appears to be an acquired function of SARS-CoV-2 ORF3a, since SARS-CoV ORF3a lacks this function. Taken together, these discoveries identify ORF3a as a potential target for intervention against COVID-19.
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COVID-19 , Quirópteros , Interferón Tipo I , Animales , Humanos , Antivirales , Autofagia , Inmunidad Innata , Proteínas de la Membrana/genética , Nucleotidiltransferasas , Pandemias , SARS-CoV-2/metabolismoRESUMEN
During March 2022 to January 2023, two Omicron waves hit Shanghai and caused a massive number of reinfections. To better understand the incidence and clinical characteristics of SARS-CoV-2 reinfection in Shanghai, China, we conducted a multicenter cohort study. COVID-19 patients first infected with BA.2 (March 1, 2022-May 23, 2022) who were quarantined in Huashan Hospital, Renji Hospital, and Shanghai Jing'an Central Hospital were followed up for reinfection from June 1, 2022 to January 31, 2023. Of 897 primary infections, 148 (16.5%) experienced reinfection. Incidence rate of reinfection was 0.66 cases per 1000 person-days. Female gender (adjusted odds ratio [aOR]= 2.19, 95% confidence interval [CI]: 1.29-3.83) was a risk factor for reinfection. The four most common symptoms of reinfections during the circulation of BA.5 sublineages were cough (62.59%), sore throat (54.42%), fatigue (48.98%), and fever (42.57%). Having received a booster vaccination was not associated with reduced severity of reinfection in comparison with not having received booster vaccination. After matched 1:1 by age and sex, we found that reinfections with BA.5 sublineages had significantly lower occurrence and severity of fever, fatigue, sore throat, and cough, as compared to primary infections with BA.5 sublineages. SARS-CoV-2 Omicron reinfections were less severe than Omicron primary infections during the circulation of the same subvariant. Protection offered by both vaccination and previous infection was poor against SARS-CoV-2 reinfection.
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COVID-19 , Faringitis , Femenino , Humanos , China/epidemiología , Estudios de Cohortes , Tos , COVID-19/epidemiología , Fatiga , Fiebre , Incidencia , Dolor , Reinfección/epidemiología , SARS-CoV-2 , MasculinoRESUMEN
Hyperspectral imaging attempts to determine distinctive information in spatial and spectral domain of a target. Over the past few years, hyperspectral imaging systems have developed towards lighter and faster. In phase-coded hyperspectral imaging systems, a better coding aperture design can improve the spectral accuracy relatively. Using wave optics, we post an equalization designed phase-coded aperture to achieve desired equalization point spread functions (PSFs) which provides richer features for subsequent image reconstruction. During the reconstruction of images, our raised hyperspectral reconstruction network, CAFormer, achieves better results than the state-of-the-art networks with less computation by substituting self-attention with channel-attention. Our work revolves around the equalization design of the phase-coded aperture and optimizes the imaging process from three aspects: hardware design, reconstruction algorithm, and PSF calibration. Our work is putting snapshot compact hyperspectral technology closer to a practical application.
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Alvarez lenses are known for their ability to achieve a broad range of optical power adjustment by utilizing complementary freeform surfaces. However, these lenses suffer from optical aberrations, which restrict their potential applications. To address this issue, we propose a field of view (FOV) attention image restoration model for continuous zooming. In order to simulate the degradation of optical zooming systems based on Alvarez lenses (OZA), a baseline OZA is designed where the polynomial for the Alvarez lenses consists of only three coefficients. By computing spatially varying point spread functions (PSFs), we simulate the degraded images of multiple zoom configurations and conduct restoration experiments. The results demonstrate that our approach surpasses the compared methods in the restoration of degraded images across various zoom configurations while also exhibiting strong generalization capabilities under untrained configurations.
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Due to severe noise and extremely low illuminance, restoring from low-light images to normal-light images remains challenging. Unpredictable noise can tangle the weak signals, making it difficult for models to learn signals from low-light images, while simply restoring the illumination can lead to noise amplification. To address this dilemma, we propose a multi-stage model that can progressively restore normal-light images from low-light images, namely Dark2Light. Within each stage, We divide the low-light image enhancement (LLIE) into two main problems: (1) illumination enhancement and (2) noise removal. Firstly, we convert the image space from sRGB to linear RGB to ensure that illumination enhancement is approximately linear, and design a contextual transformer block to conduct illumination enhancement in a coarse-to-fine manner. Secondly, a U-Net shaped denoising block is adopted for noise removal. Lastly, we design a dual-supervised attention block to facilitate progressive restoration and feature transfer. Extensive experimental results demonstrate that the proposed Dark2Light outperforms the state-of-the-art LLIE methods both quantitatively and qualitatively.
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The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Femenino , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Proteínas de Fusión OncogénicaRESUMEN
Aconitum L. poisoning is a major type of poisoning caused by herbal medicines in many countries. However, despite its toxicity, Aconitum L. is still used because of its therapeutic value. Fuzi, the lateral root of Aconitum L., is one of the most important pharmacological parts. It is necessary for rational medication to figure out the types and contents of toxic Aconitum alkaloids (AAs) in Fuzi and its processed products. The present study aims to investigate the spatial distribution of toxic AAs in Fuzi and the quantification of AAs in various processing products through mass spectrometry methods. In this study, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) was used to directly image the sections of raw Fuzi. The results showed a high content of diester alkaloids (DAs) and a relatively uniform distribution in the sections, while the content of monoester alkaloids (MAs) was low and uneven in the sections, distributed in the cortex, epidermis, vascular column, and other parts of the tissues. The content of non-ester alkaloids (NAs) was relatively minimum, and most of the NAs were distributed in the vascular column and the tightly connected cortex of the tissue. To further investigate the difference between raw and processed Fuzi, 60 known compounds were identified using UHPLC-QTOF-MS. The total contents of alkaloids in 7 processed Fuzi were lower than that in Shengfupian (SFP). Paofupian (PFP), Paotianxiong (PTX), Paofupian (PFP*), Danfupian (DFP), and Shufupian (SFP*) were the least similar. Zhengfupian (ZFP) and Chaofupian (CFP) had significantly reduced toxicity and increased efficacy compared with other processed products because the contents of active alkaloids in other processed products were also reduced. Understanding the distribution of metabolites and the composition changes after processing can guide users and herbal manufacturers to carefully choose the relatively safe and better therapeutic species of Fuzi. The information gathered from this study can contribute towards the improved and effective management of therapeutically important, nonetheless toxic, drugs such as Aconitum L.
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Aconitum , Alcaloides , Medicamentos Herbarios Chinos , Aconitum/química , Cromatografía Líquida de Alta Presión/métodos , Alcaloides/análisis , Alcaloides/química , Alcaloides/farmacología , Medicamentos Herbarios Chinos/análisis , Raíces de PlantasRESUMEN
Using Mendelian Randomization (MR) and large-scale Genome-Wide Association Study (GWAS) data, this study aimed to investigate the potential causative relationship between testosterone and sex hormone-binding globulin (SHBG) levels and the onset of several cancers, including pathway enrichment analyses of single nucleotide polymorphisms (SNPs) associated with cancer allowed for a comprehensive bioinformatics approach, which offered a deeper biological understanding of these relationships. The results indicated that increased testosterone levels in women were associated with a higher risk of breast and cervical cancers but a lower risk of ovarian cancer. Conversely, increased testosterone was linked to lower stomach cancer risk for men, whereas high SHBG levels were related to decreased risks of breast and prostate cancers. The corresponding genes of the identified SNPs, as revealed by pathway enrichment analysis, were involved in significant metabolic and proliferative pathways. These findings emphasize the need for further research into the biological mechanisms behind these associations, paving the way for potential targeted interventions in preventing and treating these cancers.
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Neoplasias , Testosterona , Masculino , Humanos , Femenino , Globulina de Unión a Hormona Sexual/análisis , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias/genéticaRESUMEN
INTRODUCTION: The SARS-CoV-2 Omicron variant has decreased virulence and pathogenicity, yet the number of Omicron infections worldwide is unprecedentedly high, with rather high mortality and severe disease rate. Chronic kidney disease (CKD) patients are particularly vulnerable to the SARS-CoV-2 Omicron variant and have unique clinical outcomes. METHODS: We retrospectively collected data from 2140 hospitalized patients with SARS-CoV-2 Omicron variant infection from March 29, 2022, to May 17, 2022. Demographic characteristics, ancillary examination results, and clinical treatments were described. Occurrence of critical COVID-19 or death and time of positive-to-negative conversion was defined as primary outcomes. The presence of COVID-19 pneumonia and the usage of respiratory or circulatory support was defined as secondary outcomes. Univariate or multivariate logistic regression analyses were performed to identify risk factors for primary outcomes. RESULTS: 15.74% of CKD patients infected with the SARS-CoV-2 Omicron variant ended up with critical COVID-19 or death. Pre-existing CKD was a risk factor for critical COVID-19 or death and prolonged time of positive-to-negative conversion of SARS-CoV-2. Nirmatrelvir-ritonavir facilitated viral clearance among COVID-19 patients with non-severe CKD. CONCLUSION: We found patients with CKD and COVID-19 due to Omicron experienced worse clinical outcomes and prolonged time of positive-to-negative conversion of SARS-CoV-2 compared to patients without CKD, which helps rationalize limited medical resources and offers guidance for appropriate clinical treatments.