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While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.
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PURPOSE: To build an Mult-Task Learning (MTL) based Artificial Intelligence(AI) model that can simultaneously predict clinical stage, histology, grade and LNM for cervical cancer before surgery. METHODS: This retrospective and prospective cohort study was conducted from January 2001 to March 2014 for the training set and from January 2018 to November 2021 for the validation set at Beijing Chaoyang Hospital, Capital Medical University. Preoperative clinical information of cervical cancer patients was used. An Artificial Neural Network (ANN) algorithm was used to build the MTL-based AI model. Accuracy and weighted F1 scores were calculated as evaluation indicators. The performance of the MTL model was compared with Single-Task Learning (STL) models. Additionally, a Turing test was performed by 20 gynecologists and compared with this AI model. RESULTS: A total of 223 cervical cancer cases were retrospectively enrolled into the training set, and 58 cases were prospectively collected as independent validation set. The accuracy of this cervical cancer AI model constructed with ANN algorithm in predicting stage, histology, grade and LNM were 75%, 95%, 86% and 76%, respectively. And the corresponding weighted F1 score were 70%, 94%, 86%, and 76%, respectively. The average time consumption of AI simultaneously predicting stage, histology, grade and LNM for cervical cancer was 0.01s (95%CI: 0.01-0.01) per 20 patients. The mean time consumption doctor and doctor with AI were 581.1s (95%CI: 300.0-900.0) per 20 patients and 534.8s (95%CI: 255.0-720.0) per 20 patients, respectively. Except for LNM, both the accuracy and F-score of the AI model were significantly better than STL AI, doctors and AI-assisted doctors in predicting stage, grade and histology. (P < 0.05) The time consumption of AI was significantly less than that of doctors' prediction and AI-assisted doctors' results. (P < 0.05 CONCLUSION: A multi-task learning AI model can simultaneously predict stage, histology, grade, and LNM for cervical cancer preoperatively with minimal time consumption. To improve the conditions and use of the beneficiaries, the model should be integrated into routine clinical workflows, offering a decision-support tool for gynecologists. Future studies should focus on refining the model for broader clinical applications, increasing the diversity of the training datasets, and enhancing its adaptability to various clinical settings. Additionally, continuous feedback from clinical practice should be incorporated to ensure the model's accuracy and reliability, ultimately improving personalized patient care and treatment outcomes.
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Inteligencia Artificial , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Estudios Prospectivos , Persona de Mediana Edad , Adulto , Estadificación de Neoplasias/métodos , Clasificación del Tumor/métodos , Redes Neurales de la Computación , Algoritmos , Anciano , Metástasis Linfática , Estudios de CohortesRESUMEN
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.
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The aim of this study was to systematically investigate structural and functional alterations in amygdala subregions using multimodal magnetic resonance imaging (MRI) in patients with tinnitus with or without affective dysfunction. Sixty patients with persistent tinnitus and 40 healthy controls (HCs) were recruited. Based on a questionnaire assessment, 26 and 34 patients were categorized into the tinnitus patients with affective dysfunction (TPAD) and tinnitus patients without affective dysfunction (TPWAD) groups, respectively. MRI-based measurements of gray matter volume, fractional anisotropy (FA), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), degree centrality (DC), and functional connectivity (FC) were conducted within 14 amygdala subregions for intergroup comparisons. Associations between the MRI properties and clinical characteristics were estimated via partial correlation analyses. Compared with that of the HCs, the TPAD and TPWAD groups exhibited significant structural and functional changes, including white matter integrity (WMI), fALFF, ReHo, DC, and FC alterations, with more pronounced WMI changes in the TPAD group, predominantly within the left auxiliary basal or basomedial nucleus (AB/BM), right central nucleus, right lateral nuclei (dorsal portion), and left lateral nuclei (ventral portion containing basolateral portions). Moreover, the TPAD group exhibited decreased FC between the left AB/BM and left middle occipital gyrus and right superior frontal gyrus (SFG), left basal nucleus and right SFG, and right lateral nuclei (intermediate portion) and right SFG. In combination, these amygdalar alterations exhibited a sensitivity of 65.4% and specificity of 96.9% in predicting affective dysfunction in patients with tinnitus. Although similar structural and functional amygdala remodeling were observed in the TPAD and TPWAD groups, the changes were more pronounced in the TPAD group. These changes mainly involved alterations in functionality and white matter microstructure in various amygdala subregions; in combination, these changes could serve as an imaging-based predictor of emotional disorders in patients with tinnitus.
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Amígdala del Cerebelo , Imagen por Resonancia Magnética , Acúfeno , Humanos , Acúfeno/diagnóstico por imagen , Acúfeno/fisiopatología , Acúfeno/patología , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Amígdala del Cerebelo/fisiopatología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Trastornos del Humor/diagnóstico por imagen , Trastornos del Humor/etiología , Trastornos del Humor/fisiopatología , Trastornos del Humor/patologíaRESUMEN
This study aims to delineate the causal relationships between idiopathic tinnitus in different stages and severity and the morphological properties in specific brain regions. We utilized a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal effects of brain structural attributes on varying severities and stages of tinnitus. Our approach involved harnessing genetic variables derived from extensive genome-wide association studies as instrumental variables, centered mainly on pertinent single-nucleotide polymorphisms associated with tinnitus. Subsequently, we integrated this data with brain structural imaging inputs to facilitate the MR analysis. We also applied reverse MR analysis to pinpoint the critical brain regions implicated in the onset of tinnitus. Our analysis revealed a demonstrable causal relationship between tinnitus and brain structural alterations, including changes primarily within the auditory cortex and hub regions of the limbic system, as well as portions of the frontal-temporal-occipital circuit. We found that individuals exhibiting cortical thickness alterations in the bilateral peri-calcarine and right superior occipital gyrus might have previously experienced tinnitus. Changes in the cortical areas of the right rectus, left inferior frontal gyrus, and right pars-orbitalis appeared unrelated to tinnitus. Furthermore, moderate tinnitus patients showed more pronounced structural alterations. This study substantiates that tinnitus could instigate substantial structural alterations mainly within the auditory-limbic-frontal-visual system, while the reciprocal causality was not supported. Moreover, the data underscores that moderate, rather than severe, tinnitus precipitates the most significant structural changes. Morphological alterations in several specific brain areas either indicate a history of tinnitus or bear no relation to it.
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Encéfalo , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Análisis de la Aleatorización Mendeliana , Acúfeno , Humanos , Acúfeno/genética , Acúfeno/patología , Acúfeno/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Polimorfismo de Nucleótido Simple , Masculino , Femenino , Índice de Severidad de la Enfermedad , Persona de Mediana Edad , AdultoRESUMEN
The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.
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Manganese oxides (MnO2) are commonly prevalent in groundwater, sediment and soil. In this study, we found that oxalate (H2C2O4) dissolved MnO2, leading to the formation of Mn(II)/(III), CO2(aq) and reactive oxygen species (·CO2-/O2·-/H2O2/·OH). Notably, CO2(aq) played a crucial role in ·OH formation, contributing to the degradation of atrazine (ATZ). To elucidate underneath mechanisms, a series of reactions with different gas-liquid ratios (GLR) were conducted. At the GLR of 0.3, 3.76, and + ∞ 79.4 %, 5.32 %, and 5.28 % of ATZ were eliminated, in which the cumulative ·OH concentration was 39.6 µM, 8.11 µM, and 7.39 µM and the cumulative CO2(aq) concentration was 11.2 mM, 4.7 mM, and 2.8 mM, respectively. The proposed reaction pathway was that CO2(aq) participated in the formation of a ternary complex [C2O4-Mn(II)-HCO4·3 H2O]-, which converted to a transition state (TS) as [C2O4-Mn(II)-CO3-OH·3 H2O]-, then decomposed to a complex radical [C2O4-Mn(II)-CO3·3 H2O]·- and ·OH after electron transfer within TS. It was novel to discover the role of CO2(aq) for ·OH yielding during MnO2 dissolution by H2C2O4. This finding helps revealing the overlooked processes that CO2(aq) influenced the fate of ATZ or other organic compounds in environment and providing us ideas for new technique development in contaminant remediation. ENVIRONMENTAL IMPLICATION: Manganese oxides and oxalate are common in soil, sediment and water. Their interactions could induce the formation of Mn(II)/(III), CO2(aq) and ·CO2-/O2·-/H2O2. This study found that atrazine could be effectively removed due to ·OH radicals under condition of high CO2(aq) concentration. The concentrations of Mn (0.0002-8.34 mg·L-1) and CO2(aq) (15-40 mg·L-1) were high in groundwater, and the surface water or rainfall seeps into groundwater and bring organic acids, which might promote the ·OH formation. The results might explain the missing steps of herbicides transformation in these environments and be helpful in developing new techniques in remediation in future.
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Aqueous trivalent manganese [Mn(III)], an important reactive intermediate, is ubiquitous in natural surface water containing humic acid (HA). However, the effect of low-molecular-weight organic acids (LMWOAs) on the formation, stability and reactivity of Mn(III) intermediate is still unknown. In this study, six LMWOAs, including oxalic acid (Oxa), salicylic acid (Sal), catechol (Cat), caffeic acid (Caf), gallic acid (Gal) and ethylene diamine tetraacetic acid (EDTA), were selected to investigate the effects of LMWOAs on the degradation of BPA induced by in situ formed Mn(III)-L in the HA/Mn(II) system under light irradiation. The chromophoric constituents of HA could absorb light radiation and generate superoxide radical to promote the oxidation of Mn(II) to form Mn(III), which was further involved in transformation of BPA. Our results implied that different LMWOAs did significantly impact on Mn(III) production and its degradation of BPA due to their different functional group. EDTA, Oxa and Sal extensively increased the Mn(III) concentration from 50 to 100 µM compared to the system without LMWOAs, following the order of EDTA > Oxa > Sal, and also enhanced the degradation of BPA with the similar patterns. In contrast, Cat, Caf and Gal had an inhibitory effect on the formation of Mn(III), which is likely because they consumed the superoxide radicals generated from irradiated HA, resulting in the inhibition of Mn(II) oxidation and further BPA removal. The product identification and theoretical calculation indicated that a single electron transfer process occurred between Mn(III)-L and BPA, forming BPA radicals and subsequent self-coupling products. Our results demonstrated that the LMWOAs with different structures could alter the cycling process of Mn via complexation and redox reactions, which would provide new implications for the removal of organic pollutants in surface water.
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Microneedles offer minimally invasive, user-friendly, and subcutaneously accessible transdermal drug delivery and have been widely investigated as an effective transdermal delivery system. Ibuprofen is a common anti-inflammatory drug to treat chronic inflammation. It is crucial to develop microneedle patches capable of efficiently delivering ibuprofen through the skin for the effective treatment of arthritis patients requiring repeated medication. In this study, the mechanical properties of a new type of polymer microneedle were studied by finite element analysis, and the experimental results showed that the microneedle could effectively deliver drugs through the skin. In addition, a high ibuprofen-loaded microneedle patch was successfully prepared by micromolding and subjected to evaluation of its infrared spectrum morphology and dissolve degree. The morphology of microneedles was characterized by scanning electron microscopy, and the mechanical properties were assessed using a built linear stretching system. In the in-vitro diffusion cell drug release test, the microneedle released 85.2 ± 1.52% (210 ± 3.7 µg) ibuprofen in the modified Franz diffusion within 4 h, exhibiting a higher drug release compared to other drug delivery methods. This study provides a portable, safe and efficient treatment approach for arthritis patients requiring daily repeated medication.
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Administración Cutánea , Liberación de Fármacos , Ibuprofeno , Agujas , Alcohol Polivinílico , Ibuprofeno/administración & dosificación , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Alcohol Polivinílico/química , Sistemas de Liberación de Medicamentos/instrumentación , Materiales Biocompatibles/química , Animales , Piel/metabolismo , Piel/efectos de los fármacos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Fenómenos Mecánicos , Humanos , Análisis de Elementos FinitosRESUMEN
To explore the causal relationship between age and brain health (cortical atrophy, white matter integrity, white matter hyperintensities and cerebral microbleeds in various brain regions) related multiparameter imaging features using two-sample Mendelian randomization. Age was determined as chronological age of the subject. Cortical volume, white matter micro-integrity, white matter hyperintensity volume and cerebral microbleeds of each brain region were included as phenotypes for brain health. Age and imaging of brain health related genetic data were analysed to determine the causal relationship using inverse-variance weighted model, validated by heterogeneity and horizontal pleiotropy variables. Age is causally related to increased volumes of white matter hyperintensities (ß = 0.151). For white matter micro-integrity, fibres of the inferior cerebellar peduncle (axial diffusivity ß = -0.128, orientation dispersion index ß = 0.173), cerebral peduncle (axial diffusivity ß = -0.136), superior fronto-occipital fasciculus (isotropic volume fraction ß = 0.163) and fibres within the limbic system were causally deteriorated. We also detected decreased cortical thickness of multiple frontal and temporal regions (P < 0.05). Microbleeds were not related with aging (P > 0.05). Aging is a threat of brain health, leading to cortical atrophy mainly in the frontal lobes, as well as the white matter degeneration especially abnormal hyperintensity and deteriorated white matter integrity around the hippocampus.
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The direct utilization of low-light images hinders downstream visual tasks. Traditional low-light image enhancement (LLIE) methods, such as Retinex-based networks, require image pairs. A spiking-coding methodology called intensity-to-latency has been used to gradually acquire the structural characteristics of an image. convLSTM has been used to connect the features. This study introduces a simplified DCENet to achieve unsupervised LLIE as well as the spiking coding mode of a spiking neural network. It also applies the comprehensive coding features of convLSTM to improve the subjective and objective effects of LLIE. In the ablation experiment for the proposed structure, the convLSTM structure was replaced by a convolutional neural network, and the classical CBAM attention was introduced for comparison. Five objective evaluation metrics were compared with nine LLIE methods that currently exhibit strong comprehensive performance, with PSNR, SSIM, MSE, UQI, and VIFP exceeding the second place at 4.4% (0.8%), 3.9% (17.2%), 0% (15%), 0.1% (0.2%), and 4.3% (0.9%) on the LOL and SCIE datasets. Further experiments of the user study in five non-reference datasets were conducted to subjectively evaluate the effects depicted in the images. These experiments verified the remarkable performance of the proposed method.
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Pelvic fractures sometimes lead to injuries of the urinary bladder, which commonly present as gross hematuria, dysuria and lower abdominal pain. As a type of urinary stone, bladder stones are usually secondary to lower urinary tract obstruction, such as benign prostatic hyperplasia, urethral stricture, and neurogenic bladder. The present case report examines an unusual case of a delayed pubic fracture penetrating the bladder, which caused a secondary bladder stone. A 53-year-old man was first hospitalized at The Second Hospital of Jiaxing (Jiaxing, China) in January 2020 because of trauma-induced bleeding in the scalp and abdominal pain. The patient underwent abdominal exploration and partial bowel resection, and his condition stabilized after surgery. After discharge, the patient had regular outpatient check-ups every 2-3 weeks. However, after 3 months, in April 2020, the patient was readmitted to the hospital because of frequent urination, an urgent need for urination and dysuria. Abdominal computed tomography imaging and cystoscopy revealed a pubic fracture that had penetrated the bladder wall, accompanied by a bladder stone. Subsequently, cystolithotomy was performed, which provided significant relief of symptoms once the catheter was removed after 2 weeks. Since then, the patient has been followed up until January 2023 and had remained asymptomatic. Bladder stones caused by necrotic bone fragmentation are rare. Bladder injuries resulting from pelvic fractures can have delayed onset; therefore, clinicians should be aware of the possibility of urogenital injury in such patients. It is crucial for clinicians to comprehend the potential mechanisms involved, analyze the clinical data of patients, closely monitor their condition and implement appropriate treatment measures when necessary.
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Wearable epidermal electronics with non- or minimally-invasive characteristics can collect, transduce, communicate, and interact with accessible physicochemical health indicators on the skin. However, due to the stratum corneum layer, rich information about body health is buried under the skin stratum corneum layer, for example, in the skin interstitial fluid. Microneedle patches are typically designed with arrays of special microsized needles of length within 1000 µm. Such characteristics potentially enable the access and sample of biomolecules under the skin or give therapeutical treatment painlessly and transdermally. Integrating microneedle patches with various electronics allows highly efficient transdermal bioelectronics, showing their great promise for biomedical and healthcare applications. This comprehensive review summarizes and highlights the recent progress on integrated transdermal bioelectronics based on microneedle patches. The design criteria and state-of-the-art fabrication techniques for such devices are initially discussed. Next, devices with different functions, including but not limited to health monitoring, drug delivery, and therapeutical treatment, are highlighted in detail. Finally, key issues associated with current technologies and future opportunities are elaborated to sort out the state of recent research, point out potential bottlenecks, and provide future research directions.
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Agujas , Humanos , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Administración Cutánea , Dispositivos Electrónicos Vestibles , Nanomedicina Teranóstica/métodos , Piel/metabolismo , AnimalesRESUMEN
OBJECTIVES: Potential reverse causality and unmeasured confounding factors are common biases in most neuroimaging studies on tinnitus and central correlates. The causal association of tinnitus with neuroimaging features also remains unclear. This study aimed to investigate the causal relationship of tinnitus with neuroplastic alterations using Mendelian randomization. DESIGN: Summary-level data from a genome-wide association study of tinnitus were derived from UK Biobank (n = 117,882). The genome-wide association study summary statistics for 4 global-brain tissue and 14 sub-brain gray matter volumetric traits were also obtained (n = up to 33,224). A bidirectional Mendelian randomization analysis was conducted to explore the causal relationship between tinnitus and neuroanatomical features at global-brain and sub-brain levels. RESULTS: Genetic susceptibility to tinnitus was causally associated with increased white matter volume (odds ratio [OR] = 2.361, 95% confidence interval [CI], 1.033 to 5.393) and total brain volume (OR = 2.391, 95% CI, 1.047 to 5.463) but inversely associated with cerebrospinal fluid volume (OR = 0.362, 95% CI, 0.158 to 0.826). A smaller gray matter volume in the left Heschl's gyrus and right insular cortex and larger gray matter volume in the posterior division of the left parahippocampal gyrus may lead to an increased risk for tinnitus (OR = 0.978, 95% CI, 0.961 to 0.996; OR = 0.987, 95% CI, 0.976 to 0.998; and OR = 1.015, 95% CI, 1.001 to 1.028, respectively). CONCLUSIONS: Genetic susceptibility to tinnitus was causally associated with increased white matter volume and total brain volume. Volume alteration in several cortical regions may indicate a higher tinnitus risk, and further research is recommended for causality inference at the level of sub-brain regions. Our findings provide genetic evidence for elucidating the underlying pathophysiological mechanisms of tinnitus-related neuroanatomical abnormalities.
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Estudio de Asociación del Genoma Completo , Acúfeno , Humanos , Análisis de la Aleatorización Mendeliana , Acúfeno/genética , Predisposición Genética a la Enfermedad , NeuroimagenRESUMEN
The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.
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Enfermedad de Alzheimer , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Hierro , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedad de Alzheimer/patologíaRESUMEN
Wearable devices have become prevalent in biomedical studies due to their convenient portability and potential utility in biomarker monitoring for healthcare. Accessing interstitial fluid (ISF) across the skin barrier, microneedle (MN) is a promising minimally invasive wearable technology for transdermal sensing and drug delivery. MN has the potential to overcome the limitations of conventional transdermal drug administration, making it another prospective mode of drug delivery after oral and injectable. Subsequently, combining MN with multiple sensing approaches has led to its extensive application to detect biomarkers in ISF. In this context, employing MN platforms and control schemes to merge diagnostic and therapeutic capabilities into theranostic systems will facilitate on-demand therapy and point-of-care diagnostics, paving the way for future MN technologies. A comprehensive analysis of the growing advances of microneedles in biomedical systems is presented in this review to summarize the latest studies for academics in the field and to offer for reference the issues that need to be addressed in MN application for healthcare. Covering an array of novel studies, we discuss the following main topics: classification of microneedles in the biomedical field, considerations of MN design, current applications of microneedles in diagnosis and therapy, and the regulatory landscape and prospects of microneedles for biomedical applications. This review sheds light on the significance of microneedle-based innovations, presenting an analysis of their potential implications and contributions to the community of wearable healthcare technologies. The review provides a comprehensive understanding of the field's current state and potential, making it a valuable resource for academics and clinicians seeking to harness the full potential of MN applications.
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Sistemas de Liberación de Medicamentos , Agujas , Estudios Prospectivos , Microinyecciones , Administración Cutánea , BiomarcadoresRESUMEN
Salmonella enterica, the etiological agent of gastrointestinal and systemic diseases, translocates a plethora of virulence factors through its type III secretion systems to host cells during infection. Among them, SpvB has been reported to harbor an ADP-ribosyltransferase domain in its C terminus, which destabilizes host cytoskeleton by modifying actin. However, whether this effector targets other host factors as well as the function of its N terminus still remains to be determined. Here, we found that SpvB targets clathrin and its adaptor AP-1 (adaptor protein 1) via interactions with its N-terminal domain. Notably, our data suggest that SpvB-clathrin/AP-1 associations disrupt clathrin-mediated endocytosis and protein secretion pathway as well. In addition, knocking down of AP-1 promotes Salmonella intracellular survival and proliferation in host cells.
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Salmonella enterica , Salmonella typhimurium , Salmonella typhimurium/metabolismo , Factor de Transcripción AP-1/metabolismo , Salmonella enterica/metabolismo , Factores de Virulencia/metabolismo , Actinas/metabolismo , Clatrina/metabolismoRESUMEN
Helicobacter pylori (H. pylori) has been regarded as a definite carcinogenic bacterium for gastric cancer (GC). This multi-omics research was designed to investigate the genetic, microbial, and metabolic changes of GC patients when they are infected with H. pylori. We first mined The Cancer Genome Atlas Stomach Adenocarcinoma (STAD) data to identify the key genes and critical pathways in H. pylori-positive individuals with GC compared to H. pylori-negative individuals with GC. Then, fresh stool samples were collected from GC individuals screened for eligibility, and we analyzed the microbial changes and metabolite alterations between H. pylori-positive and H. pylori-negative GC individuals. Finally, we tried to explore the interaction between key gut flora and metabolite changes in GC patients infected with H. pylori. We identified three genes (GCG, APOA1, and IGFBP1) with significant relevance to H. pylori infection, and the survival monogram based on the three H. pylori-related genes showed good predictive ability for overall survival among GC individuals. 16S rRNA sequencing showed that the abundance of Escherichia-Shigella, Bacteroides, Enterococcus, and Lactobacillus was upregulated in GC cases with H. pylori at the level of genus. There exists a great difference in alpha and beta diversity between H. pylori group and non-H. pylori group. The untargeted metabolome analysis identified 295 significant fecal metabolites, and the levels of penitrem E, auberganol, stercobilinogen, and lys thr are upregulated in the H. pylori group. Finally, correlation analysis showed that there exists a significant correlation between the fecal metabolites and gut bacterial strains. This is the first clinical research to investigate the difference between GC patients with H. pylori and GC patients without H. pylori via multi-omics analysis. 16S rRNA sequencing along with untargeted metabolomics demonstrated decreased microbial diversity and metabolic dysregulation in gastric carcinoma individuals with H. pylori infection.IMPORTANCEThis is the first clinical research to systematically expound the difference between gastric cancer (GC) individuals with Helicobacter pylori and GC individuals without H. pylori from the perspective of multi-omics. This clinical study identified significant genes, microbes, and fecal metabolites, which exhibited nice power for differentiating GC individuals with H. pylori infection from GC individuals without H. pylori infection. This study provides a crucial basis for a better understanding of eradication therapy among the GC population.
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We determined the structural and functional alterations in the insula and its subregions in patients with idiopathic tinnitus in order to identify the neural changes involved in the progression from recent onset to chronic tinnitus. We recruited 24 recent-onset tinnitus patients, 32 chronic tinnitus patients and 36 healthy controls. We measured the grey matter volume and fractional amplitude of low-frequency fluctuation of the insula and its subregions and the functional connectivity within the insula and between the insula and the rest of the brain. Relationships between MRI and clinical characteristics were estimated using partial correlation analysis. Both recent-onset and chronic tinnitus patients showed decreased fractional amplitude of low-frequency fluctuation in the insula and its subregions, but only chronic tinnitus patients showed bilateral grey matter atrophy in the ventral anterior insula. Abnormal functional connectivity was detected in recent-onset and chronic tinnitus patients relative to the healthy controls, but functional connectivity differences between recent-onset and chronic tinnitus patients were found in only the auditory-related cortex, frontal cortex and limbic system. Functional alterations (fractional amplitude of low-frequency fluctuation and functional connectivity of the left ventral anterior insula), but not structural changes, were correlated with clinical severity. Bilateral grey matter atrophy in the ventral anterior insula decreased regional activities in the left ventral anterior insula and left posterior insula, and abnormal functional connectivity of the insula subregions with auditory and non-auditory areas were implicated in the progression from recent onset to chronic tinnitus. This suggests that tinnitus generation and development occur in a dynamic manner and involve aberrant multi-structural and functional (regional brain activity and abnormal functional connectivity) reorganization of the insula.