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1.
Front Public Health ; 12: 1364048, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38873290

RESUMEN

Background: It is important to figure out the immunity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reinfection to understand the response of humans to viruses. A serological survey for previously infected populations in Jiangsu Province was conducted to compare the antibody level of SARS-CoV-2 in reinfection by Omicron or not. Methods: Reinfection with SARS-CoV-2 was defined as an individual being infected again after 90 days of the initial infection. Telephone surveys and face-to-face interviews were implemented to collect information. Experimental and control serum samples were collected from age-sex-matched reinfected and non-reinfected cases, respectively. IgG anti-S and neutralizing antibodies (Nab) concentrations were detected by the Magnetism Particulate Immunochemistry Luminescence Method (MCLIA). Antibody titers were log(2)-transformed and analyzed by a two-tailed Mann-Whitney U test. Subgroup analysis was conducted to explore the relationship between the strain type of primary infection, SARS-Cov-2 vaccination status, and antibody levels. Multivariate linear regression models were used to identify associations between reinfection with IgG and Nab levels. Results: Six hundred thirty-one individuals were enrolled in this study, including 327 reinfected cases and 304 non-reinfected cases. The reinfection group had higher IgG (5.65 AU/mL vs. 5.22 AU/mL) and Nab (8.02 AU/mL vs. 7.25 AU/mL) levels compared to the non-reinfection group (p < 0.001). Particularly, individuals who had received SARS-CoV-2 vaccination or were initially infected with the Wild type and Delta variant showed a significant increase in antibody levels after reinfection. After adjusting demographic variables, vaccination status and the type of primary infection together, IgG and Nab levels in the reinfected group increased by log(2)-transformed 0.71 and 0.64 units, respectively (p < 0.001). This revealed that reinfection is an important factor that affects IgG and Nab levels in the population. Conclusion: Reinfection with Omicron in individuals previously infected with SARS-CoV-2 enhances IgG and Nab immune responses.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Inmunoglobulina G , Reinfección , SARS-CoV-2 , Humanos , COVID-19/inmunología , Inmunoglobulina G/sangre , SARS-CoV-2/inmunología , Reinfección/inmunología , Reinfección/virología , China , Anticuerpos Neutralizantes/sangre , Masculino , Femenino , Anticuerpos Antivirales/sangre , Persona de Mediana Edad , Adulto , Anciano
2.
Front Genet ; 15: 1388015, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38737125

RESUMEN

LncRNAs are an essential type of non-coding RNAs, which have been reported to be involved in various human pathological conditions. Increasing evidence suggests that drugs can regulate lncRNAs expression, which makes it possible to develop lncRNAs as therapeutic targets. Thus, developing in-silico methods to predict lncRNA-drug associations (LDAs) is a critical step for developing lncRNA-based therapies. In this study, we predict LDAs by using graph convolutional networks (GCN) and graph attention networks (GAT) based on lncRNA and drug similarity networks. Results show that our proposed method achieves good performance (average AUCs > 0.92) on five datasets. In addition, case studies and KEGG functional enrichment analysis further prove that the model can effectively identify novel LDAs. On the whole, this study provides a deep learning-based framework for predicting novel LDAs, which will accelerate the lncRNA-targeted drug development process.

3.
Brain Lang ; 248: 105367, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38113600

RESUMEN

Chinese-English bilinguals read paragraphs with language switches using a rapid serial visual presentation paradigm silently while ERPs were measured (Experiment 1) or read them aloud (Experiment 2). Each paragraph was written in either Chinese or English with several function or content words switched to the other language. In Experiment 1, language switches elicited an early, long-lasting positivity when switching from the dominant language to the nondominant language, but when switching to the dominant language, the positivity started later, and was never larger than when switching to the nondominant language. In addition, switch effects on function words were not significantly larger than those on content words in any analyses. In Experiment 2, participants produced more cross-language intrusion errors when switching to the dominant than to the nondominant language, and more errors on function than content words. These results implicate different control mechanisms in bilingual language selection across comprehension and production.


Asunto(s)
Multilingüismo , Humanos , Comprensión , Lectura , Lenguaje
4.
Sci Rep ; 13(1): 22101, 2023 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-38092863

RESUMEN

We characterise in detail the larval and pupal cuticle of the black soldier fly Hermetia illucens L. (Diptera: Stratiomyidae), a key insect species in circular economy. In particular, we focus on ultrastructure using scanning and transmission electron microscopy, material characterization and composition (elements and minerals) with confocal laser scanning microscope, energy dispersive X-ray microanalysis, powder X-ray diffraction and mechanical properties with nanoindentation measurements. Calcium carbonate crystallizes on the epicuticle as blocks of calcite in the pupal cuticle. Calcium carbonate granules are stored in two specialised Malpighian tubules. CaCO3 is already present in the cuticle of young larval instars, but it is mainly in the form of amorphous calcium carbonate while the amount of calcite increases during larval development. The presence of calcite leads to cuticle hardening. Larval and pupal cuticles contain large amounts of resilin which guarantee cuticle flexibility.


Asunto(s)
Dípteros , Animales , Larva , Insectos , Carbonato de Calcio , Microscopía Electrónica de Transmisión , Pupa
6.
Cell Rep ; 42(10): 113261, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37847589

RESUMEN

Cyclic di-guanosine monophosphate (c-di-GMP) is a unique bacterial second messenger but is hijacked by host cells during bacterial infection as a pathogen-associated molecular pattern (PAMP) to trigger STING-dependent immune responses. Here, we show that upon infection, VopY, an effector of Vibrio parahaemolyticus, is injected into host cells by type III secretion system 2 (T3SS2), a secretion system unique to its pathogenic strains and indispensable for enterotoxicity. VopY is an EAL-domain-containing phosphodiesterase and is capable of hydrolyzing c-di-GMP. VopY expression in host cells prevents the activation of STING and STING-dependent downstream signaling triggered by c-di-GMP and, consequently, suppresses type I interferon immune responses. The presence of VopY in V. parahaemolyticus enables it to cause both T3SS2-dependent enterotoxicity and cytotoxicity. These findings uncover the destruction of self-derived PAMPs by injecting specific effectors to suppress PAMP-triggered immune responses as a unique strategy for bacterial pathogens to subvert immunity and cause disease.


Asunto(s)
Vibrio parahaemolyticus , Vibrio parahaemolyticus/metabolismo , Virulencia , Reconocimiento de Inmunidad Innata , Sistemas de Secreción Tipo III/metabolismo , Proteínas Bacterianas/metabolismo
7.
Microbiol Resour Announc ; 12(9): e0015223, 2023 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-37610212

RESUMEN

Vanrija sp. strain TS01 was isolated from urine sample from a leukemia patient in Nanjing, China. The closest known relative strain is Vanrija humicola with average nucleotide identity value of 93.1. The draft genome comprises 22.0 Mb in 52 contigs, with G + C content of 62.57%.

8.
Microbiol Spectr ; 11(4): e0180823, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37432106

RESUMEN

In the situation of mass vaccination against COVID-19, few studies have reported on the early kinetics of specific antibodies (IgG/IgM/IgA) of vaccine breakthrough cases. There is still a lack of epidemiological evidence about the value of serological indicators in the auxiliary diagnosis of COVID-19 infection, especially when the nucleic acid results were undetectable. Omicron breakthrough cases post-inactivated vaccination (n = 456) and COVID-19-naive individuals with two doses of inactivated vaccination (n = 693) were enrolled. Blood samples were collected and tested for SARS-CoV-2 antibody levels based on the magnetic chemiluminescence enzyme immunoassay. Among Omicron breakthrough cases, the serum IgG antibody level was 36.34 Sample/CutOff (S/CO) (95% confidence interval [CI], 31.89 to 40.79) in the acute phase and 88.45 S/CO (95% CI, 82.79 to 94.12) in the recovery phase. Serum IgA can be detected in the first week post-symptom onset (PSO) and showed an almost linear increase within 5 weeks PSO. Compared with those of breakthrough cases, IgG and IgA titers of the postimmune group were much lower (4.70 S/CO and 0.46 S/CO, respectively). Multivariate regression showed that serum IgG and IgA levels in Omicron breakthrough cases were mainly affected by the weeks PSO (P < 0.001). Receiver operating characteristic ROC0 curve analysis showed that the area under the curve (AUC) was 0.744 and 0.806 when the cutoff values of IgA and IgG were 1 S/CO and 15 S/CO, respectively. Omicron breakthrough infection can lead to a further increase in IgG and IgA levels relative to those of the immunized population. When nucleic acid real-time PCR was negative, we would use the kinetics of IgG and IgA levels to distinguish the breakthrough cases from the immunized population. IMPORTANCE This study fills a gap in the epidemiological evidence by investigating the value of serological indicators, particularly IgG and IgA levels, in the auxiliary diagnosis of COVID-19 infections when nucleic acid results are undetectable. The findings reveal that among Omicron breakthrough cases, both IgG and IgA antibody levels exhibit significant changes. Serum IgG levels increase during the acute phase and rise further in the recovery phase. Serum IgA can be detected as early as the first week post-symptom onset (PSO), showing a consistent linear increase within 5 weeks PSO. Furthermore, receiver operating characteristic (ROC) curve analysis demonstrates the potential of IgG and IgA cutoff values as diagnostic markers. The study's conclusion underscores the importance of monitoring IgG and IgA kinetics in distinguishing Omicron breakthrough cases from vaccinated individuals. These findings contribute to the development of more accurate diagnostic approaches and help inform public health strategies during the ongoing COVID-19 pandemic.


Asunto(s)
COVID-19 , Ácidos Nucleicos , Humanos , COVID-19/diagnóstico , Pandemias , SARS-CoV-2 , Anticuerpos Antivirales , Inmunoglobulina G , Inmunoglobulina A
9.
Front Microbiol ; 14: 1174200, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37323896

RESUMEN

Objective: To use genomic analysis to identify Acinetobacter spp. and to explore the distribution characteristics of ß-lactamase oxallicinases (blaOXA) among Acinetobacter species globally. Methods: Genomes of global Acinetobacter spp. were downloaded from GenBank using Aspera batch. After quality check using CheckM and QUAST software, the genomes were annotated using Prokka software to investigate the distribution of blaOXAs across Acinetobacter spp.; a phylogenetic tree was constructed to explore the evolutionary relationship among the blaOXA genes in Acinetobacter spp. Average-nucleotide identification (ANI) was performed to re-type the Acinetobacter spp. BLASTN comparison analysis was implemented to determine the sequence type (ST) of Acinetobacter baumannii strain. Results: A total of 7,853 genomes were downloaded, of which only 6,639 were left for further analysis after quality check. Among them, 282 blaOXA variants were identified from the genomes of 5,893 Acinetobacter spp.; blaOXA-23 (n = 3,168, 53.8%) and blaOXA-66 (2,630, 44.6%) were the most frequent blaOXAs, accounting for 52.6% (3,489/6639), and the co-carriage of blaOXA-23 and blaOXA-66 was seen in 2223 (37.7%) strains. The 282 blaOXA variants were divided into 27 clusters according to the phylogenetic tree. The biggest clade was blaOXA-51-family carbapenem-hydrolyzing enzymes composed of 108 blaOXA variants. Overall, 4,923 A. baumannii were identified out of the 6,639 Acinetobacter spp. strains and 291 distinct STs were identified among the 4,904 blaOXA-carrying A. baumannii. The most prevalent ST was ST2 (n = 3,023, 61.6%) followed by ST1 (n = 228, 4.6%). Conclusion: OXA-like carbapenemases were the main blaOXA-type ß-lactamase spread widely across Acinetobacter spp. Both blaOXA-23 and blaOXA-66 were the predominant blaOXAs, among all A. baumannii strains, with ST2 (belonging to CC2) being the main clone disseminated globally.

10.
Front Microbiol ; 14: 1140515, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36992935

RESUMEN

Pseudomonas aeruginosa is an opportunistic human pathogen notorious for its remarkable capacity of multi-drug resistance, and has become one of the most important model bacteria in clinical bacteriology research. Quantitative real-time PCR is a reliable method widely used in gene expression analysis, for which the selection of a set of appropriate housekeeping genes is a key prerequisite for the accuracy of the results. However, it is easy to overlook that the expression level of housekeeping gene may vary in different conditions, especially in the condition of molecular microbiology assays, where tested strains are generally cultured under the pre-set antibiotic selection pressures, and how this affects the stability of commonly used housekeeping genes remains unclear. In this study, the expression stability of ten classic housekeeping genes (algD, gyrA, anr, nadB, recA, fabD, proC, ampC, rpoS, and rpsL) under the pressure of eight laboratory commonly used antibiotics (kanamycin, gentamycin, tetracycline, chloramphenicol, hygromycin B, apramycin, tellurite, and zeocin) were tested. Results showed that the stability of housekeeping gene expression was indeed affected by the types of antibiotics added, and of course the best reference gene set varied for different antibiotics. This study provides a comprehensive summary of the effects of laboratory antibiotics on the stability of housekeeping genes in P. aeruginosa, highlighting the necessity to select housekeeping genes according to the type of antibiotics used in the initial stage of experiment.

11.
BMC Infect Dis ; 23(1): 182, 2023 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-36991368

RESUMEN

OBJECTIVE: To analyze the distribution of blaOXA among global Klebsiella pneumoniae and the characteristics of blaOXA-carrying K. pneumoniae. MATERIALS AND METHODS: The genomes of global K. pneumoniae were downloaded from NCBI by Aspera software. After quality check, the distribution of blaOXA among the qualified genomes was investigated by annotation with the resistant determinant database. The phylogenetic tree was constructed for the blaOXA variants based on the single nucleotide polymorphism (SNP) to explore the evolutionary relationship between these variants. The MLST (multi-locus sequence type) website and blastn tools were utilized to determine the sequence types (STs) of these blaOXA-carrying strains. and sample resource, isolation country, date and host were extracted by perl program for analyzing the characteristics of these strains. RESULTS: A total of 12,356 K. pneumoniae genomes were downloaded and 11,429 ones were qualified. Among them, 4386 strains were found to carry 5610 blaOXA variants which belonged to 27 varieties of blaOXAs, blaOXA-1 (n = 2891, 51.5%) and blaOXA-9 (n = 969, 17.3%) were the most prevalent blaOXA variants, followed by blaOXA-48 (n = 800, 14.3%) and blaOXA-232 (n = 480, 8.6%). The phylogenetic tree displayed 8 clades, three of them were composed of carbapenem-hydrolyzing oxacillinase (CHO). Totally, 300 distinct STs were identified among 4386 strains with ST11 (n = 477, 10.9%) being the most predominant one followed by ST258 (n = 410, 9.4%). Homo sapiens (2696/4386, 61.5%) was the main host for blaOXA-carrying K. pneumoniae isolates. The blaOXA-9-carrying K. pneumoniae strains were mostly found in the United States and blaOXA-48-carrying K. pneumoniae strains were mainly distributed in Europe and Asia. CONCLUSION: Among the global K. pneumoniae, numerous blaOXA variants were identified with blaOXA-1, blaOXA-9, blaOXA-48 and blaOXA-232 being the most prevalent ones, indicating that blaOXA rapidly evolved under the selective pressure of antimicrobial agents. ST11 and ST258 were the main clones for blaOXA-carrying K. pneumoniae.


Asunto(s)
Carbapenémicos , Klebsiella pneumoniae , Humanos , Estados Unidos , Tipificación de Secuencias Multilocus , Filogenia , Europa (Continente)
12.
Front Microbiol ; 14: 1127948, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36896426

RESUMEN

Objective: To analyze the molecular epidemiology of carbapenem-resistant Enterobacter cloacae complex (CREC) by whole-genome sequencing and to explore its clinical characteristics. Methods: Enterobacter cloacae complex isolates collected in a tertiary hospital during 2013-2021 were subjected to whole-genome sequencing to determine the distribution of antimicrobial resistance genes (ARGs), sequence types (STs), and plasmid replicons. A phylogenetic tree of the CREC strains was constructed based on the whole-genome sequences to analyze their relationships. Clinical patient information was collected for risk factor analysis. Results: Among the 51 CREC strains collected, blaNDM-1 (n = 42, 82.4%) was the main carbapenem-hydrolyzing ß-lactamase (CHßL), followed by blaIMP-4 (n = 11, 21.6%). Several other extended-spectrum ß-lactamase-encoding genes were also identified, with blaSHV-12 (n = 30, 58.8%) and blaTEM-1B (n = 24, 47.1%) being the predominant ones. Multi-locus sequence typing revealed 25 distinct STs, and ST418 (n = 12, 23.5%) was the predominant clone. Plasmid analysis identified 15 types of plasmid replicons, among which IncHI2 (n = 33, 64.7%) and IncHI2A (n = 33, 64.7%) were the main ones. Risk factor analysis showed that intensive care unit (ICU) admission, autoimmune disease, pulmonary infection, and previous corticosteroid use within 1 month were major risk factors for acquiring CREC. Logistic regression analysis showed that ICU admission was an independent risk factor for CREC acquisition and was closely related with acquiring infection by CREC with ST418. Conclusion: BlaNDM-1 and blaIMP-4 were the predominant carbapenem resistance genes. ST418 carrying BlaNDM-1 not only was the main clone, but also circulated in the ICU of our hospital during 2019-2021, which highlights the necessity for surveillance of this strain in the ICU. Furthermore, patients with risk factors for CREC acquisition, including ICU admission, autoimmune disease, pulmonary infection, and previous corticosteroid use within 1 month, need to be closely monitored for CREC infection.

13.
Lang Cogn Neurosci ; 38(1): 88-104, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36776698

RESUMEN

We examined how readers process content and function words in sentence comprehension with ERPs. Participants read simple declarative sentences using a rapid serial visual presentation (RSVP) with flankers paradigm. Sentences contained either an unexpected semantically anomalous content word, an unexpected syntactically anomalous function word or were well formed with no anomalies. ERPs were examined when target words were in the parafoveal or foveal vision. Unexpected content words elicited a typically distributed N400 when displayed in the parafovea, followed by a longer-lasting, widely distributed positivity starting around 300 ms once foveated. Unexpected function words elicited a left lateralized LAN-like component when presented in the parafovea, followed by a left lateralized, posteriorly distributed P600 when foveated. These results suggested that both semantic and syntactic processing involve two stages-the initial, fast process that can be completed in parafovea, followed by a more in depth attentionally mediated assessment that occurs with direct attention.

14.
Brief Funct Genomics ; 22(4): 366-374, 2023 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-36787234

RESUMEN

As a dynamical system, complex disease always has a sudden state transition at the tipping point, which is the result of the long-term accumulation of abnormal regulations. This paper proposes a novel approach to detect the early-warning signals of influenza A (H3N2 and H1N1) outbreaks by dysregulated dynamic network biomarkers (dysregulated DNBs) for individuals. The results of cross-validation show that our approach can detect early-warning signals before the symptom appears successfully. Unlike the traditional DNBs, our dysregulated DNBs are anchored and very few, which is essential for disease early diagnosis in clinical practice. Moreover, the genes of dysregulated DNBs are significantly enriched in the influenza-related pathways. The source code of this paper can be freely downloaded from https://github.com/YanhaoHuo/dysregulated-DNBs.git.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Humanos , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Subtipo H3N2 del Virus de la Influenza A/metabolismo , Gripe Humana/diagnóstico , Gripe Humana/genética , Biomarcadores/metabolismo
15.
Front Immunol ; 14: 1083523, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36761738

RESUMEN

Background: The quantitative level and kinetics of neutralizing antibodies (NAbs) in individuals with Omicron breakthrough infections may differ from those of vaccinated individuals without infection. Therefore, we aimed to evaluate the difference in NAb levels to distinguish the breakthrough cases from the post-immunized population to identify early infected person in an outbreak epidemic when nasal and/or pharyngeal swab nucleic acid real-time PCR results were negative. Methods: We collected 1077 serum samples from 877 individuals, including 189 with Omicron BA.2 breakthrough infection and 688 post-immunized participants. NAb titers were detected using the surrogate virus neutralization test, and were log(2)-transformed to normalize prior to analysis using Student's unpaired t-tests. Geometric mean titers (GMT) were calculated with 95% confidence intervals (CI). Linear regression models were used to identify factors associated with NAb levels. We further conducted ROC curve analysis to evaluate the NAbs' ability to identify breakthrough infected individuals in the vaccinated population. Results: The breakthrough infection group had a consistently higher NAb levels than the post-immunized group according to time since the last vaccination. NAb titers in the breakthrough infection group were 6.4-fold higher than those in the post-immunized group (GMT: 40.72 AU/mL and 6.38 AU/mL, respectively; p<0.0001). In the breakthrough infection group, the NAbs in the convalescent phase were 10.9-fold higher than in the acute phase (GMT: 200.48 AU/mL and 18.46 AU/mL, respectively; p<0.0001). In addition, the time since infection, booster vaccination, and the time since last vaccination were associated with log(2)-transformed NAb levels in the breakthrough infection group. ROC curve analysis showed that ROC area was largest (0.728) when the cut-off value of log(2)-transformed NAb was 6, which indicated that NAb levels could identify breakthrough infected individuals in the vaccinated population. Conclusion: Our study demonstrates that the NAb titers of Omicron BA.2 variant breakthrough cases are higher than in the post-immunized group. The difference in NAb levels could be used to identify cases of breakthrough infection from the post-immunized population in an outbreak epidemic.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Cinética , COVID-19/prevención & control , Anticuerpos Antivirales , Vacunación , Anticuerpos Neutralizantes , Infección Irruptiva
16.
Emerg Microbes Infect ; 12(1): 2146535, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36373485

RESUMEN

How much the vaccine contributes to the induction and development of neutralizing antibodies (NAbs) of breakthrough cases relative to those unvaccinated-infected cases is not fully understood. We conducted a prospective cohort study and collected serum samples from 576 individuals who were diagnosed with SARS-CoV-2 Delta strain infection, including 245 breakthrough cases and 331 unvaccinated-infected cases. NAbs were analysed by live virus microneutralization test and transformation of NAb titre. NAbs titres against SARS-CoV-2 ancestral and Delta variant in breakthrough cases were 7.8-fold and 4.0-fold higher than in unvaccinated-infected cases, respectively. NAbs titres in breakthrough cases peaked at the second week after onset/infection. However, the NAbs titres in the unvaccinated-infected cases reached their highest levels during the third week. Compared to those with higher levels of NAbs, those with lower levels of NAbs had no difference in viral clearance duration time (P>0.05), did exhibit higher viral load at the beginning of infection/maximum viral load of infection. NAb levels were statistically higher in the moderate cases than in the mild cases (P<0.0001). Notably, in breakthrough cases, NAb levels were highest longer than 4 months after vaccination (Delta strain: 53,118.2 U/mL), and lowest in breakthrough cases shorter than 1 month (Delta strain: 7551.2 U/mL). Cross-neutralization against the ancestral strain and the current circulating isolate (Omicron BA.5) was significantly lower than against the Delta variant in both breakthrough cases and unvaccinated-infected cases. Our study demonstrated that vaccination could induce immune responses more rapidly and greater which could be effective in controlling SARS-CoV-2.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Estudios Prospectivos , Pruebas de Neutralización , COVID-19/prevención & control , Vacunación , Anticuerpos Neutralizantes , Anticuerpos Antivirales
17.
Eur J Med Chem ; 247: 115030, 2023 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-36586298

RESUMEN

The PI3K-Akt-mTOR signaling pathway is a highly frequently activated signal transduction pathway in human malignancies, which has been a hot target for anti-tumoral drug discovery. Based on our previous research, a function-oriented synthesis (FOS) of imidazo[1,2-a]pyrazines and imidazo[1,2-b]pyridazines was conducted, and their anticancer activities in vitro and in vivo were evaluated. Among them, compound 42 exhibited excellent dual PI3K/mTOR inhibitory activity, with IC50 values on PI3Kα and mTOR of 0.06 nM and 3.12 nM, respectively, much better than our previous reported compound 15a. Furthermore, compound 42 exhibited significant in vitro and in vivo anti-tumoral activities, great kinase selectivity, low hepatotoxicity, modest plasma clearance and acceptable oral bioavailability, which is a promising PI3K/mTOR targeted anti-cancer drug candidate.


Asunto(s)
Antineoplásicos , Piridazinas , Humanos , Línea Celular Tumoral , Proliferación Celular , Inhibidores mTOR , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Piridazinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo
18.
Neuropsychology ; 37(7): 813-826, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35925735

RESUMEN

OBJECTIVE: The present study investigated cognitive mechanisms underlying the ability to stop "autocorrect" errors elicited by unexpected words in a read-aloud task, and the utility of autocorrection for predicting Alzheimer's disease (AD) biomarkers. METHOD: Cognitively normal participants (total n = 85; n = 64 with cerebrospinal fluid [CSF] biomarkers) read aloud six short paragraphs in which 10 critical target words were replaced with autocorrect targets, for example, The player who scored that final [paint] for the local team reported [him] experience. Autocorrect targets either replaced the most expected/dominant completion (i.e., point) or a less expected/nondominant completion (i.e., basket), and within each paragraph half of the autocorrect targets were content words (e.g., point/paint) and half were function words (e.g., his/him). Participants were instructed to avoid autocorrecting. RESULTS: Participants produced more autocorrect errors in paragraphs with dominant than with nondominant targets, and with function than with content targets. Cognitively normal participants with high CSF Tau/Aß42 (i.e., an AD-like biomarker profile) produced more autocorrect total errors than those below the Tau/Aß42 threshold, an effect also significant with dominant-function targets alone (e.g., saying his instead of him). A logistic regression model with dominant-function errors and age showed errors as the stronger predictor of biomarker status (sensitivity 83%; specificity 85%). CONCLUSIONS: Difficulty stopping autocorrect errors is associated with biomarkers indicating preclinical AD, and reveals promise as a diagnostic tool. Greater vulnerability of function over content words to autocorrection in individuals with AD-like biomarkers implicates monitoring and attention (rather than semantic processing) in the earliest of cognitive changes associated with AD risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Asunto(s)
Enfermedad de Alzheimer , Masculino , Humanos , Enfermedad de Alzheimer/psicología , Lectura , Semántica , Atención , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides , Proteínas tau
19.
Children (Basel) ; 11(1)2023 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-38255369

RESUMEN

Objectives: Psychological issues among adolescents represent a prevalent challenge in today's society. The purpose of this study is to explore the associations among moderate-to-vigorous physical activity, self-disclosure, social anxiety, and social avoidance in adolescents. Methods: This study collected cross-sectional data from 427 students in eight provincial key junior and senior high schools in the central China region of three provinces using snowball sampling and convenience sampling from July to August 2023. A structural equation model was employed to investigate the relationship between moderate-to-vigorous physical activity and social avoidance among adolescents. Results: The findings indicate that moderate-to-vigorous physical activity is negatively correlated with social anxiety (standardized coefficient = -0.219, p < 0.001) and positively correlated with self-disclosure (standardized coefficient = 0.454, p < 0.001). Social anxiety is negatively correlated with self-disclosure (standardized coefficient = -0.220, p < 0.001). Social avoidance is positively correlated with social anxiety (standardized coefficient = 0.461, p < 0.001) and negatively correlated with self-disclosure (standardized coefficient = -0.331, p < 0.001). Conclusions: The chain-mediated dual-path model between moderate-to-vigorous physical activity and social avoidance is facilitated by social anxiety and self-disclosure. In other words, adolescents who engage in more moderate to high-intensity physical activities exhibit lower levels of social anxiety, and those who have a stronger inclination for self-disclosure tend to demonstrate lower levels of social avoidance. In light of these findings, it is recommended that the government, society, schools, and families collaborate synergistically to promote the holistic well-being of adolescents and advance the development of a healthier China.

20.
BMC Microbiol ; 22(1): 255, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-36266616

RESUMEN

OBJECTIVE: To analyze the characteristics of global ß-lactamase-producing Enterobacter cloacae including the distribution of ß-lactamase, sequence types (STs) as well as plasmid replicons. METHODS: All the genomes of the E. cloacae were downloaded from GenBank. The distribution of ß-lactamase encoding genes were investigated by genome annotation after the genome quality was checked. The STs of these strains were analyzed by multi-locus sequence typing (MLST). The distribution of plasmid replicons was further explored by submitting these genomes to the genome epidemiology center. The isolation information of these strains was extracted by Per program from GenBank. RESULTS: A total of 272 out of 276 strains were found to carry ß-lactamase encoding genes. Among them, 23 varieties of ß-lactamase were identified, blaCMH (n = 130, 47.8%) and blaACT (n = 126, 46.3%) were the most predominant ones, 9 genotypes of carbapenem-hydrolyzing ß-lactamase (CHßLs) were identified with blaVIM (n = 29, 10.7%) and blaKPC (n = 24, 8.9%) being the most dominant ones. In addition, 115 distinct STs for the 272 ß-lactamase-carrying E. cloacae and 48 different STs for 106 CHßLs-producing E. cloacae were detected. ST873 (n = 27, 9.9%) was the most common ST. Furthermore, 25 different plasmid replicons were identified, IncHI2 (n = 65, 23.9%), IncHI2A (n = 64, 23.5%) and IncFII (n = 62, 22.8%) were the most common ones. Notably, the distribution of plasmid replicons IncHI2 and IncHI2A among CHßLs-producing strains were significantly higher than theat among non-CHßLs-producing strains (p < 0.05). CONCLUSION: Almost all the E. cloacae contained ß-lactamase encoding gene. Among the global E. cloacae, blaCMH and blaACT were main blaAmpC genes. BlaTEM and blaCTX-M were the predominant ESBLs. BlaKPC, blaVIM and blaNDM were the major CHßLs. Additionally, diversely distinct STs and different replicons were identified.


Asunto(s)
Enterobacter cloacae , beta-Lactamasas , Enterobacter cloacae/genética , beta-Lactamasas/genética , Tipificación de Secuencias Multilocus , Pruebas de Sensibilidad Microbiana , Carbapenémicos/farmacología , Genómica
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