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1.
Microb Pathog ; : 106646, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38631414

RESUMO

Porcine viral diarrhea is a common ailment in clinical settings, causing significant economic losses to the swine industry. Notable culprits behind porcine viral diarrhea encompass transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and porcine rotavirus-A (PoRVA). Co-infections involving the viruses are a common occurrence in clinical settings, thereby amplifying the complexities associated with differential diagnosis. As a consequence, it is therefore necessary to develop a method that can detect and differentiate all four porcine diarrhea viruses (TGEV, PEDV, PDCoV, and PoRVA) with a high sensitivity and specificity. Presently, polymerase chain reaction (PCR) is the go-to method for pathogen detection. In comparison to conventional PCR, TaqMan real-time PCR offers heightened sensitivity, superior specificity, and enhanced accuracy. This study aimed to develop a quadruplex real-time RT-qPCR assay, utilizing TaqMan probes, for the distinctive detection of TGEV, PEDV, PDCoV, and PoRVA. The quadruplex real-time RT-qPCR assay, as devised in this study, exhibited the capacity to avoid the detection of unrelated pathogens and demonstrated commendable specificity, sensitivity, repeatability, and reproducibility, boasting a limit of detection (LOD) of 27 copies/µL. In a comparative analysis involving 5483 clinical samples, the results from the commercial RT-qPCR kit and the quadruplex RT-qPCR for TGEV, PEDV, PDCoV, and PoRVA detection were entirely consistent. Following sample collection from October to March in Guangxi Zhuang Autonomous Region, we assessed the prevalence of TGEV, PEDV, PDCoV, and PoRVA in piglet diarrhea samples, revealing positive detection rates of 0.2% (11/5483), 8.82% (485/5483), 1.22% (67/5483), and 4.94% (271/5483), respectively. The co-infection rates of PEDV/PoRVA, PEDV/PDCoV, TGEV/PED/PoRVA, and PDCoV/PoRVA were 0.39%, 0.11%, 0.01%, and 0.03%, respectively, with no detection of other co-infections, as determined by the quadruplex real-time RT-qPCR. This research not only established a valuable tool for the simultaneous differentiation of TGEV, PEDV, PDCoV, and PoRVA in practical applications but also provided crucial insights into the prevalence of these viral pathogens causing diarrhea in Guangxi.

2.
Pers Soc Psychol Bull ; : 1461672231210451, 2023 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-37997808

RESUMO

Studies have found large differences in masks use during the pandemic. We found evidence that cultural tightness explains mask use differences and this association was more robust in tight situations like subways. In Study 1, we observed 23,551 people's actual mask use in public places around China. People wore masks more in tight situations; however, differences did not extend to outdoor streets and public parks, where norms are looser. We replicated this finding using a data from 15,985 people across China. Finally, in a preregistered study we observed mask use with the removal of COVID-19 restrictions, people still wore masks more in tight situations like subways than in loose situations of parks. These findings suggest that norm tightness has a lasting association with people's health-protective behaviors, especially in tight situations. It provides insight into how different cultures might respond with future pandemics and in what situations people adopt health-protective behaviors.

3.
Viruses ; 15(11)2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-38005924

RESUMO

The porcine reproductive and respiratory syndrome virus (PRRSV) has caused significant economic losses to the swine industry. The U.S., China, and Peru have reported NADC30-like or NADC34-like PRRSV-infected piglets, which have been identified as the cause of a significant number of abortions in clinics. Although the pathogenicity of NADC30-like PRRSV and NADC34-like PRRSV in piglets exhibits significant variability globally, studies on their pathogenicity in China are limited. In this study, the animal experiments showed that within 8-14 days post-infection, both piglets infected with NADC30-like PRRSV GXGG-8011 and those infected with NADC34-like PRRSV LNSY-GY exhibited significant weight loss compared to the control piglets. Additionally, the viremia of the LNSY-GY persisted for 28 days, while the viremia of piglets infected with the GXGG-8011 lasted for 17 days. Similarly, the duration of viral shedding through the fecal-oral route after the LNSY-GY infection was longer than that observed after the GXGG-8011 infection. Furthermore, post-infection, both the LNSY-GY and GXGG-8011 led to pronounced histopathological lesions in the lungs of piglets, including interstitial pneumonia and notable viral colonization. However, the antibody production in the LNSY-GY-infected group occurred earlier than that in the GXGG-8011-infected group. Our research findings indicate that LNSY-GY is a mildly pathogenic strain in piglets, whereas we speculate that the GXGG-8011 might be a highly pathogenic strain.


Assuntos
Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Suínos , Virulência , Viremia , Genoma Viral , Filogenia , China
4.
Bioorg Med Chem Lett ; 94: 129454, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37591316

RESUMO

Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Ensaios de Triagem em Larga Escala , Hipoglicemiantes/farmacologia , Octanos/química , Octanos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia
5.
Front Cardiovasc Med ; 10: 1153625, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37265567

RESUMO

Aims: The pathogenesis of disease progression targets for patients with heart failure after acute myocardial infarction was investigated by using plasma proteomics. Methods: The plasma proteomes of acute myocardial infarction patients with (MI-HF) and without (MI-WHF) heart failure were compared. Each group consisted of 10 patients who were matched for age and sex. The peptides were analyzed by 2-dimensional liquid chromatography coupled to tandem mass spectrometry in a high definition mode. Parallel reaction monitoring (PRM) verified the selected target proteins. Results: We identified and quantified 2,589 and 2,222 proteins, respectively, and found 117 differentially expressed proteins (DEPs) (≥1.5-fold), when the MI-HF and MI-WHF groups were compared. Of these 51 and 66 were significantly up-regulated and down-regulated, respectively. The significant DEPs was subjected to protein-protein interaction network analysis which revealed a central role of the NF-κB signaling pathway in the MI-HF patients. PRM verified that MB, DIAPH1, VNN1, GOT2, SLC4A1, CRP, CKM, SOD3, F7, DLD, PGAM2, GOT1, UBA7 and HYOU1 were 14 proteins which were highly expressed in MI-HF patients. Conclusions: These findings showed a group of proteins related to the NF-κB signaling pathway in the pathogenesis of patients with poor outcomes after experiencing MI-HF. These proteins may be useful candidate markers for the diagnosis of MI-HF as well as help to elucidate the pathophysiology of this major cause of mortality in older patients.

6.
Bioorg Med Chem Lett ; 92: 129394, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37379958

RESUMO

Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1). This work resulted in compound 3 that showed an improved safety profile. We hypothesized that this improvement was related to diminished binding of 3 to non-translating ribosomes and an apparent improvement in transcript selectivity. Herein, we describe our efforts to further optimize this series of inhibitors through modulation of the heterocyclic head group and the amine fragment. Some of the effort was guided by an emerging cryo electron microscopy structure of the binding mode of 1 in the ribosome. These efforts led to the identification of 15 that was deemed suitable for evaluation in a humanized PCSK9 mouse model and a rat toxicology study. Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate.

7.
Int J Ophthalmol ; 16(4): 547-553, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37077475

RESUMO

AIM: To observe the clinical efficacy of the combined use of small incision lenticule extraction (SMILE)-derived lenticule patches in corneal dermoid excision, with fixation of the lenticule patches assisted by fibrin glue. METHODS: Seventeen eyes of 17 patients with corneal dermoid were treated with dermoid removal combined with SMILE-derived lenticule transplantation. All lenticule patches were fixed by fibrin glue. Ocular changes were assessed using slit lamp microscopy and anterior-segmental optical coherence tomography. The best-corrected visual acuity (BCVA) and ocular dioptric variations were examined preoperatively and postoperatively. Intraocular pressure (IOP) was also monitored in all visited time. RESULTS: Totally, 18 lenticule patches were used on 17 eyes of 17 cornea dermoid patients. The mean follow-up time was 11.47±5.28mo. All lenticule patches were successfully glued, kept on its location and maintained transparent during the follow-up time, with a consecutive epithelial cover for 1wk. Nine of the patients could coordinate visual and optometry exam well. Their preoperative BCVA is 0.60±0.35 in decimal, significantly improved to 0.80±0.26 in decimal at 6mo postoperatively (Z=-2.392, P=0.017), but the changes of their corneal astigmatism diopters showed no significance, with 2.22±1.91 D preoperatively, and 2.28±1.31 D at 6mo postoperatively (Z=-0.135, P=0.893). Limbal pannus formation occurred in 4 (23.52%) cases and decreased with the application of tacrolimus eyedrops. IOP increased in 2 (11.76%) cases, but well decreased by timolol maleate eyedrops. All the adult patients or guardians of minor patients were satisfied with the cosmetic improvement. CONCLUSION: Dermoid excision combined with transplantation of SMILE-derived lenticule patches using fibrin glue is a safe and effective novel tectonic keratoplasty procedure for corneal dermoid.

8.
Front Neurosci ; 17: 1087488, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37008223

RESUMO

Cross-modal correspondence has been consistently evidenced between shapes and other sensory attributes. Especially, the curvature of shapes may arouse the affective account, which may contribute to understanding the mechanism of cross-modal integration. Hence, the current study used the functional magnetic resonance imaging (fMRI) technique to examine brain activity's specificity when people view circular and angular shapes. The circular shapes consisted of a circle and an ellipse, while the angular shapes consisted of a triangle and a star. Results show that the brain areas activated by circular shapes mainly involved the sub-occipital lobe, fusiform gyrus, sub and middle occipital gyrus, and cerebellar VI. The brain areas activated by angular shapes mainly involve the cuneus, middle occipital gyrus, lingual gyrus, and calcarine gyrus. The brain activation patterns of circular shapes did not differ significantly from those of angular shapes. Such a null finding was unexpected when previous cross-modal correspondence of shape curvature was considered. The different brain regions detected by circular and angular shapes and the potential explanations were discussed in the paper.

9.
Scand J Psychol ; 64(4): 437-452, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36892531

RESUMO

Multiple object tracking (MOT) is generally regarded as a pure attention-consuming task that draws heavily on attention resources. In the present study, we adopted a cross-channel visual-audio dual-task paradigm, i.e., the MOT task combined with the concurrent auditory N-back working memory task, to test whether working memory indeed plays a necessary role in the process of multiple tracking, as well as to further identify the specific types of working memory components involved in this process. Experiments 1a and 1b examined the relationship between the MOT task and nonspatial object working memory (OWM) processing by manipulating the tracking load and working memory load, respectively. Results in both experiments indicated that the concurrent nonspatial OWM task did not have a significant effect on the tracking capacity of the MOT task. In contrast, Experiments 2a and 2b examined the relationship between the MOT task and spatial working memory (SWM) processing by a similar approach. Results in both experiments indicated that the concurrent SWM task significantly impaired the tracking capacity of the MOT task, showing a gradual decrease with increasing SWM load. Overall, our study provides empirical evidence that multiple object tracking does involve working memory, primarily related to spatial working memory rather than nonspatial object working memory, which sheds more light on the mechanisms of multiple object tracking.


Assuntos
Atenção , Memória de Curto Prazo , Humanos
10.
Sci Total Environ ; 846: 157462, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-35868383

RESUMO

Tris(2-chloroethyl) phosphate (TCEP), as a typical chlorinated flame retardant, is attracting more attention as a carcinogen. Although persulfate-based oxidation exhibits good performance in removing refractory organic pollutants, the kinetics of persulfate-based remediation are affected by inorganic anions, which causes inaccurate remediation efficiency. This study combines steady-state radical concentration modelling with isotope fractionation to investigate the effects of inorganic anions on TCEP degradation by UV/persulfate (UV/PS). In the absence of anions during UV/PS system, the observed degradation rate was (9.7 ± 0.1) × 10-5 s-1, which was approximately 93 % attributed to sulfate radical (SO4-•) oxidation based on radical modelling. Carbon isotope fractionation, coupled with the identification of transformation products by mass spectrometry, suggests a carbon bond split during TCEP degradation with a carbon isotopic fractionation value (ε) of -1.6 ± 0.2 ‰ (± 95 % confidence intervals). With respect to co-existing anions in UV/PS system, the addition of chloride (Cl-) had a negligible effect on degradation rates, while the addition of hydrogencarbonate (HCO3-) caused them to decrease, and the addition of hydrogenphosphate (HPO42-) caused them to increase. Radical modelling suggested that SO4-• was transformed to chlorine radicals (Cl•/Cl2-•), phosphate radicals (HPO4-•), and carbonate radicals (CO3-•). Furthermore, the overlapping 95 % confidence intervals (C.I.) and the statistical tests (p > 0.05) both agree that Cl- and HPO42- gain identical ε values. Nevertheless, when HCO3- coexisted in the UV/PS system, the ε values were distinct. The addition of HCO3- would result in ε variation of TCEP in the UV activated PS process, which should receive more attention when applying remediation.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Ânions , Carbono , Isótopos/análise , Cinética , Oxirredução , Fosfatos , Fosfinas , Sulfatos/química , Raios Ultravioleta , Poluentes Químicos da Água/análise
11.
ACS Med Chem Lett ; 13(1): 55-62, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35059124

RESUMO

CD33/Siglec 3 is a myeloid lineage cell surface receptor that is known to regulate microglia activity. Multiple genome-wide association studies (GWAS) have identified genetic variants in the CD33 gene that convey protection from late-onset Alzheimer's disease. Furthermore, mechanistic studies into GWAS-linked variants suggest that disease protection is attributed to the alternative splicing of exon 2 of the CD33 pre-mRNA. Using a phenomimetic screen, a series of compounds were found to enhance the exclusion of CD33 exon 2, acting as a chemomimetic of the GWAS-linked gene variants. Additional studies confirmed that meyloid lineage cells treated with several of these compounds have a reduced full-length V-domain containing CD33 protein, while targeted RNA-seq concordantly demonstrated that compound 1 increases exon 2 skipping in cellular mRNA pools. These studies demonstrate how pharmacological interventions can be used to manipulate disease-relevant pre-mRNA splicing and provide a starting point for future efforts to identify small molecules that alter neuroimmune function that is rooted in the human biology of neurodegenerative disease.

12.
Br J Psychol ; 113(3): 653-676, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34921401

RESUMO

Previous studies on perceptual grouping found that people can use spatiotemporal and featural information to group spatially separated rigid objects into a unit while tracking moving objects. However, few studies have tested the role of objects' self-motion information in perceptual grouping, although it is of great significance to the motion perception in the three-dimensional space. In natural environments, objects always move in translation and rotation at the same time. The self-rotation of the objects seriously destroys objects' rigidity and topology, creates conflicting movement signals and results in crowding effects. Thus, this study sought to examine the specific role played by self-rotation information on grouping spatially separated non-rigid objects through a modified multiple object tracking (MOT) paradigm with self-rotating objects. Experiment 1 found that people could use self-rotation information to group spatially separated non-rigid objects, even though this information was deleterious for attentive tracking and irrelevant to the task requirements, and people seemed to use it strategically rather than automatically. Experiment 2 provided stronger evidence that this grouping advantage did come from the self-rotation per se rather than surface-level cues arising from self-rotation (e.g. similar 2D motion signals and common shapes). Experiment 3 changed the stimuli to more natural 3D cubes to strengthen the impression of self-rotation and again found that self-rotation improved grouping. Finally, Experiment 4 demonstrated that grouping by self-rotation and grouping by changing shape were statistically comparable but additive, suggesting that they were two different sources of the object information. Thus, grouping by self-rotation mainly benefited from the perceptual differences in motion flow fields rather than in deformation. Overall, this study is the first attempt to identify self-motion as a new feature that people can use to group objects in dynamic scenes and shed light on debates about what entities/units we group and what kinds of information about a target we process while tracking objects.


Assuntos
Percepção de Movimento , Atenção , Sinais (Psicologia) , Humanos , Rotação
13.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34726479

RESUMO

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.


Assuntos
Tratamento Farmacológico da COVID-19 , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Animais , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Coronavirus/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Lactamas/administração & dosagem , Lactamas/farmacocinética , Leucina/administração & dosagem , Leucina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Prolina/administração & dosagem , Prolina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/administração & dosagem , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacos
14.
Front Psychol ; 12: 689251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163414

RESUMO

At the beginning of the coronavirus disease 2019 (COVID-19) outbreak, college students returning home from Wuhan, Hubei Province, experienced various degrees of discrimination. This study first investigates perceived discrimination among college students returning home from Wuhan. Then, an experimental method is used to investigate the effectiveness of an intervention designed to reduce the perceived discrimination among those who returned to towns outside of Hubei Province. A total of 63 college students participated in the experiment. In the experimental group (N = 31), a wise intervention based on reading and writing was adopted to intervene in perceived discrimination among the participants. The results showed that the perceived discrimination among students returning from Wuhan to towns outside of Hubei Province was significantly higher than that among students returning to towns within Hubei Province. The wise intervention reduced the perceived discrimination in the experimental group but not in the control group. Further analysis found that perceived social support fully mediated the relationship between the intervention and perceived discrimination. These results provide insights on how the content of intervention (perceived social support) and the form of intervention (wise intervention) can prevent the occurrence of psychological problems in epidemic situations.

15.
Front Psychol ; 12: 644704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790842

RESUMO

Facial emotional recognition is something used often in our daily lives. How does the brain process the face search? Can taste modify such a process? This study employed two tastes (sweet and acidic) to investigate the cross-modal interaction between taste and emotional face recognition. The behavior responses (reaction time and correct response ratios) and the event-related potential (ERP) were applied to analyze the interaction between taste and face processing. Behavior data showed that when detecting a negative target face with a positive face as a distractor, the participants perform the task faster with an acidic taste than with sweet. No interaction effect was observed with correct response ratio analysis. The early (P1, N170) and mid-stage [early posterior negativity (EPN)] components have shown that sweet and acidic tastes modified the ERP components with the affective face search process in the ERP results. No interaction effect was observed in the late-stage (LPP) component. Our data have extended the understanding of the cross-modal mechanism and provided electrophysiological evidence that affective facial processing could be influenced by sweet and acidic tastes.

16.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846787

RESUMO

It has been reported that lncRNA­NR024118 can suppress lipopolysaccharide (LPS)­induced inflammatory responses, which promote sepsis. The present study aimed to investigate the involvement of NR024118 in sepsis. Research subjects included 82 patients with sepsis without myocardial dysfunction (MD), 35 patients with sepsis with MD and 82 healthy controls. The expression levels of NR024118 in plasma collected from these participants and LPS­induced AC16 cells were measured by reverse transcription­quantitative PCR. The expression levels of IL­16 in these plasma samples and LPS­induced AC16 cells were measured by ELISA. The correlation between the expression levels of NR024118 and IL­6 across plasma samples were analyzed by Pearson's correlation coefficient. The action potential duration (APD) was measured at 50 and 90% repolarization. Cell apoptosis was determined by cell apoptosis assay. The expression levels of p­transcription factor p65 were detected by western blot analysis. NF­κB activity were analyzed by luciferase reporter assay. It was found that NR024118 was downregulated and IL­6 was upregulated in the plasma of patients with sepsis. Among patients with sepsis, the individuals with MD exhibited even lower expression levels of NR024118 and higher expression levels of IL­6. Among patients with sepsis with MD, the expression levels of NR024118 and IL­6 were inversely correlated. LPS could induce MD to construct the sepsis models based on the increased expression levels of TNF­α, IL­1ß, IL­6 and shortened APD by LPS­mediated induction. Overexpression of NR024118 significantly reduced the secretion of IL­6 and apoptosis of cardiomyocytes under LPS treatment. Functional studies demonstrated that NR024118 had negative regulation on p65 phosphorylation and NF­κB activation. NR024118 was suppressed in sepsis and inhibited LPS­induced apoptosis of cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Regulação para Baixo , Lipopolissacarídeos/efeitos adversos , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Sepse/metabolismo , Adulto , Idoso , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta , Interleucina-6 , Masculino , Pessoa de Meia-Idade , NF-kappa B , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
J Med Chem ; 64(1): 326-342, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356244

RESUMO

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (ß6 Glu → Val) on the ß-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.


Assuntos
Anemia Falciforme/tratamento farmacológico , Hemoglobina A/efeitos dos fármacos , Hemoglobina Falciforme/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Animais , Eritrócitos/metabolismo , Camundongos , Oxigênio/metabolismo , Quinolinas/química
18.
Front Psychol ; 11: 1822, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849074

RESUMO

The regulatory effect of embodied emotion on one's general emotion and the impact of the compatibility or incompatibility of the two types of emotion on creative thinking are still debatable. The purpose of this study is to investigate these issues experimentally. In Experiment 1, participants completed an explicit positive and negative emotion test [Positive and Negative Affect Schedule (PANAS)] and an implicit positive and negative emotion test [Implicit Positive and Negative Affect Test (IPANAT)] twice on a computer after emotional video priming was used to induce negative emotions and facial expression manipulation was performed to induce embodied positive or negative emotions. It was found that maintaining the expression of a suppressed smile was helpful in regulating negative emotions (p = 0.047). Specifically, the implicit negative emotions induced by facial expression manipulation had a positive regulating effect on the implicit negative emotions induced by the video (T1, M = 47.813; to T2, M = 44.188). In Experiment 2, the positive or negative emotions of the participants were induced using emotional videos, and facial expression manipulation was used to induce their embodied positive or negative emotions. Then, the participants completed a creative test by completing alternative use tasks (AUTs) and Chinese character riddles. The AUT fluency score in the emotionally compatible group was significantly higher than that in the emotionally incompatible group (p = 0.032), but while experiencing negative emotions, the emotionally compatible group had a significantly higher originality score and insight in Chinese character riddle score than the emotionally incompatible group (p = 0.017, p = 0.004). Therefore, embodied negative emotion has a significant regulating effect on implicit negative emotion. The compatibility of emotion activated by facial expression and viewing a video contributes to creative thinking, whereas the incompatibility of emotion hinders creative thinking. The compatibility of emotion under positive emotions improved thinking fluency, whereas under negative emotions, it activated originality and insight in creative thinking. The influence of such emotional compatibility on creative thinking may be due to the regulating effect of embodied emotions on implicit emotions induced by emotional stimuli.

19.
Front Psychol ; 11: 1940, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849139

RESUMO

In real-world scenarios, objects' surface features sometimes change as they move, impairing the continuity of objects. However, it is still unknown how our visual system adapts to this dynamic change. Hence, the present study investigated the role of feature changes in attentive tracking through a modified multiple object tracking (MOT) task. The feature heterogeneity and feature stability were manipulated in two experiments. The results from Experiment 1 showed that the tracking performance under feature-changed condition was lower than that under the feature-fixed condition only when the objects were four colors grouped or all unique, suggesting that the performance decrease was moderated by the feature heterogeneity. In Experiment 2, we further examined this effect by manipulating the frequency of feature change. The results showed that when the target set was one color or two colors grouped (the color grouping for the distractor set corresponded with it), the tracking performance decreased significantly as the feature-change frequency increased. However, this trend was not the case when the objects were of the same color or eight unique colors. In addition, a relatively consistent effect appeared both in Experiments 1 and 2. When objects have unique features, the tracking performance decreased significantly as the increase of feature heterogeneity in each frequency of feature changes. Taken together, we concluded that unstable features could be utilized in attentive tracking, and the extent to which the observers relied on surface feature information to assist tracking depended on the level of feature heterogeneity and the frequency of feature change.

20.
Front Psychol ; 10: 924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105626

RESUMO

Previous research has revealed the uniqueness-facilitation effect in the multiple object tracking (MOT) task: simple distinct identities and surface features of moving targets could facilitate attentional tracking. By adapting compound stimuli, the present study investigated whether the global or local properties played the main role in the uniqueness-facilitation effect in the MOT task. The uniqueness of local properties, of global properties or of both local and global properties were considered. Observers' tracking performance in alternative conditions were compared with that in the homogeneous condition wherein all stimuli have identical local and global properties. Results from two experiments suggest that the global properties played the key role in facilitating tracking. The distinctiveness of local properties can also facilitate tracking with global properties being homogeneous. However, when the stimuli's global properties are distinct from each other-whether the local properties being unique or not-observers' tracking performance can achieve the same level as that in the unitary-uniqueness condition wherein the moving objects were distinct unitary letters. These results revealed a global superiority effect in the MOT task. Finally, the facilitation effects of the global and local properties might depend on the stimulus sparsity. When the compound stimuli had fewer local elements, the uniqueness facilitation effect on tracking decreased.

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