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1.
EMBO J ; 42(23): e113279, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37881155

RESUMEN

The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP-1. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.


Asunto(s)
Nucleótidos , Transducción de Señal , Humanos , Citocinas , Inmunidad , Macrófagos/metabolismo , Nucleótidos/metabolismo , Replicación Viral
2.
Nature ; 594(7862): 246-252, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33845483

RESUMEN

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.


Asunto(s)
COVID-19/metabolismo , Interacciones Huésped-Patógeno , Proteoma/metabolismo , Proteómica , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Animales , Antivirales/farmacología , Autofagia/efectos de los fármacos , COVID-19/inmunología , COVID-19/virología , Línea Celular , Conjuntos de Datos como Asunto , Evaluación Preclínica de Medicamentos , Interacciones Huésped-Patógeno/inmunología , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Fosforilación , Mapas de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Proteoma/química , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/virología , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitinación , Proteínas Virales/química , Proteínas Virales/metabolismo , Proteínas Viroporinas/metabolismo
3.
EMBO J ; 41(17): e111608, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35833542

RESUMEN

The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Animales , Antivirales/farmacología , Inflamación/tratamiento farmacológico , Metiltransferasas/metabolismo , Ratones , Caperuzas de ARN/metabolismo , ARN Viral/genética , Ribosa , Proteínas no Estructurales Virales/genética
4.
EMBO Rep ; 25(9): 3777-3788, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39060455

RESUMEN

RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness.


Asunto(s)
COVID-19 , Interferón lambda , ARN Mensajero , SARS-CoV-2 , Animales , Femenino , Humanos , Ratones , Antivirales , Chlorocebus aethiops , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Inmunomodulación , Interferones/metabolismo , Liposomas , Nanopartículas/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , SARS-CoV-2/inmunología , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Carga Viral , Replicación Viral , Interferón lambda/administración & dosificación , Interferón lambda/genética
5.
Mol Cell Proteomics ; 22(7): 100589, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37301377

RESUMEN

Spontaneous deamidation of asparaginyl residues in proteins, if not repaired or cleared, can set in motion a cascade that leads to deteriorated health. Previously, we have discovered that deamidated human serum albumin (HSA) is elevated in the blood of patients with Alzheimer's disease and other neurodegenerative diseases, while the level of endogenous antibodies against deamidated HSA is significantly diminished, creating an imbalance between the risk factor and the defense against it. Endogenous antibodies against deamidated proteins are still unexplored. In the current study, we employed the SpotLight proteomics approach to identify novel amino acid sequences in antibodies specific to deamidated HSA. The results provide new insights into the clearance mechanism of deamidated proteins, a possible avenue for prevention of neurodegeneration.


Asunto(s)
Proteómica , Albúmina Sérica Humana , Humanos , Proteómica/métodos , Proteínas , Secuencia de Aminoácidos , Anticuerpos
6.
Fish Shellfish Immunol ; 151: 109689, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38866349

RESUMEN

Succinate dehydrogenase (SDH) is a crucial enzyme in the tricarboxylic acid cycle (TCA) and has established roles in immune function. However, the understanding of SDH in Penaeus vannamei, particularly its involvement in immune responses, is currently limited. Through affinity proteomics, a potential interaction between hemocyanin (HMC) and SDH in shrimp has been identified. The successful cloning of PvSDH in this study has revealed a high degree of evolutionary conservation. Additionally, it has been found that hemocyanin regulates SDH not only at the transcriptional and enzymatic levels but also through confirmed protein-protein interactions observed via Co-immunoprecipitation (CoIP) assay. Moreover, by combining PvHMC knockdown and Vibrio parahaemolyticus challenge, it was demonstrated that fumaric acid, a product of SDH, enhances the host's immune resistance to pathogen infection by modulating the expression of antimicrobial peptides. This research provides new insights into HMC as a crucial regulator of SDH, potentially impacting glycometabolism and the dynamics of immune responses.


Asunto(s)
Proteínas de Artrópodos , Hemocianinas , Penaeidae , Succinato Deshidrogenasa , Vibrio parahaemolyticus , Animales , Penaeidae/inmunología , Penaeidae/genética , Hemocianinas/inmunología , Hemocianinas/genética , Hemocianinas/metabolismo , Vibrio parahaemolyticus/fisiología , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Proteínas de Artrópodos/metabolismo , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/inmunología , Glucosa/metabolismo , Inmunidad Innata/genética , Regulación de la Expresión Génica/inmunología , Secuencia de Aminoácidos , Filogenia , Alineación de Secuencia
7.
Biomed Chromatogr ; 37(1): e5523, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36336973

RESUMEN

Occupational chronic cadmium poisoning (OCCP) can cause irreversible organ damage. Currently, no effective treatment is available for OCCP, and effective and sensitive biomarkers for treatment evaluation are still lacking. In this study, metabolomics techniques were used to analyze changes in endogenous metabolites in the urine of patients with OCCP after 15 years of treatment. Thirty urine samples from female patients with OCCP and healthy female controls (n = 15 per group) were assessed using gas chromatography-time-of-flight mass spectrometry and ultra-high-performance liquid chromatography-Q-Exactive mass spectrometry. The OCCP group had higher concentrations of blood urea nitrogen and urinary cadmium but near-normal urinary concentrations of ß2 -microglobulin and retinol-binding protein. Compared with the control group, the OCCP group had 66 significantly different metabolites with a variable importance in projection score >1 and p < 0.05. These differential metabolites were involved in various metabolic pathways, such as creatine metabolism, nicotinate and nicotinamide metabolism, the pentose phosphate pathway, d-glutamine and d-glutamate metabolism, and amino acid metabolism. Compared with the control group, the OCCP group had significantly higher urinary concentrations of creatine, glutamic acid, quinolinic acid and nicotinic acid. In a receiver operator characteristic analysis, the area under the curve of creatine was higher than those for glutamic acid, quinolinic acid and nicotinic acid, indicating that urinary concentrations of creatine could be used as a sensitive biomarker for the diagnosis and prognosis of OCCP and for monitoring its treatment.


Asunto(s)
Intoxicación por Cadmio , Niacina , Humanos , Femenino , Creatina , Ácido Quinolínico , Ácido Glutámico , Metabolómica/métodos , Biomarcadores
8.
Hum Genet ; 140(4): 609-623, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33140241

RESUMEN

Alzheimer's disease (AD) is one of the most common neurodegeneration diseases caused by multiple factors. The mechanistic insight of AD remains limited. To disclose molecular mechanisms of AD, many studies have been proposed from transcriptome analyses. However, no analysis across multiple levels of transcription has been conducted to discover co-expression networks of AD. We performed gene-level and isoform-level analyses of RNA sequencing (RNA-seq) data from 544 brain tissues of AD patients, mild cognitive impaired (MCI) patients, and healthy controls. Gene and isoform levels of co-expression modules were constructed by RNA-seq data. The associations of modules with AD were evaluated by integrating cognitive scores of patients, Genome-wide association studies (GWAS), alternative splicing analysis, and dementia-related genes expressed in brain tissues. Totally, 29 co-expression modules were found with expressions significantly correlated with the cognitive scores. Among them, two isoform modules were enriched with AD-associated SNPs and genes whose mRNA splicing displayed significant alteration in relation to AD disease. These two modules were further found enriched with dementia-related genes expressed in four brain regions of 125 AD patients. Analyzing expressions of these two modules revealed expressions of 39 isoforms (corresponding to 35 genes) significantly correlated with cognitive scores of AD patients, in which 38 isoforms were significantly up-regulated in AD patients comparing to controls, and 33 isoforms (corresponding to 29 genes) were not reported as AD-related previously. Employing the co-expression modules and the drug-induced gene expression data from Connectivity Map (CMAP), 12 drugs were predicted as significant in restoring the gene expression of AD patients towards health, which include nine drugs reported for relieving AD. In comparison, four of the top 12 significant drugs were known for relieving AD if the drug prediction was performed by the genes expressed significantly different in AD and healthy controls. Analysis of multiple levels of the transcriptomic organization is useful in suggesting AD-related co-expression networks and discovering drugs.


Asunto(s)
Enfermedad de Alzheimer/genética , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Isoformas de Proteínas/genética , Transcriptoma , Empalme Alternativo , Enfermedad de Alzheimer/tratamiento farmacológico , Conjuntos de Datos como Asunto , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/metabolismo , Empalme del ARN , RNA-Seq , Tacrolimus/uso terapéutico , Vorinostat/uso terapéutico
9.
Anal Chem ; 91(5): 3327-3335, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30701963

RESUMEN

Lung cancer is the primary cause of cancer-associated mortality worldwide, which makes the identification of reliable lung cancer biomarkers a pressing need for early diagnosis and prognosis. RGS11, which is a regulator of G-protein signaling and also a lung cancer biomarker, plays an important role in cancer-related metastasis. However, trace levels of RGS11 (in the range of pg/mL) in serum samples make it difficult to quantify using currently available enzyme-linked immunosorbent assay (ELISA) kits and, therefore, this hinders progress in the discovery of new approaches for treating lung cancer. The aim of this study is to develop a rapid, sensitive, and reliable platform for the detection of RGS11 lung cancer biomarker based on a suspension immunoassay coupled with an isothermal exponential amplification strategy. Our study was initiated by the functionalization of magnetic beads with anti-RGS11 antibodies (Ab-MB) by EDC (1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide)/NHS ( N-hydroxysulfosuccinimide) activation. Ab-MB served as a sensing probe for the competitive immunorecognitions between known concentrations of His-tag RGS11 and unknown concentrations of target RGS11 in serum. The reporter anti-His antibodies, which were modified with primers that induced an isothermal exponential amplification reaction, were subsequently introduced to the reaction mixture that resulted in the formation of immunosandwich complexes. The exponentially amplified DNA duplex that was intercalated with SYBR Green was designated as a signal reporter for the assessment of RGS11 in an inversely proportional relationship. The sensing platform was excellent for the determination of RGS11 with an exceptional detection limit of 148 fg/mL and a linear dynamic range of 0.1-10 pg/mL using a minimal sample volume (20 µL) and with a reaction time of 1.5 h. In addition, we challenged the sensing platform with RGS11-spiked samples (in 2× diluted serum), and an acceptable recovery rate (>90%) was observed. Finally, 24 clinical samples acquired from patients with advanced lung cancer (C), inflammation (I), and heart failure (H) were analyzed by this newly developed sensing platform and a commercial ELISA kit for validation. This sensing platform has potential in biomedical applications for clinically diagnosing liquid biopsy samples for patients with lung cancer. Moreover, the universal design of our proposed system is easily adapted to detect any other protein if a His-tag recombinant protein is available.


Asunto(s)
Biomarcadores de Tumor/sangre , Inmunoensayo/métodos , Neoplasias Pulmonares/diagnóstico , Proteínas RGS/sangre , Anticuerpos Inmovilizados/química , Anticuerpos Inmovilizados/inmunología , Reacciones Antígeno-Anticuerpo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Histidina/genética , Histidina/inmunología , Histidina/metabolismo , Humanos , Límite de Detección , Neoplasias Pulmonares/metabolismo , Magnetismo , Técnicas de Amplificación de Ácido Nucleico , Oligopéptidos/genética , Oligopéptidos/inmunología , Oligopéptidos/metabolismo , Proteínas RGS/genética , Proteínas RGS/inmunología
11.
Zhongguo Zhong Yao Za Zhi ; 39(8): 1485-9, 2014 Apr.
Artículo en Zh | MEDLINE | ID: mdl-25039187

RESUMEN

OBJECTIVE: To study the inhibitory effect of wogonin on the growth and proliferation of breast cancer cells MDA-MB-23, and observe its effect on the adhesion, migration and invasion of MDA-MB-23 cells, in order to further study its molecular mechanism. METHOD: MTT assay was used to detect the effect of wogonin on MDA-MB-23 cell growth. Ki-67 assay was adopted to test the effect of wogonin on cell proliferation. Scratch test, adherence test and invasion chamber assay were taken to detect the effect on the migration and invasion abilities of MDA-MB-231 cells. Proliferation and metastasis-related proteins and relevant signaling pathways were detected by Western blotting. RESULT: Wogonin could remarkably inhibit the growth and proliferation of MDA-MB-231 cells, significantly inhibit migration, adhesion and invasion abilities of breast cancer cells at a low concentration, and effectively inhibit the expression of Survivin, Bcl-2, ICAM-1, MMP-2, MMP-9 proteins of MDA-MB-231 cells. CONCLUSION: Wogonin could notably inhibit growth and proliferation of breast cancer cells, and inhibit migration, adhesion and invasion of MDA-MB-231 cells. Its invasive and adhesive effects on MDA-MB-231 cells may be related to the decrease in ICAM-1, MMP-2, MMP-9 expressions.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Flavanonas/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Transducción de Señal/efectos de los fármacos
12.
Cell Syst ; 15(10): 911-929.e8, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39368468

RESUMEN

The abundance of a protein is defined by its continuous synthesis and degradation, a process known as protein turnover. Here, we systematically profiled the turnover of proteins in influenza A virus (IAV)-infected cells using a pulse-chase stable isotope labeling by amino acids in cell culture (SILAC)-based approach combined with downstream statistical modeling. We identified 1,798 virus-affected proteins with turnover changes (tVAPs) out of 7,739 detected proteins (data available at pulsechase.innatelab.org). In particular, the affected proteins were involved in RNA transcription, splicing and nuclear transport, protein translation and stability, and energy metabolism. Many tVAPs appeared to be known IAV-interacting proteins that regulate virus propagation, such as KPNA6, PPP6C, and POLR2A. Notably, our analysis identified additional IAV host and restriction factors, such as the splicing factor GPKOW, that exhibit significant turnover rate changes while their total abundance is minimally affected. Overall, we show that protein turnover is a critical factor both for virus replication and antiviral defense.


Asunto(s)
Virus de la Influenza A , Gripe Humana , Replicación Viral , Humanos , Gripe Humana/metabolismo , Gripe Humana/virología , Marcaje Isotópico , Interacciones Huésped-Patógeno , Células A549 , Células de Riñón Canino Madin Darby , Células HEK293
13.
Front Med (Lausanne) ; 11: 1393548, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38854664

RESUMEN

Background: Brucella infection is uncommon among peritoneal dialysis (PD) patients in non-endemic areas, and the occurrence of both peritonitis and abdominal aortitis is rare. Case presentation: In December 2023, a 63-year-old male patient undergoing PD was admitted to Shaoxing Second Hospital due to fever, abdominal pain, and cloudy dialysate. Upon physical examination, diffuse mild abdominal pain and tenderness were observed. Subsequent investigation into the patient's medical history revealed consumption of freshly slaughtered lamb from local farmers 3 days prior to the onset of symptoms. Various diagnostic tests, including routine blood tests, procalcitonin levels, and PD fluid analysis, indicated the presence of infection. Abdominal computed tomography (CT) imaging revealed localized lumen widening of the abdominal aorta with surrounding exudative changes. On the sixth day in the hospital, blood and PD fluid cultures confirmed Brucella melitensis infection. The patient was diagnosed with brucella-associated peritonitis and aortitis. Treatment was adjusted to include rifampin and doxycycline for 6 weeks, and the decision was made to keep the PD catheter. Remarkably, the patient exhibited resolution of peritonitis and abdominal aortitis within the initial week of the adjusted treatment. Currently, the patient continues to receive ongoing clinical monitoring. Conclusion: Brucella is rare but can cause PD-associated peritonitis and arteritis. Prompt diagnosis and treatment can lead to a good outcome in PD patients. Dual therapy is effective, but the need for catheter removal is unclear. Consider international guidelines and patient factors when deciding on catheter removal.

14.
Artículo en Inglés | MEDLINE | ID: mdl-39255077

RESUMEN

Ultra-wide field (UWF) retinal imaging can improve the detection rate of retinal hemorrhage as compared with conventional fundus images. However, hemorrhages in UWF retinal images can also become smaller and more widely distributed, which can be time consuming and labor intensive. With the development of computer technology, automatic segmentation techniques can assist physicians in diagnosis. However, the lack of publicly available UWF retinal hemorrhage segmentation datasets has limited the development of automatic hemorrhage segmentation techniques in UWF retinal images. We present a large-scale high-quality UWF retinal hemorrhage segmentation dataset, named UWF-RHS Dataset, for public use. To the best of our knowledge, we are the first team to make the UWF retinal hemorrhage segmentation dataset publicly available. In addition, we propose a multi-scale attention subtraction network (MASNet) for UWF retinal hemorrhage segmentation. Specifically, highly focused lesion features are extracted by using the proposed multi-scale attention subtraction (MAS) module at the progress of the skip-connection. Several comparative experiments and ablation experiments were performed at the UWF-RHS Dataset, and all experiments state that our proposed method is effective in diagnosing retinal hemorrhages with state-of-the-art results. The proposed UWF-RHS dataset and MASNet will greatly facilitate the development of automated segmentation techniques for UWF retinal hemorrhages. Links to the UWF-RHS dataset and the MASNet model code are available from https://github.com/wurenkai/UWF-RHS-Dataset-and-MASNet.

15.
Front Med (Lausanne) ; 11: 1421109, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39421872

RESUMEN

Background: Icodextrin is a type of peritoneal dialysis (PD) osmolyte that can be extended retention times (8-16 h) and may offer a viable alternative to conventional glucose dialysis solutions for PD patients. Nonetheless, prolonged use of icodextrin may lead to allergic rash, and rarely severe skin lesions. Case presentation: In February 2024, a 45-year-old male was admitted to the Department of Nephrology at Shaoxing Second Hospital presenting with a 3-day history of intense generalized pruritic erythematous rash. Physical examination revealed diffuse erythematous pruritic rash and exfoliative rash, particularly on the abdominal. Abnormal laboratory findings included elevated eosinophil count and total IgE levels, indicative of an allergic rash. Standard anti-allergic regim was initiated. However, on the third day in the hospital, the patient developed new pustules on his neck and arms. Subsequent historical investigation uncovered that the individual had previously administered icodextrin 2 weeks prior due to volume overload, and the last intraperitoneal administration time was second day of hospitalization. The dermatologist rendered a diagnosis of generalized exfoliative rash and acute localized exanthematous pustulosis (ALEP) induced by icodextrin, and initiated prophylactic antimicrobial therapy accordingly. Furthermore, the patient declined to undergo a skin biopsy. Noteworthy is the observation that the rash ameliorated and the pustules resolved by the seventh day post-admission. Presently, the patient is still under clinical follow-up. Conclusion: This article aims to report the first case of severe allergic rash caused by icodextrin in Chinese PD patients and highlight the potential for icodextrin to trigger ALEP. A literature review of similar cases found that severe allergic rash induced by icodextrin is rare, the underlying mechanism remains poorly understood, and the prognosis is positive with proper treatment.

16.
Front Public Health ; 12: 1363362, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38827609

RESUMEN

Background: Heavy metal exposure is an important cause of reduced bone mineral density (BMD). Epidemiological studies focusing on the effects of mixed heavy metal exposure on BMD in middle-aged and older people are scarce. In single-metal studies, men and women have shown distinct responses of BMD to environmental metal exposure. This study therefore aimed to elucidate the association between mixed heavy metal exposure and BMD and to investigate whether it is sex-specific. Methods: Data from the 2017-2020 National Health and Nutrition Examination Survey were selected for this cross-sectional study. The study used three statistical methods, i.e., linear regression, Bayesian kernel machine regression (BKMR) modeling, and weighted quartiles (WQS) regression, to explore the association between the urinary concentrations of 11 metals (barium, cadmium, cobalt, cesium, manganese, molybdenum, lead, antimony, tin, thallium, and Tungsten), either individually or as a mixture, and total femoral BMD. Results: A total of 1,031 participants were included in this study. Femoral BMD was found to be higher in men than women. A significant negative correlation between the urinary concentrations of the 10 metals and femoral BMD was found in the overall cohort. Further gender sub-stratified analyses showed that in men, urinary metal concentrations were negatively correlated with femoral BMD, with cobalt and barium playing a significant and non-linear role in this effect. In women, although urinary metal concentrations negatively modulated femoral BMD, none of the correlations was statistically significant. Antimony showed sex-specific differences in its effect. Conclusion: The urinary concentrations of 10 mixed heavy metals were negatively correlated with femoral BMD in middle-aged and older participants, and this effect showed gender differences. These findings emphasize the differing role of mixed metal exposure in the process of BMD reduction between the sexes but require further validation by prospective studies.


Asunto(s)
Densidad Ósea , Fémur , Metales Pesados , Encuestas Nutricionales , Humanos , Femenino , Masculino , Estudios Transversales , Anciano , Metales Pesados/orina , Persona de Mediana Edad , Factores Sexuales , Exposición a Riesgos Ambientales , Teorema de Bayes , Anciano de 80 o más Años
17.
Comput Biol Med ; 179: 108923, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39053335

RESUMEN

Stereo matching and instrument segmentation of laparoscopic surgical scenarios are key tasks in robotic surgical automation. Many researchers have been studying the two tasks separately for stereo matching and instrument segmentation. However, the relationship between these two tasks is often neglected. In this paper, we propose a model framework for multi-tasking with complementary functions for stereo matching and surgical instrument segmentation (MCF-SMSIS). We aim to complement the features of instrument prediction segmentation to the parallax matching block of stereo matching. We also propose two new evaluation metrics (MINPD and MAXPD) for assessing how well the parallax range matches the migrated domain when the model used for the stereo matching task undergoes domain migration. We performed stereo matching experiments on the SCARED , SERV-CT dataset as well as instrumentation segmentation experiments on the AutoLaparo dataset. The results demonstrate the effectiveness of the proposed method. In particular, stereo matching supplemented with instrument features reduced EPE, >3px and RMSE Depth in the surgical instrument section by 9.5%, 12.7% and 6.51%, respectively. The instrumentation segmentation performance also achieves a DSC value of 0.9233. Moreover, MCF-SMSIS takes only 0.14 s to infer a set of images. The model code and model weights for each stage are available from https://github.com/wurenkai/MCF-SMSIS.


Asunto(s)
Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Laparoscopía , Imagenología Tridimensional/métodos , Algoritmos
18.
iScience ; 27(7): 110243, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39006478

RESUMEN

Many clinical studies indicate a significant decrease of peripheral T cells in Parkinson's disease (PD). There is currently no mechanistic explanation for this important observation. Here, we found that small extracellular vesicles (sEVs) derived from in vitro and in vivo PD models suppressed IL-4 and INF-γ production from both purified CD4+ and CD8+ T cells and inhibited their activation and proliferation. Furthermore, neuronal-enriched sEVs (NEEVs) isolated from plasma of A53T-syn mice and culture media of human dopaminergic neurons carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naive CD4+ T cells. Mechanistically, the suppressed phenotype induced by NEEVs was associated with altered programmed death ligand 1 (PD-L1) level in T cells. Blocking PD-L1 with an anti-PD-L1 antibody or a small molecule inhibitor BMS-1166 reversed T cell suppression. Our study provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease.

19.
J Vis Exp ; (204)2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38407282

RESUMEN

We report on the detailed steps of a method to estimate the biomass of invasive plants based on UAV remote sensing and computer vision. To collect samples from the study area, we prepared a sample square assembly to randomize the sampling points. An unmanned aerial camera system was constructed using a drone and camera to acquire continuous RGB images of the study area through automated navigation. After completing the shooting, the aboveground biomass in the sample frame was collected, and all correspondences were labeled and packaged. The sample data was processed, and the aerial images were segmented into small images of 280 x 280 pixels to create an image dataset. A deep convolutional neural network was used to map the distribution of Mikania micrantha in the study area, and its vegetation index was obtained. The organisms collected were dried, and the dry weight was recorded as the ground truth biomass. The invasive plant biomass regression model was constructed using the K-nearest neighbor regression (KNNR) by extracting the vegetation index from the sample images as an independent variable and integrating it with the ground truth biomass as a dependent variable. The results showed that it was possible to predict the biomass of invasive plants accurately. An accurate spatial distribution map of invasive plant biomass was generated by image traversal, allowing precise identification of high-risk areas affected by invasive plants. In summary, this study demonstrates the potential of combining unmanned aerial vehicle remote sensing with machine learning techniques to estimate invasive plant biomass. It contributes significantly to the research of new technologies and methods for real-time monitoring of invasive plants and provides technical support for intelligent monitoring and hazard assessment at the regional scale.


Asunto(s)
Computadores , Inteligencia , Biomasa , Análisis por Conglomerados , Aprendizaje Automático
20.
Nat Commun ; 15(1): 6778, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39117661

RESUMEN

Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-ß pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV.


Asunto(s)
Fibroblastos , Monkeypox virus , Mpox , Proteínas Virales , Humanos , Monkeypox virus/genética , Fosforilación , Mpox/virología , Mpox/metabolismo , Fibroblastos/virología , Fibroblastos/metabolismo , Proteínas Virales/metabolismo , Proteínas Virales/genética , Proteoma/metabolismo , Interacciones Huésped-Patógeno , Transducción de Señal , Proteómica/métodos , Transcriptoma , Antivirales/farmacología , Multiómica
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