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The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
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NAD/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Carbazoles/farmacología , Línea Celular Tumoral , Células Cultivadas , Citocinas/agonistas , Citocinas/genética , Citocinas/metabolismo , Doxorrubicina/farmacología , Humanos , Redes y Vías Metabólicas , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Nicotinamida Fosforribosiltransferasa/metabolismoRESUMEN
Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho ß (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation of KLB in these HCC cells resulted in a fitness defect more severe than that resulting from inactivation of FGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed that FGFR3 restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
Deep learning techniques have been applied to medical image segmentation and demonstrated expert-level performance. Due to the poor generalization abilities of the models in the deployment in different centres, common solutions, such as transfer learning and domain adaptation techniques, have been proposed to mitigate this issue. However, these solutions necessitate retraining the models with target domain data and annotations, which limits their deployment in clinical settings in unseen domains. We evaluated the performance of domain generalization methods on the task of MRI segmentation of nasopharyngeal carcinoma (NPC) by collecting a new dataset of 321 patients with manually annotated MRIs from two hospitals. We transformed the modalities of MRI, including T1WI, T2WI and CE-T1WI, from the spatial domain to the frequency domain using Fourier transform. To address the bottleneck of domain generalization in MRI segmentation of NPC, we propose a meta-learning approach based on frequency domain feature mixing. We evaluated the performance of MFNet against existing techniques for generalizing NPC segmentation in terms of Dice and MIoU. Our method evidently outperforms the baseline in handling the generalization of NPC segmentation. The MF-Net clearly demonstrates its effectiveness for generalizing NPC MRI segmentation to unseen domains (Dice = 67.59%, MIoU = 75.74% T1W1). MFNet enhances the model's generalization capabilities by incorporating mixed-feature meta-learning. Our approach offers a novel perspective to tackle the domain generalization problem in the field of medical imaging by effectively exploiting the unique characteristics of medical images.
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Imagen por Resonancia Magnética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Imagen por Resonancia Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Femenino , Masculino , AlgoritmosRESUMEN
The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.
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Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Citotoxinas/metabolismo , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/patología , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
Transition-metal-catalyzed C-H activation has greatly benefited the synthesis and development of functional polymer materials, and the construction of multifunctional fused (hetero)cyclic polymers via novel C-H activation-based polyannulations has emerged as a charming but challenging area in recent years. Herein, we report the first cobalt(III)-catalyzed cascade C-H activation/annulation polymerization (CAAP) approach that can efficiently transform readily available aryl thioamides and internal diynes into multifunctional sulfur-containing fused heterocyclic (SFH) polymers. Within merely 3 h, a series of SFH polymers bearing complex and multisubstituted S,N-doped polycyclic units are facilely and efficiently produced with high molecular weights (absolute Mn up to 220400) in excellent yields (up to 99%), which are hard to achieve by traditional methods. The intermediate-terminated SFH polymer can be used as a reactive macromonomer to controllably extend or modify polymer main chains. The structural diversity can be further enriched through facile S-oxidation and N-methylation reactions of the SFH polymers. Benefiting from the unique structures, the obtained polymers exhibit excellent solution processability, high thermal and morphological stability, efficient and readily tunable aggregate-state fluorescence, stimuli-responsive properties, and high and UV-modulatable refractive indices of up to 1.8464 at 632.8 nm. These properties allow the SFH polymers to be potentially applied in diverse fields, including metal ion detection, photodynamic killing of cancer cells, fluorescent photopatterning, and gradient-index optical materials.
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BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Metotrexato , Metilprednisolona , Humanos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Femenino , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Adulto , Metilprednisolona/uso terapéutico , Metilprednisolona/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto Joven , Resultado del Tratamiento , Quimioterapia Combinada , Anciano , Adolescente , Enfermedad AgudaRESUMEN
Preeclampsia (PE) is a multisystem pregnancy disorder characterized by impaired remodeling of placental spiral arteries, which leads to the release of pro-inflammatory cytokines and anti-angiogenic agents. However, treatment options for PE are limited, with termination of pregnancy being the only curative option. In this work, we investigated the effects of human amniotic epithelial cells (hAECs) in PE rat model. The rats were induced with Lipopolysaccharide (LPS) on gestational day (GD) 14.5 followed by injection of hAECs and human umbilical cord mesenchymal stem cells (hUC-MSCs) 24 hours later. The hAECs treatment resulted in a reduction in blood pressure and proteinuria in the PE rat model. Futhermore, hAECs treatmentdecreased levels of pro-inflammatory cytokines, reduced inflammatory cells aggregation, and alleviated the damage to placental spiral arteries by downregulating the expression of anti-angiogenic factor and upregulating proangiogenic factor. In vitro experiments comfirmed that hAECs treatment restored the proliferation, migration, and angiogenesis of LPS-damaged human umbilical vein endothelial cells (hUVECs). Additionally, hAECs treatmenthad positive effects on fetal weight and neurological development in the PE group, with no negative effects onthe physical development or fertility of offspring rats. These results suggested that hAECs transplantation may be a novel adjuvant therapeutic strategy for PE by reducing the inflammatory andenhancing placental spiral artery angiogenesis.
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BACKGROUND: Ethanol elicits a rapid stimulatory effect and a subsequent, prolonged sedative response, which are potential predictors of EtOH consumption by decreasing adenosine signaling; this phenomenon also reflects the obvious sex difference. cAMP-PKA signaling pathway modulation can influence the stimulatory and sedative effects induced by EtOH in mice. This study's objective is to clarify the role of phosphodiesterase (PDE) in mediating the observed sex differences in ethanol responsiveness between male and female animals. METHODS: EtOH was administered intraperitoneally (i.p.) for 7 days to identify the changes in PDE isoforms in response to EtOH treatment. Additionally, EtOH consumption and preference of male and female C57BL/6J mice were assessed using the drinking-in-the-dark (DID) and two-bottle choice (2BC) tests. Further, pharmacological inhibition of PDE7A heterozygote knockout mice was performed to investigate its effects on ethanol-induced stimulation and sedation in both male and female mice. Finally, Western blotting analysis was performed to evaluate the alterations in cAMP-PKA/Epac2 pathways. RESULTS: Ethanol administration resulted in an immediate upregulation in PDE7A expression in female mice, indicating a strong association between PDE7A and ethanol stimulation. Through the pharmacological inhibition of PDE7A KD mice, we have demonstrated, for the first time, that PDE7A selectively attenuates ethanol responsiveness and consumption exclusively in female mice may be associated with the cAMP-PKA/Epac2 pathway and downstream phosphorylation of CREB and ERK1/2. CONCLUSIONS: PDE7A inhibition or knockdown attenuates EtOH responsiveness and consumption exclusively in female mice associated the change of cAMP-PKA/Epac2 signaling pathways, thereby highlighting its potential as a novel therapeutic target for alcohol use disorder.
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Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.
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3',5'-AMP Cíclico Fosfodiesterasas , Enfermedad de Alzheimer , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Femenino , Masculino , Ratones , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , 3',5'-AMP Cíclico Fosfodiesterasas/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismoRESUMEN
Correction for 'A poly(thymine)-templated fluorescent copper nanoparticle hydrogel-based visual and portable strategy for an organophosphorus pesticide assay' by Jihua Chen et al., Analyst, 2019, 144, 2423-2429, https://doi.org/10.1039/C9AN00017H.
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BACKGROUND: To further clarify the acne profile of Chinese adult women, we included 1,156,703 adult women. An artificial intelligence algorithm was used to analyze images taken by high-resolution mobile phones to further explore acne levels in Chinese adult women. METHOD: In this study, we assessed the severity of acne by evaluating patients' selfies through a smartphone application. Furthermore, we gathered basic user information through a questionnaire, including details such as age, gender, skin sensitivity, and dietary habits. RESULTS: This study showed a gradual decrease in acne severity from the age of 25 years. A trough was reached between the ages of 40 and 44, followed by a gradual increase in acne severity. In terms of skin problems and acne severity, we have found that oily skin, hypersensitive skin, frequent makeup application and unhealthy dietary habits can affect the severity of acne. For environment and acne severity, we observed that developed city levels, cold seasons and high altitude and strong radiation affect acne severity in adult women. For the results of the AI analyses, the severity of blackheads, pores, dark circles and skin roughness were positively associated with acne severity in adult women. CONCLUSIONS: AI analysis of high-res phone images in Chinese adult women reveals acne severity trends. Severity decreases after 25, hits a low at 40-44, then gradually rises. Skin type, sensitivity, makeup, diet, urbanization, seasons, altitude, and radiation impact acne. Blackheads, pores, dark circles, and skin roughness are linked to acne severity. These findings inform personalized skincare and public health strategies for adult women.
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Acné Vulgar , Inteligencia Artificial , Adulto , Humanos , Femenino , Acné Vulgar/epidemiología , Acné Vulgar/complicaciones , Piel , China/epidemiologíaRESUMEN
PURPOSE: Agitation is a common behavioural problem following traumatic brain injury (TBI). Intensive care unit (ICU) physicians' perspectives regarding TBI-associated agitation are unknown. Our objective was to describe physicians' beliefs and perceived importance of TBI-associated agitation in critically ill patients. METHODS: Following current standard guidance, we built an electronic, self-administrated, 42-item survey, pretested it for reliability and validity, and distributed it to 219 physicians working in 18 ICU level-1 trauma centres in Canada. We report the results using descriptive statistics. RESULTS: The overall response rate was 93/219 (42%), and 76/93 (82%) respondents completed the full survey. Most respondents were men with ten or more years of experience. Respondents believed that pre-existing dementia (90%) and regular recreational drug use (86%) are risk factors for agitation. Concerning management, 91% believed that the use of physical restraints could worsen agitation, 90% believed that having family at the bedside reduces agitation, and 72% believed that alpha-2 adrenergic agonists are efficacious for managing TBI agitation. Variability was observed in beliefs on epidemiology, sex, gender, age, socioeconomic status, and other pharmacologic options. Respondents considered TBI agitation frequent enough to justify the implementation of management protocols (87%), perceived the current level of clinical evidence on TBI agitation management to be insufficient (84%), and expressed concerns about acute and long-term detrimental outcomes and burden to patients, health care professionals, and relatives (85%). CONCLUSION: Traumatic brain injury-associated agitation in critically ill patients was perceived as an important issue for most ICU physicians. Physicians agreed on multiple approaches to manage TBI-associated agitation although agreement on epidemiology and risk factors was variable.
RéSUMé: OBJECTIF: L'agitation est un problème de comportement courant à la suite d'un traumatisme crânien (TC). Le point de vue des médecins des unités de soins intensifs (USI) sur l'agitation associée aux traumatismes crâniens est inconnu. Notre objectif était de décrire les croyances et l'importance perçue par les médecins de l'agitation associée aux traumatismes crâniens chez les patient·es gravement malades. MéTHODE: Conformément aux lignes directrices standard actuelles, nous avons élaboré un sondage électronique auto-administré de 42 questions, l'avons testé au préalable pour en vérifier la fiabilité et la validité, et l'avons distribué à 219 médecins travaillant dans les USI de 18 centres de traumatologie de niveau 1 au Canada. Les résultats sont présentés à l'aide de statistiques descriptives. RéSULTATS: Le taux de réponse global a été de 93 sur 219 (42 %) et 76 sur 93 (82 %) personnes interrogées ont répondu à l'ensemble du sondage. La plupart des répondant·es étaient des hommes comptant dix ans ou plus d'expérience. Les répondant·es sont d'avis que la démence préexistante (90 %) et la consommation régulière de drogues à des fins récréatives (86 %) sont des facteurs de risque d'agitation. En ce qui concerne la prise en charge, 91 % des répondant·es estiment que l'utilisation de contentions physiques peut aggraver l'agitation, 90 % croient que le fait d'avoir de la famille au chevet du patient ou de la patiente réduit l'agitation et 72 % pensent que les agonistes alpha-2 adrénergiques sont efficaces pour gérer l'agitation causée par les traumatismes crâniens. Une variabilité a été observée dans les croyances concernant l'épidémiologie, le sexe, le genre, l'âge, le statut socio-économique et d'autres options pharmacologiques. Les répondant·es considéraient que l'agitation liée aux traumatismes crâniens était suffisamment fréquente pour justifier la mise en Åuvre de protocoles de prise en charge (87 %), estimaient que le niveau actuel de données probantes cliniques sur la prise en charge de l'agitation causée par un traumatisme crânien était insuffisant (84 %), et se sont dit·es préoccupé·es par les conséquences préjudiciables aiguës et à long terme et par le fardeau pour les patient·es, les professionnel·les de la santé et les proches (85 %). CONCLUSION: L'agitation associée à un traumatisme crânien chez les patient·es gravement malades était perçue comme un problème important pour la plupart des médecins des soins intensifs. Les médecins s'entendaient sur plusieurs approches pour gérer l'agitation associée aux traumatismes crâniens, bien que l'accord sur l'épidémiologie et les facteurs de risque était variable.
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Lesiones Traumáticas del Encéfalo , Médicos , Masculino , Humanos , Femenino , Enfermedad Crítica , Reproducibilidad de los Resultados , Canadá/epidemiología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/epidemiología , Encuestas y CuestionariosRESUMEN
Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.
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Proteína C-Reactiva , Enfermedades Inflamatorias del Intestino , Humanos , Peso Corporal , Modelos BiológicosRESUMEN
Four new γ-lactam alkaloids, suberitolactams A-D (1-4), two new pyridine alkaloids, suberitopyridines A-B (7-8), and two known compounds (5-6) were isolated from the South China Sea sponge Pseudospongosorites suberitoides. The structures were elucidated by detailed 1D and 2D NMR experiments along with HRESIMS analysis and single crystal X-ray diffraction. Compoundsâ 1 and 8 showed moderate to weak antiviral activity against H1â N1 virus with IC50 values of 27.6 and 13.3â µM, respectively.
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Alcaloides , Antivirales , Lactamas , Poríferos , Piridinas , Animales , Alcaloides/aislamiento & purificación , Alcaloides/química , Alcaloides/farmacología , Poríferos/química , Lactamas/química , Lactamas/aislamiento & purificación , Lactamas/farmacología , Piridinas/química , Piridinas/aislamiento & purificación , Piridinas/farmacología , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , China , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Cristalografía por Rayos X , Estructura Molecular , Conformación Molecular , Modelos MolecularesRESUMEN
The aim of this paper was to explore the application of multi-channel synchronized dynamic strain gauges in monitoring the neutral axis (N.A.) position of prestressed concrete box girders. The N.A. position has recently been proposed as an indicator for monitoring the health of bridge structures. Laboratory experiments were conducted on a prestressed T-beam under different prestress level conditions to investigate the correlation between the prestress magnitude and the N.A. position. In the development of the multi-channel synchronized dynamic strain gauges, edge computing was employed to significantly reduce the amount of data transmitted from the sensor nodes on-site. In edge computing, only the dynamic strain response caused by the maximum vehicle load in each minute is transmitted. This approach greatly enhances the monitoring efficiency and enables the realization of on-site non-computer-based monitoring systems. The laboratory test results of the prestressed T-beam showed that the N.A. position tends to move slightly downward as the prestress force increases. In other words, when the prestress force decreases due to loss, the N.A. position exhibits a slight upward movement. This study selected a newly constructed prestressed box girder as the subject for on-site measurement of the N.A. position using multi-channel synchronized dynamic strain gauges shortly after the prestress was applied. The on-site monitoring data indeed revealed a gradual upward movement of the N.A. position. This phenomenon confirmed that soon after the completion of prestressed concrete bridges, there is a gradual loss of prestress due to the significant shrinkage and creep effects of the early-age concrete. The on-site monitoring result aligned with the findings from the laboratory experiments, where the N.A. position was observed to move upward as the prestress decreased.
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Car-lock sounds are designed to inform the lock status of vehicles. However, drivers often experience a lack of confidence regarding whether the car is locked, and car thefts persistently occur, frequently attributed to unlocked doors. Without identification of critical factors for evaluating effects of car-lock sounds on drivers, a strategy to car-lock sound design with increased locking efficiency remains implicit. This study proposes a method to identify critical factors influencing drivers' perceived certainty of car-lock status and behaviours during car-locking. An experiment was conducted to simulate the locking process and verbal protocol analysis was employed to comprehend participants' cognitive processes and behaviours. The results show that mechanical sound yielded high certainty and few hesitations, while tonal and crisp sound elicited low certainty and frequent hesitations. Seven critical factors on participants' behaviours and cognitive processes were identified, which provides a data-driven approach for future research in car-lock sounds evaluation and design.
The effect of car-lock sounds on drivers is significant to inform the locking status of vehicles. However, the strategy for car-lock sounds evaluation remains implicit. This study proposes a method to identify critical factors on drivers' behaviours and cognitive processes that would inform further car-lock sounds evaluation and design.
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Numerous studies have shown a fact that phase transformation and/or reconstruction are likely to occur and play crucial roles in electrochemical scenarios. Nevertheless, a decisive factor behind the diverse photoelectrochemical activity and selectivity of various copper/silicon photoelectrodes is still largely debated and missing in the community, especially the possibly dynamic behaviors of metal catalyst/semiconductor interface. Herein, through in situ X-ray absorption spectroscopy and transmission electron microscope, a model system of Cu nanocrystals with well-defined facets on black p-type silicon (BSi) is unprecedentedly demonstrated to reveal the dynamic phase transformation of forming irreversible silicide at Cu nanocrystal-BSi interface during photoelectrocatalysis, which is validated to originate from the atomic interdiffusion between Cu and Si driven by light-induced dynamic activation process. Significantly, the adaptive junction at Cu-Si interface is activated by an expansion of interatomic Cu-Cu distance for CO2 electroreduction, which efficiently restricts the C-C coupling pathway but strengthens the bonding with key intermediate of *CHO for CH4 yield, resulting in a remarkable 16-fold improvement in the product ratio of CH4/C2 products and an intriguing selectivity switch. This work offers new insights into dynamic structural transformations of metal/semiconductor junction and design of highly efficient catalysts toward photosynthesis.
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Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL.
Asunto(s)
Linfoma de Células B Grandes Difuso , Humanos , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia Tirosina Quinasa/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Transducción de Señal , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Fluorescent polyelectrolytes have attracted enormous attention as functional polymer materials. In contrast with the widely studied conjugated polyelectrolytes with ionic groups in side chains, fluorescent main-chain charged polyelectrolytes (MCCPs) have rarely been explored due to the large synthetic difficulty. Herein, we develop a facile and atom-economical N-heterocyclic carbene-directed cascade C-H activation/annulation polymerization strategy that can transform readily available imidazolium substrates and internal diynes into multifunctional fluorescent MCCPs with complex structures and high molecular weights (absolute Mn up to 135â¯600) in nearly quantitative yields. The presence of multisubstituted polycyclic N-heteroaromatic cations in polymer backbones endow the obtained MCCPs with excellent solution processability, high thermal stability, and dual-state efficient fluorescence in both solution and aggregate states. Benefiting from the strong electron-withdrawing capability of the cationic heterocycles in main chains, multicolored aggregate-state fluorescence can be readily achieved by modifying the substituents around the cationic ring-fused core. Taking advantage of the good photosensitivity of the fluorescent MCCP thin films, multiscale and high-resolution fluorescent photopatterns with different colors can be facilely prepared with potential applications in optical display devices and anticounterfeiting systems. Moreover, the strong electrostatic interactions of these cationic MCCPs with anionic polyelectrolytes enable them to form multicolored fluorescent interfacial polyelectrolyte complexation microfibers with directly visualized internal structures. Such flexible microfibers can be further made into diversified forms of fiber-based macroscopic patterns or painting.
RESUMEN
PURPOSE: To report 2-year results from the Archway clinical trial of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, randomized, multicenter, open-label, active-comparator-controlled trial. PARTICIPANTS: Patients with previously treated nAMD diagnosed within 9 months of screening and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). Patients were followed through 4 complete refill-exchange intervals (â¼2 years). MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline averaged over weeks 44 and 48, weeks 60 and 64, and weeks 88 and 92 (noninferiority margin, -3.9 ETDRS letters). RESULTS: The PDS Q24W was noninferior to monthly ranibizumab, with differences in adjusted mean change in BCVA score from baseline averaged over weeks 44/48, 60/64 and 88/92 of -0.2 (95% confidence interval [CI], -1.8 to +1.3), +0.4 (95% CI, -1.4 to +2.1) and -0.6 ETDRS letters (95% CI, -2.5 to +1.3), respectively. Anatomic outcomes were generally comparable between arms through week 96. Through each of 4 PDS refill-exchange intervals, 98.4%, 94.6%, 94.8%, and 94.7% of PDS Q24W patients assessed did not receive supplemental ranibizumab treatment. The PDS ocular safety profile was generally unchanged from primary analysis. Prespecified ocular adverse events of special interest (AESI) were reported in 59 (23.8%) PDS and 17 (10.2%) monthly ranibizumab patients. The most common AESI reported in both arms was cataract (PDS Q24W, 22 [8.9%]; monthly ranibizumab, 10 [6.0%]). Events in the PDS Q24W arm included (patient incidence) 10 (4.0%) conjunctival erosions, 6 (2.4%) conjunctival retractions, 4 (1.6%) endophthalmitis cases, and 4 (1.6%) implant dislocations. Serum ranibizumab sampling showed that the PDS continuously released ranibizumab over the 24-week refill-exchange interval and ranibizumab serum concentrations were within the range experienced with monthly ranibizumab. CONCLUSIONS: The PDS Q24W showed noninferior efficacy to monthly ranibizumab through approximately 2 years, with approximately 95% of PDS Q24W patients not receiving supplemental ranibizumab treatment in each refill-exchange interval. The AESIs were generally manageable, with learnings continually implemented to minimize PDS-related AEs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.