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1.
EMBO J ; 42(15): e111247, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37357972

RESUMO

Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP-ribosyl cyclase to produce cyclic ADP-ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial-expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults.


Assuntos
Antígenos CD , ADP-Ribose Cíclica , Animais , ADP-Ribosil Ciclase 1/genética , Antígenos CD/metabolismo , ADP-Ribose Cíclica/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Astrócitos/metabolismo , Sinapses/metabolismo
2.
J Biol Chem ; 300(5): 107286, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38636657

RESUMO

Hepatitis C virus (HCV) infection is tightly connected to the lipid metabolism with lipid droplets (LDs) serving as assembly sites for progeny virions. A previous LD proteome analysis identified annexin A3 (ANXA3) as an important HCV host factor that is enriched at LDs in infected cells and required for HCV morphogenesis. To further characterize ANXA3 function in HCV, we performed proximity labeling using ANXA3-BioID2 as bait in HCV-infected cells. Two of the top proteins identified proximal to ANXA3 during HCV infection were the La-related protein 1 (LARP1) and the ADP ribosylation factor-like protein 8B (ARL8B), both of which have been previously described to act in HCV particle production. In follow-up experiments, ARL8B functioned as a pro-viral HCV host factor without localizing to LDs and thus likely independent of ANXA3. In contrast, LARP1 interacts with HCV core protein in an RNA-dependent manner and is translocated to LDs by core protein. Knockdown of LARP1 decreased HCV spreading without altering HCV RNA replication or viral titers. Unexpectedly, entry of HCV particles and E1/E2-pseudotyped lentiviral particles was reduced by LARP1 depletion, whereas particle production was not altered. Using a recombinant vesicular stomatitis virus (VSV)ΔG entry assay, we showed that LARP1 depletion also decreased entry of VSV with VSV, MERS, and CHIKV glycoproteins. Therefore, our data expand the role of LARP1 as an HCV host factor that is most prominently involved in the early steps of infection, likely contributing to endocytosis of viral particles through the pleiotropic effect LARP1 has on the cellular translatome.


Assuntos
Anexina A3 , Hepacivirus , Hepatite C , Antígeno SS-B , Internalização do Vírus , Humanos , Anexina A3/metabolismo , Anexina A3/genética , Autoantígenos/metabolismo , Autoantígenos/genética , Células HEK293 , Hepacivirus/metabolismo , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Hepatite C/genética , Interações Hospedeiro-Patógeno , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/virologia , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Proteínas do Core Viral/metabolismo , Proteínas do Core Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/genética
4.
IUBMB Life ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38708996

RESUMO

Pancreatic cancer is one of the deadliest diseases with a poor prognosis and a five-survival rate. The STAT3 pathway is hyperactivated which contributes to the sustained proliferative signals in pancreatic cancer cells. We have isolated kaempferide (KF), an O-methylated flavonol, from the green propolis of Mimosa tenuiflora and examined its effect on two forms of cell death namely, apoptosis and paraptosis. KF significantly increased the cleavage of caspase-3 and PARP. It also downmodulated the expression of Alix (an intracellular inhibitor of paraptosis) and increased the expression of CHOP and ATF4 (transcription factors that promote paraptosis) indicating that KF promotes apoptosis as well as paraptosis. KF also increased intracellular reactive oxygen species (ROS) suggesting the perturbance of the redox state. N-acetylcysteine reverted the apoptosis- and paraptosis-inducing effects of KF. Some ROS inducers are known to suppress the STAT3 pathway and investigation revealed that KF downmodulates STAT3 and its upstream kinases (JAK1, JAK2, and Src). Additionally, KF also elevated the expression of SHP-1, a tyrosine phosphatase which is involved in the negative modulation of the STAT3 pathway. Knockdown of SHP-1 prevented KF-driven STAT3 inhibition. Altogether, KF has been identified as a promoter of apoptosis and paraptosis in pancreatic cancer cells through the elevation of ROS generation and SHP-1 expression.

5.
Protein Expr Purif ; 217: 106444, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38365166

RESUMO

The matrix of the stationary phase is a crucial element in affinity chromatography for protein purification. Various materials, including polymer or magnetic materials, have been employed as the matrix in the purification of His-tagged protein. Here, for the first time, we utilized a combination of melanin and alginate, both natural polymer materials, to synthesize Ni-melanin/alginate (Ni-M/A) beads for His-tagged protein purification. We investigated the binding of His-tagged Mpro on the Ni-M/A beads, referred to as Ni-M/A-Mpro, and assessed the elution efficiency of Mpro from the beads. Our examination involved FTIR, EDS, XRD, SDS-PAGE, and Western blotting methods. FTIR spectra revealed notable changes in the stretching patterns and intensities of hydroxyl, amine, carbonyl, imine and amide chemical groups, when Mpro protein was present in the Ni-M/A sample. XRD spectra demonstrated the occurrence of two Nickel peaks at 35-40 deg and 40-45 deg in Ni-M/A, but only one nickel peak at 35-40 deg in Ni-M/A-Mpro, indicating the binding of Mpro on the Nickel ions. EDS analysis reported a decrease in the concentration of Nickel on the surface of Ni-M/A from 16% to 7% when Mpro protein was loaded into the stationary phase. Importantly, our data indicated that the purity of the His-tagged protein Mpro after purification reached 97% after just one-step purification using the Ni-M/A stationary phase. Moreover, the binding capacity of Ni-M/A for Mpro was approximately 5.2 mg/g with recovery efficiency of 40%. Our results suggested Ni-M/A as a highly potential solid phase for affinity chromatography in the purification of His-tagged protein.


Assuntos
Melaninas , Níquel , Níquel/química , Histidina/química , Cromatografia de Afinidade/métodos , Íons , Polímeros , Alginatos
6.
BMC Infect Dis ; 24(1): 813, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39134980

RESUMO

BACKGROUND: Diphtheria is a re-emerging infectious disease and public health concern worldwide and in Vietnam with increasing cases in recent years. This study aimed to assess the anti-diphtheria toxoid antibodies status in Khanh Hoa Province and identify factors contributing to the vaccination policy in the south-central coast of Vietnam. METHODS: This was a cross-sectional study to evaluate the seroprevalence of anti-diphtheria toxoid antibodies among 1,195 participants, aged 5 - 40 years in Khanh Hoa Province, Vietnam. Immunoglobulin G antibody levels against diphtheria were detected using a commercial anti-diphtheria toxoid enzyme-linked immunosorbent assay (SERION ELISA classic Diphtheria Immunoglobulin G) and were categorized following the World Health Organization guidelines. RESULTS: The mean anti-diphtheria toxoid antibody levels were 0.07 IU/ml (95% Confidence Interval: 0.07-0.08). Anti-diphtheria toxoid antibody levels were found to be associated with age and history of diphtheria vaccination. The 5-15 years age group had the highest levels (0.09 IU/ml), while the older age group had the lowest antibody level (p < 0.001). Individuals who received three doses (adjusted Odds ratio: 2.34, 95%CI: 1.35 - 4.07) or 4+ doses (adjusted Odds ratio: 2.45, 95%CI: 1.29 - 4.64) had a higher antibody level compared to those who received only one dose regardless of age. CONCLUSION: It is crucial to promote routine vaccination coverage to over 95% for children under one year of age with three primary doses of the diphtheria-containing vaccine, including additional doses at 18 months and 7 years of age. Booster doses should be promoted and administered to adolescents and adults every 10 years.


Assuntos
Anticorpos Antibacterianos , Toxoide Diftérico , Difteria , Vacinação , Humanos , Estudos Transversais , Vietnã/epidemiologia , Adolescente , Adulto , Estudos Soroepidemiológicos , Masculino , Criança , Feminino , Adulto Jovem , Difteria/prevenção & controle , Difteria/imunologia , Difteria/epidemiologia , Anticorpos Antibacterianos/sangue , Pré-Escolar , Toxoide Diftérico/imunologia , Toxoide Diftérico/administração & dosagem , Vacinação/estatística & dados numéricos , Imunoglobulina G/sangue , Ensaio de Imunoadsorção Enzimática
7.
BMC Infect Dis ; 24(1): 622, 2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38910264

RESUMO

BACKGROUND: Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence of antimicrobial resistance has led to an urgent and critical situation in developing countries, including Vietnam. This study aimed to investigate the distribution and antimicrobial resistance of bacteria in patients with AE-COPD using both conventional culture and multiplex real-time PCR. Additionally, associations between clinical characteristics and indicators of pneumonia in these patients were examined. METHODS: This cross-sectional prospective study included 92 AE-COPD patients with pneumonia and 46 without pneumonia. Sputum specimens were cultured and examined for bacterial identification, and antimicrobial susceptibility was determined for each isolate. Multiplex real-time PCR was also performed to detect ten bacteria and seven viruses. RESULTS: The detection rates of pathogens in AE-COPD patients with pneumonia were 92.39%, compared to 86.96% in those without pneumonia. A total of 26 pathogenic species were identified, showing no significant difference in distribution between the two groups. The predominant bacteria included Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, followed by Acinetobacter baumannii and Streptococcus mitis. There was a slight difference in antibiotic resistance between bacteria isolated from two groups. The frequency of H. influenzae was notably greater in AE-COPD patients who experienced respiratory failure (21.92%) than in those who did not (9.23%). S. pneumoniae was more common in patients with stage I (44.44%) or IV (36.36%) COPD than in patients with stage II (17.39%) or III (9.72%) disease. ROC curve analysis revealed that C-reactive protein (CRP) levels could distinguish patients with AE-COPD with and without pneumonia (AUC = 0.78). CONCLUSION: Gram-negative bacteria still play a key role in the etiology of AE-COPD patients, regardless of the presence of pneumonia. This study provides updated evidence for the epidemiology of AE-COPD pathogens and the appropriate selection of antimicrobial agents in Vietnam.


Assuntos
Antibacterianos , Bactérias , Farmacorresistência Bacteriana , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Transversais , Vietnã/epidemiologia , Estudos Prospectivos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/isolamento & purificação , Bactérias/efeitos dos fármacos , Bactérias/classificação , Bactérias/genética , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/epidemiologia , Testes de Sensibilidade Microbiana , Escarro/microbiologia , Idoso de 80 Anos ou mais , Pneumonia/microbiologia , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia
8.
Phys Chem Chem Phys ; 26(26): 18449-18458, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38916072

RESUMO

In this study, we developed a high-performance non-enzymatic electrochemical sensor based on urchin-like CoP3/Cu3P heterostructured nanorods supported on a three-dimensional porous copper foam, namely, CoP3/Cu3P NRs/CF, for the detection of dopamine. Benefiting from the promising intrinsic catalytic activities of CoP3 and Cu3P, urchin-like microsphere structures, and a large electrochemically active surface area for exposing numerous accessible catalytic active sites, the proposed CoP3/Cu3P NRs/CF shows extraordinary electrochemical response towards the electrocatalytic oxidation of dopamine. As a result, the CoP3/Cu3P NRs/CF sensing electrode has a broad detection window (from 0.2 to 2000 µM), low detection limit (0.51 µM), high electrochemical sensitivity (0.0105 mA µM-1 cm-2), excellent selectivity towards dopamine in the coexistence of some interfering species, and good stability for dopamine determination. More importantly, the CoP3/Cu3P NRs/CF catalyst also exhibits excellent catalytic activity, sensitivity, and selectivity for dopamine detection under simulated human body conditions at a physiological pH of 7.25 (0.1 M PBS) at 36.6 °C.


Assuntos
Cobre , Dopamina , Técnicas Eletroquímicas , Nanotubos , Dopamina/análise , Dopamina/química , Cobre/química , Técnicas Eletroquímicas/métodos , Nanotubos/química , Porosidade , Catálise , Cobalto/química , Eletrodos , Limite de Detecção , Oxirredução
9.
Int J Med Sci ; 21(2): 200-206, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169660

RESUMO

Purpose: This retrospective study assessed the value of histogram parameters of the apparent diffusion coefficient (ADC) map (HA) in differentiating between benign and malignant testicular tumors. We compared the diagnostic performance of two different volume-of-interest (VOI) placement methods: VOI 1, the entire tumor; VOI 2, the tumor excluding its cystic, calcified, hemorrhagic, and necrotic portions. Materials and methods: We retrospectively evaluated 45 patients with testicular tumors examined with scrotal contrast-enhanced magnetic resonance imaging. These patients underwent surgery with the pathological result of seven benign and 39 malignant tumors. We calculated the HA parameters, including mean, median, maximum, minimum, kurtosis, skewness, entropy, standard deviation (SD), mean of positive pixels, and uniformity of positive pixels by the two different VOI segmentation methods. We compared these parameters using the chi-square test, Mann-Whitney U test, and area under the receiver operating characteristic curve (AUC) to determine their optimal cut-off, sensitivity (Se), and specificity (Sp). Result: This study included 45 patients with 46 testicular lesions (seven benign and 39 malignant tumors), one of which had bilateral testicular seminoma. With the VOI 1 method, benign lesions had significantly lower maximum ADC (p = 0.002), ADC skewness (p = 0.017), and ADC variance (p = 0.000) than malignant lesions. In contrast, their minimum ADC was significantly higher ADC (p = 0.000). With the VOI 2 method, the benign lesions had significantly higher ADC SD (p = 0.048) and maximum ADC (p = 0.015) than malignant lesions. In contrast, their minimum ADC was significantly lower (p = 0.000). With the VOI 1 method, maximum ADC, ADC variance, and ADC skewness performed well in differentiating benign and malignant testicular lesions with cut-offs (Se, Sp, AUC) of 1846.000 (74.4%, 100%, 0.883), 39198.387 (79.5%, 85.7%, 0.868), and 0.893 (48.7%, 100%, 0.758). Conclusion: The HA parameters showed value in differentiating benign and malignant testicular neoplasms. The entire tumor VOI placement method was preferable to the VOI placement method excluding cystic, calcified, hemorrhagic, and necrotic portions in measuring HA parameters. Using this VOI segmentation, maximum ADC performed best in discriminating benign and malignant testicular lesions, followed by ADC variance and skewness.


Assuntos
Interpretação de Imagem Assistida por Computador , Neoplasias Testiculares , Masculino , Humanos , Estudos Retrospectivos , Interpretação de Imagem Assistida por Computador/métodos , Reprodutibilidade dos Testes , Imagem de Difusão por Ressonância Magnética/métodos , Curva ROC , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/cirurgia , Sensibilidade e Especificidade
10.
Pediatr Int ; 66(1): e15770, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38641933

RESUMO

BACKGROUND: WAS gene mutational analysis is crucial to establish a definite diagnosis of Wiskott-Aldrich syndrome (WAS). Data on the genetic background of WAS in Vietnamese patients have not been reported. METHODS: We recruited 97 male, unrelated patients with WAS and analyzed WAS gene mutation using Sanger sequencing technology. RESULTS: We identified 36 distinct hemizygous pathogenic mutations, with 17 novel variants, from 38 patients in the entire cohort (39.2%). The mutational spectrum included 14 missense, 12 indel, five nonsense, four splicing, and one non-stop mutations. Most mutations appear only once, with the exception of c.37C>T (p.R13X) and c.374G>A (p.G125E) each of which occurs twice in unrelated patients. CONCLUSION: Our data enrich the mutational spectrum of the WAS gene and are crucial for understanding the genetic background of WAS and for supporting genetic counseling.


Assuntos
Síndrome de Wiskott-Aldrich , Humanos , Masculino , Análise Mutacional de DNA , Mutação , Vietnã , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/genética
11.
Parasitol Res ; 123(2): 133, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38358454

RESUMO

Toxocara canis is a globally distributed zoonotic parasite. The parasite has recently become a concern for public health in Vietnam. This cross-sectional study aimed to identify and quantify the risk factors associated with T. canis infection in dogs in Dak Lak province in the Central Highlands of Vietnam. The risk factors were identified using a mixed-effects logistic regression model and quantified using population attributable fractions. Examination of fecal samples collected from 1455 dogs using the sodium nitrate flotation technique showed 37.32% (95% CI: 34.83-39.86) of dogs infected with T. canis. The factors, including study location, multiple dogs living in a household, dog age, dog breed, and places keeping dogs were associated with a dog's likelihood of being T. canis infection. The household and individual dog levels contributed 17% and 82%, respectively, to the prevalence of T. canis in dogs. The adjusted population attributable fraction for confining dogs and raising an individual dog per household was 52% and 27%, respectively. The result of this study indicated that to minimize the burden of T. canis, intervention measures should target individual dogs and household levels.


Assuntos
Canidae , Toxocara canis , Cães , Animais , Estudos Transversais , Prevalência , Vietnã/epidemiologia , Fatores de Risco
12.
Eur Heart J ; 44(27): 2458-2469, 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37062040

RESUMO

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. CONCLUSION: Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Fístula Esofágica , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Fibrilação Atrial/diagnóstico , Resultado do Tratamento , Incidência , Fatores de Risco , Fístula Esofágica/epidemiologia , Fístula Esofágica/etiologia , Fístula Esofágica/diagnóstico , Prognóstico , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos
13.
Sensors (Basel) ; 24(10)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38794018

RESUMO

This paper explores the development of a smart Structural Health Monitoring (SHM) platform tailored for long-span bridge monitoring, using the Forth Road Bridge (FRB) as a case study. It discusses the selection of smart sensors available for real-time monitoring, the formulation of an effective data strategy encompassing the collection, processing, management, analysis, and visualization of monitoring data sets to support decision-making, and the establishment of a cost-effective and intelligent sensor network aligned with the objectives set through comprehensive communication with asset owners. Due to the high data rates and dense sensor installations, conventional processing techniques are inadequate for fulfilling monitoring functionalities and ensuring security. Cloud-computing emerges as a widely adopted solution for processing and storing vast monitoring data sets. Drawing from the authors' experience in implementing long-span bridge monitoring systems in the UK and China, this paper compares the advantages and limitations of employing cloud- computing for long-span bridge monitoring. Furthermore, it explores strategies for developing a robust data strategy and leveraging artificial intelligence (AI) and digital twin (DT) technologies to extract relevant information or patterns regarding asset health conditions. This information is then visualized through the interaction between physical and virtual worlds, facilitating timely and informed decision-making in managing critical road transport infrastructure.

14.
Sensors (Basel) ; 24(12)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38931804

RESUMO

Accurately predicting the distance an object will travel to its destination is very important in various sports. Acceleration sensors as a means of real-time monitoring are gaining increasing attention in sports. Due to the low energy output and power density of Triboelectric Nanogenerators (TENGs), recent efforts have focused on developing various acceleration sensors. However, these sensors suffer from significant drawbacks, including large size, high complexity, high power input requirements, and high cost. Here, we described a portable and cost-effective real-time refreshable strategy design comprising a series of individually addressable and controllable units based on TENGs embedded in a flexible substrate. This results in a highly sensitive, low-cost, and self-powered acceleration sensor. Putting, which accounts for nearly half of all strokes played, is obviously an important component of the golf game. The developed acceleration sensor has an accuracy controlled within 5%. The initial velocity and acceleration of the forward movement of a rolling golf ball after it is hit by a putter can be displayed, and the stopping distance is quickly calculated and predicted in about 7 s. This research demonstrates the application of the portable TENG-based acceleration sensor while paving the way for designing portable, cost-effective, scalable, and harmless ubiquitous self-powered acceleration sensors.

15.
Angew Chem Int Ed Engl ; : e202409973, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837490

RESUMO

Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC50 of 30 nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets.

16.
PLoS Pathog ; 17(4): e1009496, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33872335

RESUMO

LINE-1 (L1) retrotransposons are autonomous transposable elements that can affect gene expression and genome integrity. Potential consequences of exogenous viral infections for L1 activity have not been studied to date. Here, we report that hepatitis C virus (HCV) infection causes a significant increase of endogenous L1-encoded ORF1 protein (L1ORF1p) levels and translocation of L1ORF1p to HCV assembly sites at lipid droplets. HCV replication interferes with retrotransposition of engineered L1 reporter elements, which correlates with HCV RNA-induced formation of stress granules and can be partially rescued by knockdown of the stress granule protein G3BP1. Upon HCV infection, L1ORF1p localizes to stress granules, associates with HCV core in an RNA-dependent manner and translocates to lipid droplets. While HCV infection has a negative effect on L1 mobilization, L1ORF1p neither restricts nor promotes HCV infection. In summary, our data demonstrate that HCV infection causes an increase of endogenous L1 protein levels and that the observed restriction of retrotransposition of engineered L1 reporter elements is caused by sequestration of L1ORF1p in HCV-induced stress granules.


Assuntos
Carcinoma Hepatocelular/virologia , DNA Helicases/metabolismo , Hepacivirus/fisiologia , Hepatite C/virologia , Neoplasias Hepáticas/virologia , Elementos Nucleotídeos Longos e Dispersos/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Ribonucleoproteínas/metabolismo , Linhagem Celular Tumoral , Grânulos Citoplasmáticos/virologia , DNA Helicases/genética , Humanos , Gotículas Lipídicas/virologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Ribonucleoproteínas/genética
17.
J Cardiovasc Electrophysiol ; 34(12): 2617-2620, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37964504

RESUMO

INTRODUCTION: Acquired Wolff-Parkinson-White (WPW) syndrome can occur after congenital heart disease (CHD) surgery. METHODS AND RESULTS: A 27-year-old male with Ebstein's anomaly and manifest WPW syndrome received catheter ablation twice. The first electrophysiology study (EPS) induced orthodromic atrioventricular reentrant tachycardia and successfully eliminated the posteroseptal accessory pathway (AP). Six months after the Cone procedure, the patient suffered from palpitation. The second EPS was performed and abolished the right lateral AP. CONCLUSION: The appearance of a new AP after the reconstruction of CHD is a rare finding and should raise suspicion of an acquired AP connection.


Assuntos
Feixe Acessório Atrioventricular , Ablação por Cateter , Anomalia de Ebstein , Cardiopatias Congênitas , Taquicardia Supraventricular , Síndrome de Wolff-Parkinson-White , Masculino , Humanos , Adulto , Feixe Acessório Atrioventricular/cirurgia , Síndrome de Wolff-Parkinson-White/diagnóstico , Síndrome de Wolff-Parkinson-White/cirurgia , Arritmias Cardíacas/cirurgia , Cardiopatias Congênitas/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Eletrocardiografia
18.
Neurochem Res ; 48(7): 2175-2186, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36853481

RESUMO

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6ß, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6ß deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed that Atf6b-/- mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased in Atf6b-/- mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior in Atf6b-/- mice. These findings suggest that ATF6ß deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6ß could play a role in psychiatric conditions in the emotional centers of the brain.


Assuntos
Calreticulina , Receptores de Hormônio Liberador da Corticotropina , Camundongos , Animais , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Calreticulina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Ansiedade/metabolismo , Corticosterona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Fator 6 Ativador da Transcrição/metabolismo
19.
Fish Shellfish Immunol ; 143: 109191, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37890736

RESUMO

Oxygen nanobubble (NB-O2) technology has been introduced to the aquaculture industry in recent years. This treatment usually results in a tremendously high level of dissolved oxygen (DO) in the water. However, little is known about the possible negative effects of hyperoxia due to NB-O2 treatment (hyper-NB-O2) on farmed fish. Here, we investigated i) the effect of short-term hyper-NB-O2 exposure (single treatment) on the innate immunity in Nile tilapia, Oreochromis niloticus, and ii) the effect of long-term hyper-NB-O2 exposure (26-day treatments) on survival, growth performance, gill histology, and gut microbiome in Nile tilapia. A single treatment with NB-O2 for 10 min in 50 L of water resulted in 24.2 ± 0.04 mg/L DO (approximately 2-3 × 107 nanoscale oxygen bubbles/mL). This treatment did not result in differences in expression of several immune-related genes (e.g., TNF-α, LYZ and HPS70) in various tissues (e.g., gill, head kidney, and spleen) compared to the non-treated control. Over a 26-day period of exposure, no significant differences were observed in survival and growth performance of the fish, but minor histological changes were occasionally noted on the gills. Analysis of the gut microbiome revealed a significant increase in the genera Bosea, Exiguobacterium, Hyphomicrobium, and Singulisphaera in the group receiving NB-O2. Moreover, no signs of "gas bubble disease" were observed in the fish throughout the duration of the experiment. Overall, these results suggest that both short- and long-term hyper-NB-O2 exposure appears to be benign and has no obvious adverse effects on fish.


Assuntos
Ciclídeos , Doenças dos Peixes , Microbioma Gastrointestinal , Hiperóxia , Animais , Brânquias , Imunidade Inata , Oxigênio , Água
20.
Circ J ; 87(12): 1750-1756, 2023 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-37866912

RESUMO

BACKGROUND: Circumferential pulmonary vein isolation (CPVI) has supplanted segmental PVI (SPVI) as standard procedure for atrial fibrillation (AF). However, there is limited evidence examining the efficacy of these strategies in redo ablations. In this study, we investigated the difference in recurrence rates between SPVI and CPVI in redo ablations for PV reconnection.Methods and Results: This study retrospectively enrolled 543 patients who had undergone AF ablation between 2015 and 2017. Among them, 167 patients (30.8%, including 128 male patients and 100 patients with paroxysmal AF) underwent redo ablation for recurrent AF. Excluding 26 patients without PV reconnection, 141 patients [90 patients of SPVI (Group 1) and 51 patients of CPVI (Group 2)] were included. The AF-free survival rates were 53.3% and 56.9% in Group 1 and Group 2, respectively (P=0.700). The atrial flutter (AFL)-free survival rates were 90% and 100% in Group 1 and Group 2, respectively (P=0.036). The ablation time was similar between groups, and there no major complications were observed. CONCLUSIONS: For redo AF ablation procedures, SPVI and CPVI showed similar outcomes, except for a higher AFL recurrence rate for SPVI after long-term follow-up (>2 years). This may be due to a higher probability of residual PV gaps causing reentrant AFL.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Masculino , Fibrilação Atrial/cirurgia , Veias Pulmonares/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Recidiva , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos
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