RESUMO
Biomimetic neuromorphic sensing systems, inspired by the structure and function of biological neural networks, represent a major advancement in the field of sensing technology and artificial intelligence. This review paper focuses on the development and application of electrolyte gated transistors (EGTs) as the core components (synapses and neuros) of these neuromorphic systems. EGTs offer unique advantages, including low operating voltage, high transconductance, and biocompatibility, making them ideal for integrating with sensors, interfacing with biological tissues, and mimicking neural processes. Major advances in the use of EGTs for neuromorphic sensory applications such as tactile sensors, visual neuromorphic systems, chemical neuromorphic systems, and multimode neuromorphic systems are carefully discussed. Furthermore, the challenges and future directions of the field are explored, highlighting the potential of EGT-based biomimetic systems to revolutionize neuromorphic prosthetics, robotics, and human-machine interfaces. Through a comprehensive analysis of the latest research, this review is intended to provide a detailed understanding of the current status and future prospects of biomimetic neuromorphic sensory systems via EGT sensing and integrated technologies.
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Biomimética , Eletrólitos , Redes Neurais de Computação , Transistores Eletrônicos , Biomimética/instrumentação , Eletrólitos/química , Humanos , Técnicas Biossensoriais/instrumentação , Robótica/instrumentação , Materiais Biomiméticos/químicaRESUMO
Dynamic glucose monitoring is important to reduce the risk of metabolic diseases such as diabetes. Wearable biosensors based on organic electrochemical transistors (OECTs) have been developed due to their excellent signal amplification capabilities and biocompatibility. However, traditional wearable biosensors are fabricated on flat substrates with limited gas permeability, resulting in the inefficient evaporation of sweat, reduced wear comfort, and increased risk of inflammation. Here, we proposed breathable OECT-based glucose sensors by designing a porous structure to realize optimal breathable and stretchable properties. The gas permeability of the device and the relationship between electrical properties under different tensile strains were carefully investigated. The OECTs exhibit exceptional electrical properties (gm ~1.51 mS and Ion ~0.37 mA) and can retain up to about 44% of their initial performance even at 30% stretching. Furthermore, obvious responses to glucose have been demonstrated in a wide range of concentrations (10-7-10-4 M) even under 30% strain, where the normalized response to 10-4 M is 26% and 21% for the pristine sensor and under 30% strain, respectively. This work offers a new strategy for developing advanced breathable and wearable bioelectronics.
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Técnicas Biossensoriais , Glicemia , Automonitorização da Glicemia , Porosidade , Técnicas Biossensoriais/métodos , Glucose , Transistores EletrônicosRESUMO
BACKGROUND: Coronary heart disease (CHD) has become the leading cause of death and one of the most serious epidemic diseases worldwide. CHD is characterized by urgency, danger and severity, and dynamic treatment strategies for CHD patients are needed. We aimed to build and validate an AI model for dynamic treatment recommendations for CHD patients with the goal of improving patient outcomes and learning best practices from clinicians to help clinical decision support for treating CHD patients. METHODS: We formed the treatment strategy as a sequential decision problem, and applied an AI supervised reinforcement learning-long short-term memory (SRL-LSTM) framework that combined supervised learning (SL) and reinforcement learning (RL) with an LSTM network to track patients' states to learn a recommendation model that took a patient's diagnosis and evolving health status as input and provided a treatment recommendation in the form of whether to take specific drugs. The experiments were conducted by leveraging a real-world intensive care unit (ICU) database with 13,762 admitted patients diagnosed with CHD. We compared the performance of the applied SRL-LSTM model and several state-of-the-art SL and RL models in reducing the estimated in-hospital mortality and the Jaccard similarity with clinicians' decisions. We used a random forest algorithm to calculate the feature importance of both the clinician policy and the AI policy to illustrate the interpretability of the AI model. RESULTS: Our experimental study demonstrated that the AI model could help reduce the estimated in-hospital mortality through its RL function and learn the best practice from clinicians through its SL function. The similarity between the clinician policy and the AI policy regarding the surviving patients was high, while for the expired patients, it was much lower. The dynamic treatment strategies made by the AI model were clinically interpretable and relied on sensible clinical features extracted according to monitoring indexes and risk factors for CHD patients. CONCLUSIONS: We proposed a pipeline for constructing an AI model to learn dynamic treatment strategies for CHD patients that could improve patient outcomes and mimic the best practices of clinicians. And a lot of further studies and efforts are needed to make it practical.
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Doença das Coronárias , Sistemas de Apoio a Decisões Clínicas , Algoritmos , Inteligência Artificial , Doença das Coronárias/terapia , Humanos , Unidades de Terapia IntensivaRESUMO
Wearable biosensing and food safety inspection devices with high thermal stability, high brightness, and broad near-infrared (NIR) phosphor-converted light-emitting diodes (pc-LEDs) could accelerate the next-generation NIR light applications. In this work, NIR La3-xGdxGa5GeO14:Cr3+ (x = 0 to 1.5) phosphors were successfully fabricated by a high-temperature solid-state method. Here, by doping Gd3+ ions into the La3+ sites in the La3Ga5GeO14 matrix, a 7.9-fold increase in the photoluminescence (PL) intensity of the Cr3+ ions, as well as a remarkably broadened full width at half-maximum (FWHM) of the corresponding PL spectra, is achieved. The enhancements in the PL, PLE intensity, and FWHM are attributed to the suppression of the nonradiative transition process of Cr3+ when Gd3+ ions are doped into the host, which can be demonstrated by the decay curves. Moreover, the La1.5Gd1.5Ga5GeO14:Cr3+ phosphor displays an abnormally negative thermal phenomenon that the integral PL intensity reaches 131% of the initial intensity when the ambient temperature increases to 160 °C. Finally, the broadband NIR pc-LED was fabricated based on the as-explored La1.5Gd1.5Ga5GeO14:Cr3+ phosphors combined with a 460 nm chip, and the potential applications for the broadband NIR pc-LEDs were discussed in detail.
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Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.
Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Proteínas Semelhantes a Angiopoietina/metabolismo , Ácidos Graxos/metabolismo , Hormônios Peptídicos/metabolismo , Período Pós-Prandial , Proteína 3 Semelhante a Angiopoietina , Proteína 8 Semelhante a Angiopoietina , Biomarcadores/metabolismo , HumanosRESUMO
BACKGROUND: With the wide application of Electronic Medical Record (EMR) systems, it has become a daily work for doctors using keyboards to input clinical information into the EMR system. Chinese Input Method Engine (IME) is essential for doctors to convert pinyin to Chinese characters, and an efficient IME would improve doctors' healthcare work. We developed a tool (called TestIME) to evaluating the efficiency of the current IMEs used in doctors' working scenario. The proposed TestIME consists of four major function modules: 1) Test tasks assignment, to ensure that participants using different IMEs to complete the same test task in a random order; 2) IME automatic switching, to automatically switch the input method engines without changing the experimental settings; 3) participants' behavior monitoring, to record the participants' keystrokes and timestamp during the typing process; 4) questionnaire, to collect the participants' subjective data. In addition, we designed a preliminary experiment to demonstrate the usability of TestIME. We selected three sentences from EMR corpus and news corpus as test texts respectively, and recruited four participants in a medical school to complete text entry tasks using the TestIME. RESULTS: Our TestIME was able to generate 72 files that record the detailed participants' keyboard behavior while transcribing test texts, and 4 questionnaires that reflect participants' psychological states. These profiles can be downloaded in a structured format (CSV) from the TestIME for further analysis. CONCLUSIONS: We developed a tool (TestIME) to evaluate Chinese input methods in the EMR entry tasks. In the given text input scenario in healthcare, the TestIME is capable to record doctors' keyboard behavior, frequently used Chinese terms, IME usability feedback etc. These user profiles are important to improve current IME tools for doctors and further improve healthcare service.
Assuntos
Registros Eletrônicos de Saúde , Idioma , China , Humanos , Médicos , Inquéritos e Questionários , Interface Usuário-ComputadorRESUMO
BACKGROUND: The financial relationship between physicians and industries has become a hotly debated issue globally. The Physician Payments Sunshine Act of the US Affordable Care Act (2010) promoted transparency of the transactions between industries and physicians by making remuneration data publicly accessible in the Open Payments Program database. Meanwhile, according to the World Health Organization, the majority of all noncommunicable disease deaths were caused by cardiovascular disease. OBJECTIVE: This study aimed to investigate the distribution of non-research and non-ownership payments made to thoracic surgeons, to explore the regularity of financial relationships between industries and thoracic surgeons. METHODS: Annual statistical data were obtained from the Open Payments Program general payment dataset from 2014-2016. We characterized the distribution of annual payments with single payment transactions greater than US $10,000, quantified the major expense categories (eg, Compensation, Consulting Fees, Travel and Lodging), and identified the 30 highest-paying industries. Moreover, we drew out the financial relations between industries to thoracic surgeons using chord diagram visualization. RESULTS: The three highest categories with single payments greater than US $10,000 were Royalty or License, Compensation, and Consulting Fees. Payments related to Royalty or License transferred from only 5.38% of industries to 0.75% of surgeons with the highest median (US $13,753, $11,992, and $10,614 respectively) in 3-year period. In contrast, payments related to Food and Beverage transferred from 93.50% of industries to 98.48% of surgeons with the lowest median (US $28, $27, and $27). The top 30 highest-paying industries made up approximately 90% of the total payments (US $21,036,972, $23,304,996, and $28,116,336). Furthermore, just under 9% of surgeons received approximately 80% of the total payments in each of the 3 years. Specifically, the 100 highest cumulative payments, accounting for 52.69% of the total, transferred from 27 (6.05%) pharmaceutical industries to 86 (1.89%) thoracic surgeons from 2014-2016; 7 surgeons received payments greater than US $1,000,000; 12 surgeons received payments greater than US $400,000. The majority (90%) of these surgeons received tremendous value from only one industry. CONCLUSIONS: There exists a great discrepancy in the distribution of payments by categories. Royalty or License Fees, Compensation, and Consulting Fees are the primary transferring channels of single large payments. The massive transfer from industries to surgeons has a strong "apical dominance" and excludability. Further research should focus on discovering the fundamental driving factors for the strong concentration of certain medical devices and how these payments will affect the industry itself.
Assuntos
Bases de Dados Factuais/economia , Patient Protection and Affordable Care Act/normas , Cirurgiões/economia , Compensação e Reparação , História do Século XXI , Humanos , Tórax , Estados UnidosRESUMO
BACKGROUND: Health question-answering (QA) systems have become a typical application scenario of Artificial Intelligent (AI). An annotated question corpus is prerequisite for training machines to understand health information needs of users. Thus, we aimed to develop an annotated classification corpus of Chinese health questions (Qcorp) and make it openly accessible. METHODS: We developed a two-layered classification schema and corresponding annotation rules on basis of our previous work. Using the schema, we annotated 5000 questions that were randomly selected from 5 Chinese health websites within 6 broad sections. 8 annotators participated in the annotation task, and the inter-annotator agreement was evaluated to ensure the corpus quality. Furthermore, the distribution and relationship of the annotated tags were measured by descriptive statistics and social network map. RESULTS: The questions were annotated using 7101 tags that covers 29 topic categories in the two-layered schema. In our released corpus, the distribution of questions on the top-layered categories was treatment of 64.22%, diagnosis of 37.14%, epidemiology of 14.96%, healthy lifestyle of 10.38%, and health provider choice of 4.54% respectively. Both the annotated health questions and annotation schema were openly accessible on the Qcorp website. Users can download the annotated Chinese questions in CSV, XML, and HTML format. CONCLUSIONS: We developed a Chinese health question corpus including 5000 manually annotated questions. It is openly accessible and would contribute to the intelligent health QA system development.
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Inteligência Artificial , Informação de Saúde ao Consumidor , Comportamento de Busca de Informação , Informática Médica , China , HumanosRESUMO
BACKGROUND: In question answering (QA) system development, question classification is crucial for identifying information needs and improving the accuracy of returned answers. Although the questions are domain-specific, they are asked by non-professionals, making the question classification task more challenging. OBJECTIVE: This study aimed to classify health care-related questions posted by the general public (Chinese speakers) on the Internet. METHODS: A topic-based classification schema for health-related questions was built by manually annotating randomly selected questions. The Kappa statistic was used to measure the interrater reliability of multiple annotation results. Using the above corpus, we developed a machine-learning method to automatically classify these questions into one of the following six classes: Condition Management, Healthy Lifestyle, Diagnosis, Health Provider Choice, Treatment, and Epidemiology. RESULTS: The consumer health question schema was developed with a four-hierarchical-level of specificity, comprising 48 quaternary categories and 35 annotation rules. The 2000 sample questions were coded with 2000 major codes and 607 minor codes. Using natural language processing techniques, we expressed the Chinese questions as a set of lexical, grammatical, and semantic features. Furthermore, the effective features were selected to improve the question classification performance. From the 6-category classification results, we achieved an average precision of 91.41%, recall of 89.62%, and F1 score of 90.24%. CONCLUSIONS: In this study, we developed an automatic method to classify questions related to Chinese health care posted by the general public. It enables Artificial Intelligence (AI) agents to understand Internet users' information needs on health care.
Assuntos
Informação de Saúde ao Consumidor/métodos , Atenção à Saúde/tendências , Internet/estatística & dados numéricos , Processamento de Linguagem Natural , Povo Asiático , Humanos , Inquéritos e QuestionáriosRESUMO
The exploration of the agricultural carbon emission reduction effect of digital rural construction offers a promising path towards achieving dual carbon goals. This study establishes an evaluation system for digital rural construction and analyzes its impact on agricultural carbon emissions using various creative techniques including panel fixed effects, mediation effects, threshold effects, and spatial Durbin models based on provincial panel data from 2011 to 2021.It is found that: (1) The impact of digital rural construction on agricultural carbon emissions exhibits a "inverted U-shaped" pattern, with a nonlinear effect on emissions through promoting agricultural green total factor productivity and adjusting agricultural structure.(2) Digital rural construction has both promoting and inhibiting effects on agricultural carbon emissions, both locally and in adjacent areas. It also demonstrates a threshold effect, with rural human capital as the sole threshold. Once the threshold value 8.830 is surpassed, the agricultural carbon emission reduction effect becomes prominent.(3)Digital rural construction has a dual effect on local agricultural carbon emissions in terms of both promoting and then restraining the emissions, which has a spatial spill-over effect in the neighboring areas. This study contributes to our understanding of carbon reduction pathways by highlighting the comprehensive utilization of digital rural construction and expanding research on the dynamic context of its impact on carbon emissions.
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Agricultura , Carbono , Humanos , China , Desenvolvimento EconômicoRESUMO
Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.
Assuntos
Fosfatos , Insuficiência Renal Crônica , Ratos , Camundongos , Animais , Fosfatos/metabolismo , Trocador 3 de Sódio-Hidrogênio , Roedores , Absorção Intestinal , Insuficiência Renal Crônica/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismoRESUMO
Complex and high-security-level anti-counterfeiting strategies with multiple luminescent modes are extremely critical for meeting the requirement of constantly developing information storage and information security. In this work, Tb3+ ions doped Sr3Y2Ge3O12 (SYGO) and Tb3+/Er3+ co-doped SYGO phosphors are successfully fabricated and are unitized for anti-counterfeiting and information encoding under distinct stimuli sources. The green photoluminescence (PL), long persistent luminescence (LPL), mechano-luminescence (ML), and photo-stimulated luminescence (PSL) behaviors are respectively observed under the stimuli of ultraviolet (UV), thermal disturbance, stress, and 980 nm diode laser. Based on the time-dependence of the filling and releasing rate of the carriers from the shallow traps, the dynamic information encryption strategy is proposed by simply changing the UV pre-irradiation time or shut-off time. Moreover, a tunable color from green to red is realized by prolonging the 980 nm laser irradiation time, which is attributed to the elaborate cooperation of the PSL and upconversion (UC) behaviors. The anti-counterfeiting method based on SYGO: Tb3+ and SYGO: Tb3+, Er3+ phosphors herein possess an extremely high-security level with attractive performance for designing advanced anti-counterfeiting technology.
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The retinal degeneration 10 (rd10) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated Pde6b gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the Pde6b gene defect. We used a combination of immunohistochemistry (DAB, immunofluorescence), electron microscopy (EM), subcellular fractionation, and Western blot analysis on the retinal preparations obtained from both rd10 and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca2+) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca2+ buffering proteins in both photoreceptors and non-photoreceptor neuronal cells before any noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of the autophagy proteins p62 and LC3, together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs including pTDP-43 and FET family RBPs and stress granule formation. We conclude that progressive neurodegeneration in the rd10 mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation.
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Degeneração Retiniana , Retinose Pigmentar , Camundongos , Animais , Degeneração Retiniana/patologia , Retinose Pigmentar/genética , Homeostase , Autofagia , Proteínas de Ligação a RNARESUMO
In two proof-of-concept studies, we established and validated the Bacterial Growth Inhibition Screen (BGIS), which explores recombinant protein toxicity in Escherichia coli as a largely overlooked and alternative means for basic characterization of functional eukaryotic protein domains. By applying BGIS, we identified an unrecognized RNA-interacting domain in the DEK oncoprotein (this study) and successfully combined BGIS with random mutagenesis as a screening tool for loss-of-function mutants of the DNA modulating domain of DEK [1]. Collectively, our findings shed new light on the phenomenon of recombinant protein toxicity in E. coli. Given the easy and rapid implementation and wide applicability, BGIS will extend the repertoire of basic methods for the identification, analysis and unbiased manipulation of proteins.
Assuntos
Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/toxicidade , Testes de Toxicidade/métodos , Animais , Viés , Biocatálise , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/toxicidade , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/toxicidade , Escherichia coli/genética , Humanos , Mutação com Perda de Função , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas Oncogênicas/toxicidade , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/toxicidade , Domínios Proteicos/genética , RNA/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/toxicidade , Receptores da Família Eph/química , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Receptores da Família Eph/toxicidade , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Reprodutibilidade dos Testes , Fatores de Tempo , Testes de Toxicidade/normasRESUMO
The DEK oncoprotein regulates cellular chromatin function via a number of protein-protein interactions. However, the biological relevance of its unique pseudo-SAP/SAP-box domain, which transmits DNA modulating activities in vitro, remains largely speculative. As hypothesis-driven mutations failed to yield DNA-binding null (DBN) mutants, we combined random mutagenesis with the Bacterial Growth Inhibition Screen (BGIS) to overcome this bottleneck. Re-expression of a DEK-DBN mutant in newly established human DEK knockout cells failed to reduce the increase in nuclear size as compared to wild type, indicating roles for DEK-DNA interactions in cellular chromatin organization. Our results extend the functional roles of DEK in metazoan chromatin and highlight the predictive ability of recombinant protein toxicity in E. coli for unbiased studies of eukaryotic DNA modulating protein domains.
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Cromatina/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , DNA/metabolismo , Escherichia coli/efeitos dos fármacos , Mutação com Perda de Função , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas Recombinantes/toxicidade , Viés , Núcleo Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Cromatina/química , Cromatina/genética , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/toxicidade , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genoma Bacteriano/efeitos dos fármacos , Genoma Bacteriano/genética , Humanos , Mutagênese , Nucleossomos/química , Nucleossomos/genética , Nucleossomos/metabolismo , Proteínas Oncogênicas/química , Proteínas Oncogênicas/toxicidade , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/toxicidade , Domínios Proteicos/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Testes de Toxicidade/métodosRESUMO
Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.
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Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Autofagia , Homeostase , Humanos , MutaçãoRESUMO
Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose - regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-ß in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.
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Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Retículo Endoplasmático/metabolismo , Exossomos/metabolismo , Degeneração Neural/metabolismo , Proteínas de Ligação a RNA/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Animais , Autofagia/fisiologia , Encéfalo/patologia , Chaperona BiP do Retículo Endoplasmático , Exossomos/patologia , Feminino , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Proteínas Associadas à Matriz Nuclear/metabolismo , Receptores sigma/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Receptor Sigma-1RESUMO
This study used descriptive statistical analyses to investigate the payment characteristics and to discuss the regularity of highest paying industries. Payments by 4.70% of highest paying industries (N=446) accounted for 85% of the total (US $72,458,304) in 2014-2016. A tiny minority of highest paying industries control the majority of payments. Large payments from these industries are highly associated with few specific products. Furthermore, payment patterns among the industries include concentration and diversification.
Assuntos
Indústria Farmacêutica , Cirurgia Torácica , Centers for Medicare and Medicaid Services, U.S. , Mineração de Dados , Gastos em Saúde , Estados UnidosRESUMO
Most deaths from breast cancer result from tumour recurrence, which is typically an incurable disease. Down-regulation of the pro-apoptotic tumour suppressor protein prostate apoptosis response-4 (PAR-4) is required for breast cancer recurrence and resistance to chemotherapy. Recent advances in the analysis of apoptotic signalling networks have uncovered an important role for activation of caspase-8 following DNA damage by genotoxic drugs. DNA damage induces depletion of IAP proteins and causes caspase-8 activation by promoting the formation of a cytosolic cell death complex. We demonstrate that loss of PAR-4 in triple negative breast cancer cell lines (TNBC) mediates resistance to DNA damage-induced apoptosis and prevents activation of caspase-8. Moreover, loss of PAR-4 prevents DNA damage-induced cIAP1 depletion. PAR-4 functions downstream of caspase-8 by cleavage-induced nuclear translocation of the C-terminal part and we demonstrate that nuclear translocation of the C-terminal PAR-4 fragment leads to depletion of cIAP1 and subsequent caspase-8 activation. Specifically targeting cIAP1 with RNAi or Smac mimetics (LCL161) overcomes chemo-resistance induced by loss of PAR-4 and restores caspase-8 activation. Our data identify cIAP1 as important downstream mediator of PAR-4 and we provide evidence that combining Smac mimetics and genotoxic drugs creates vulnerability for synthetic lethality in TNBC cells lacking PAR-4.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Trombina/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Dano ao DNA , Feminino , Humanos , Proteínas Inibidoras de Apoptose/genética , Células MCF-7 , Proteínas de Neoplasias/genética , Receptores de Trombina/genética , Tiazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
The nuclear protein DEK is an endogenous DNA-binding chromatin factor regulating hematopoiesis. DEK is one of only 2 known secreted nuclear chromatin factors, but whether and how extracellular DEK regulates hematopoiesis is not known. We demonstrated that extracellular DEK greatly enhanced ex vivo expansion of cytokine-stimulated human and mouse hematopoietic stem cells (HSCs) and regulated HSC and hematopoietic progenitor cell (HPC) numbers in vivo and in vitro as determined both phenotypically (by flow cytometry) and functionally (through transplantation and colony formation assays). Recombinant DEK increased long-term HSC numbers and decreased HPC numbers through a mechanism mediated by the CXC chemokine receptor CXCR2 and heparan sulfate proteoglycans (HSPGs) (as determined utilizing Cxcr2-/- mice, blocking CXCR2 antibodies, and 3 different HSPG inhibitors) that was associated with enhanced phosphorylation of ERK1/2, AKT, and p38 MAPK. To determine whether extracellular DEK required nuclear function to regulate hematopoiesis, we utilized 2 mutant forms of DEK: one that lacked its nuclear translocation signal and one that lacked DNA-binding ability. Both altered HSC and HPC numbers in vivo or in vitro, suggesting the nuclear function of DEK is not required. Thus, DEK acts as a hematopoietic cytokine, with the potential for clinical applicability.