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1.
Brief Bioinform ; 24(6)2023 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-37930030

RESUMEN

Bacterial infections often involve virulence factors that play a crucial role in the pathogenicity of bacteria. Accurate detection of virulence factor genes (VFGs) is essential for precise treatment and prognostic management of hypervirulent bacterial infections. However, there is a lack of rapid and accurate methods for VFG identification from the metagenomic data of clinical samples. Here, we developed a Reads-based Virulence Factors Scanner (RVFScan), an innovative user-friendly online tool that integrates a comprehensive VFG database with similarity matrix-based criteria for VFG prediction and annotation using metagenomic data without the need for assembly. RVFScan demonstrated superior performance compared to previous assembly-based and read-based VFG predictors, achieving a sensitivity of 97%, specificity of 98% and accuracy of 98%. We also conducted a large-scale analysis of 2425 clinical metagenomic datasets to investigate the utility of RVFScan, the species-specific VFG profiles and associations between VFGs and virulence phenotypes for 24 important pathogens were analyzed. By combining genomic comparisons and network analysis, we identified 53 VFGs with significantly higher abundances in hypervirulent Klebsiella pneumoniae (hvKp) than in classical K. pneumoniae. Furthermore, a cohort of 1256 samples suspected of K. pneumoniae infection demonstrated that RVFScan could identify hvKp with a sensitivity of 90%, specificity of 100% and accuracy of 98.73%, with 90% of hvKp samples consistent with clinical diagnosis (Cohen's kappa, 0.94). RVFScan has the potential to detect VFGs in low-biomass and high-complexity clinical samples using metagenomic reads without assembly. This capability facilitates the rapid identification and targeted treatment of hvKp infections and holds promise for application to other hypervirulent pathogens.


Asunto(s)
Infecciones Bacterianas , Factores de Virulencia , Humanos , Factores de Virulencia/genética , Metagenoma , Virulencia/genética , Klebsiella pneumoniae/genética , Infecciones Bacterianas/genética
2.
J Cardiothorac Surg ; 18(1): 165, 2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37118775

RESUMEN

OBJECTIVES: To analyze the epidemiological characteristics and trends in death after thoracotomy in children with congenital heart disease (CHD). METHODS: The clinical data of children with CHD aged 0-14 years who died after thoracotomy in our hospital from January 1, 2005, to December 31, 2020, were retrospectively collected to analyze the characteristics of and trends in postoperative death. RESULTS: A total of 502 patients (365 males; 72.7%) died from January 1, 2005, to December 31, 2020, with an average of 31 deaths per year. For these patients, the median age was 2.0 months, the median length of hospital stay was 16.0 days, the median postoperative time to death was 5.0 days, and the median risk adjustment in congenital heart surgery-1 (RACHS-1) score was 3.0. 29.5% underwent emergency surgery, 16.9% had postoperative ECMO support, and 15.9% received postoperative blood purification treatment. In the past 16 years, the deaths of children with CHD under 1 year old accounted for 80.5% of all deaths among children with CHD aged 0-14 years, and deaths (349 cases) under 6 kg accounted for 69.5% of all deaths. Age at death, weight, and disease type were characterized by annual changes. CONCLUSIONS: The postoperative deaths of children with CHD mainly occurred in infants and toddlers who weighed less than 6.0 kg, and TGA and PA were the most lethal CHDs. The proportion of deaths has been increasing across the years among patients who are young, have a low body weight, and have complex cyanotic CHD.


Asunto(s)
Cardiopatías Congénitas , Masculino , Lactante , Humanos , Estudios Retrospectivos , Cardiopatías Congénitas/cirugía , Tiempo de Internación , Hospitales , Toracotomía
3.
Org Biomol Chem ; 21(6): 1303-1315, 2023 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-36648089

RESUMEN

An efficient approach to access chiral N-α indole substituted pyrrolidine and piperidine skeletons has been developed through a AgSbF6-catalyzed N-α aza-Friedel-Crafts alkylation of N,O-acetals 6a, 6b, 9, and 11a-11d with indoles. As a result, a series of 2,3-trans N-α indole substituted pyrrolidines 8a-8x and piperidines 10a-10j were prepared in moderate to excellent yields and with excellent diastereoselectivities (dr up to 99 : 1). Moreover, several 2,5-cis-N-α indole substituted pyrrolidine derivatives 12a-12k were synthesized according to this strategy with moderate to good yields and diastereoselectivities (dr up to 99 : 1).

4.
Respir Med Case Rep ; 41: 101792, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36568318

RESUMEN

Invasive pulmonary aspergillosis (IPA) is a serious fungal infection, with a high degree of mortality in immunocompromised individuals. Diagnosis of IPA is challenging in that clinical manifestations are not specific, with sensitivity of traditional detection procedures low. We report a case of IPA in a chronic granulomatous disease (CGD) infant who was initially suspected to have a lung tumor. Aspergillus fumigatus was identified as the pathogen in bronchoalveolar lavage fluid (BALF) by next-generation sequencing (mNGS). The patient recovered rapidly following a change of appropriate antifungal treatment and was discharged. This case highlights the additional value of BALF-mNGS for the diagnosis of pediatric invasive pulmonary fungal infection in immune-deficient children.

5.
Molecules ; 27(21)2022 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-36364344

RESUMEN

The occurrence and development of neurodegenerative diseases is related to a variety of physiological and pathological changes. Neuroinflammation is one of the major factors that induces and aggravates neurodegenerative diseases. The most important manifestation of neuroinflammation is the activation of microglia. Therefore, inhibiting the abnormal activation of microglia is an important way to alleviate the occurrence of neuroinflammatory diseases. In this research, the inhibitory effect of tabersonine (Tab) on neuroinflammation was evaluated by establishing the BV2 neuroinflammation model induced by lipopolysaccharide (LPS). It was found that Tab significantly inhibited the production and expression of nitric oxide (NO), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and reactive oxygen species (ROS) in BV-2 cells stimulated by LPS. In addition, Tab can also inhibit the activation of nuclear factor-κB (NF-κB) induced by LPS, thus regulating inflammatory mediators such as inducible nitric oxide synthase (iNOS). These results indicated that Tab regulated the release of inflammatory mediators such as NO, IL-1ß, TNF-α, and IL-6 by inhibiting NF-κB signaling pathway, and exerting its anti-neuroinflammatory effect. This is the first report regarding the inhibition on LPS-induced neuroinflammation in BV2 microglia cells of Tab, which indicated the drug development potential of Tab for the treatment of neurodegenerative diseases.


Asunto(s)
Lipopolisacáridos , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Microglía , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Antiinflamatorios/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Óxido Nítrico/metabolismo
6.
Microbiol Spectr ; 10(5): e0148822, 2022 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-36169415

RESUMEN

Pneumonia is the leading cause of death in children; the pathogens are often difficult to diagnose. In this study, the performance of metagenomic next-generation sequencing (mNGS) using bronchoalveolar lavage fluid (BALF) samples from 112 children with confirmed pneumonia has been evaluated. mNGS performed a significantly higher positive detection rate (91.07%, 95% confidence interval [CI] 83.80% to 95.40%) and coincidence rate against the final diagnosis (72.32%, 95% CI 62.93% to 80.15%) than that of conventional methods (70.54%, 95% CI 61.06% to 78.58% and 56.25%, 95% CI 46.57% to 65.50%, respectively) (P < 0.01 and P < 0.05, respectively). Bacteria, viruses, and their mixed infections were common in children with pneumonia. Streptococcus pneumoniae was the most common bacterial pathogen in children with pneumonia, while Haemophilus parainfluenzae and Haemophilus influenzae seemed more likely to cause nonsevere pneumonia in children. In contrast, human cytomegalovirus (CMV) infection and the simultaneous bacterial infections could cause severe pneumonia, especially in children with underlying diseases. After adjustments of antibiotics based on mNGS and conventional methods, the conditions improved in 109 (97.32%) children. mNGS of BALF samples has shown great advantages in diagnosing the pathogenic etiology of pneumonia in children, especially when considering the limited volumes of BALF and the previous use of empirical antibiotics, contributing to the timely adjustment of antibiotic treatments, which can potentially improve the prognosis and decrease the mortality. IMPORTANCE Our study indicates high efficiency of mNGS using BALF for the detection of causative pathogens that cause pneumonia in children. mNGS can be a potential diagnostic tool to supplement conventional methods for children's pneumonia.


Asunto(s)
Metagenómica , Neumonía , Niño , Humanos , Líquido del Lavado Bronquioalveolar , Sensibilidad y Especificidad , Metagenómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neumonía/diagnóstico , Neumonía/microbiología , Bacterias/genética , Antibacterianos
7.
Front Pediatr ; 10: 903617, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36046481

RESUMEN

Background: Talaromyces marneffei (TM) bloodstream infections are life- threatening in immunocompromised individuals. The lack of specific clinical features for these infections and poor sensitivity associated with routine examination procedures make diagnosis challenging. Untimely diagnosis and delayed antifungal treatment threatens the life of such patients. Case description: We report a case of a TM bloodstream infection, confirmed by the results of blood culture, of a child who was HIV negative and possessed a CD40LG gene mutation. A diagnosis of TM was established by blood metagenomic next-generation sequencing (mNGS) of the patient's blood, which was confirmed by microbiological culture of blood. On admission, this previously healthy male patient was 8-months of age, who presented with recurrent fever and a cough of 6-days in duration. His condition did not improve after antibacterial treatment for 5-days, with significant and recurrent fever and worsening spirit. He was referred to the Department of Pediatrics in our tertiary medical institution with a white blood cell count of 21.5*10∧9/L, C-reactive protein of 47.98 mg/L, and procalcitonin of 0.28 ng/mL. A bloodstream infection was not excluded and blood was collected for microbial culture. The patient received a 1-day treatment of cefoperazone sulbactam and 6-days of imipenem cilastatin. Symptoms did not improve and fever persisted. Blood was submitted for mNGS analysis and within 14-h, 14,352 TM reads were detected with a relative abundance of 98.09%. Antibiotic treatment was immediately changed to intravenous amphotericin B combined with oral itraconazole. The condition of the child gradually improved. Blood culture showed TM on the 7th day after hospitalization, confirming bloodstream infection. After the 13th day of hospital admission, the patient's body temperature dropped close to 38°C and was discharged on the 30th day of hospitalization. Oral itraconazole was prescribed with follow up at the outpatient clinic. Conclusions: HIV-negative patients with CD40LG mutations may be potential hosts for TM. TM infections are rare in children and their detection by conventional microbial culture methods are inadequate for an early diagnosis. mNGS is a rapid detection method that permits early diagnosis of uncommon infectious agents, such as TM, allowing for improved patient outcomes.

8.
Public Relat Rev ; 48(4): 102230, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35910261

RESUMEN

In times of a national crisis such as COVID-19, it is important for organizations to show that they are good corporate citizens. At the same time, organizations should carefully select the type of messages that resonate with stakeholders so as to reduce stakeholder skepticism. This study examines how U.S. Fortune 500 companies discussed their COVID-19 pandemic CSR actions on Facebook over 15 months and how the public responded to such messages. We identified three CSR themes: internal stakeholder proactive CSR, external stakeholder proactive CSR, and external stakeholder accommodative CSR. When publics engaged, external stakeholder proactive CSR was significantly associated with better behavioral engagement outcomes, more positive emotional engagement outcomes, and less negative emotions. However, such effects are moderated by industry type. Our findings inform public relations theory and practice and suggest that in times of major crises, organizations should prioritize proactive approaches to engage external stakeholders while being mindful of specific institutional contexts.

9.
Health Commun ; 37(10): 1276-1284, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-33591839

RESUMEN

In times of public health emergencies, health agencies need to engage and communicate with the public in real-time to share updates and accurate information. This is especially the case for the COVID-19 pandemic where public engagement can potentially save lives and flatten the curve. This paper considers how the use of interactive features and strategic network positions of health agencies on social media influenced their public engagement outcomes. Specifically, we analyzed 203 U.S. public health agencies' Twitter activity and the public engagement they received by extracting data from a large-scale Twitter dataset collected from January 21st to May 31st, 2020. Results show that health agencies' network position in addition to their two-way communication strategy greatly influenced the level of public engagement with their COVID-19 related content on Twitter. Findings highlight the benefits of strategic social media communication of public health agencies resides not only in how agencies use social media but also in their formation of network position to amplify their visibility. As official sources of health and risk information, public health agencies should coordinate their social media communication efforts to strategically position themselves in advantageous network positions to augment public engagement outcomes.


Asunto(s)
COVID-19 , Medios de Comunicación Sociales , COVID-19/epidemiología , Comunicación , Humanos , Pandemias , Salud Pública
10.
Int J Gen Med ; 14: 8797-8803, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34858047

RESUMEN

OBJECTIVE: Earlobe crease (ELC) has been considered as a skin sign of atherosclerosis, and its pathophysiological mechanism is still unclear. Our study aims to test the hypothesis that ELC patients with lower serum levels of the age-suppressing hormone Klotho, which is not only associated with premature aging but also with endothelial dysfunction, may be associated with atherosclerosis. METHODS: A total of 135 patients aged 40-68 years underwent coronary angiography. According to the presence or absence of coronary heart disease (CAD) and ELC, they were divided into three groups: CAD group and ELC group (ELC group, n = 45); no ELC group (non-ELC group, n = 45). There was no ELC or CAD in the control group (control group, n = 45). Serum Klotho concentration was obtained by enzyme-linked immunosorbent assay (ELISA). RESULTS: The Klotho level in the ELC group was 365.6 ± 38.1 pg/mL, while the Klotho level in the non-ELC group was 568.8 ± 44.9 pg/mL. It is worth noting that the Klotho level of the ELC group was significantly lower than that of the non-ELC group (P < 0.001). The serum Klotho level of the control group was higher than that of the non-ELC group (593.3±45.3 vs 568.8±44.9 pg/mL, P = 0.702), but the difference was not statistically significant. Multiple logistic regression analysis showed that the Klotho level is a parameter that affects the appearance of ELC. CONCLUSION: Serum Klotho levels were considerably lower in patients with ELC. We concluded that the perturbations of Klotho in patients might be associated with ELC and with CAD.

11.
Comput Human Behav ; 122: 106838, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34754136

RESUMEN

NGOs are important civil actors in societies' emergency and disaster responses, and they come together on social media to identify prominent issues and coordinate issue responses. This research explores how U.S. NGO form topic-driven communities on social media to discuss and build representational strategic networks around issues related to the COVID-19 pandemic. Drawing from Issue Niche Theory, we examined how NGOs' networks and discourse evolved before and after the general public paid great attention to the COVID-19 issue and how such patterns changed across the whole issue niche and sub-issue niches. We analyzed the evolution of Twitter-based networks and discourse of 2,588 NGOs in the first five months of the COVID-19 outbreak in the United States. Our analysis revealed important factors that shape tie formation patterns in the NGOs' communities in this novel issue niche. The findings show that NGOs' discourses help to orient the organizational community to identify most salient issues. Finally, changes in the discourse patterns reflected changes in the communication networks in the NGO community.

12.
Org Biomol Chem ; 19(11): 2492-2501, 2021 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-33656504

RESUMEN

The Zn(OTf)2-catalyzed hydroamination of ynamides 2a-2l with aromatic amines 1a-1r was developed. This protocol features broad substrate scope of aromatic amines, good functional group tolerance for ynamides, and excellent regioselectivities. As a result, a variety of substituted amidine compounds 3aa-3oa, 3ab-3al and 3pa-3rk were prepared in moderate to excellent yields and with high regioselectivities.

13.
Nature ; 569(7754): 116-120, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30944474

RESUMEN

A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3.


Asunto(s)
Período Crítico Psicológico , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Oxitocina/metabolismo , Recompensa , Envejecimiento/fisiología , Animales , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Femenino , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Transducción de Señal/efectos de los fármacos
14.
Glia ; 67(5): 915-934, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30632636

RESUMEN

Optogenetics has been widely expanded to enhance or suppress neuronal activity and it has been recently applied to glial cells. Here, we have used a new approach based on selective expression of melanopsin, a G-protein-coupled photopigment, in astrocytes to trigger Ca2+ signaling. Using the genetically encoded Ca2+ indicator GCaMP6f and two-photon imaging, we show that melanopsin is both competent to stimulate robust IP3-dependent Ca2+ signals in astrocyte fine processes, and to evoke an ATP/Adenosine-dependent transient boost of hippocampal excitatory synaptic transmission. Additionally, under low-frequency light stimulation conditions, melanopsin-transfected astrocytes can trigger long-term synaptic changes. In vivo, melanopsin-astrocyte activation enhances episodic-like memory, suggesting melanopsin as an optical tool that could recapitulate the wide range of regulatory actions of astrocytes on neuronal networks in behaving animals. These results describe a novel approach using melanopsin as a precise trigger for astrocytes that mimics their endogenous G-protein signaling pathways, and present melanopsin as a valuable optical tool for neuron-glia studies.


Asunto(s)
Astrocitos/metabolismo , Red Nerviosa/metabolismo , Neuronas/metabolismo , Optogenética/métodos , Opsinas de Bastones/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Compuestos Azo/farmacología , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Quelantes/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/citología , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Pirimidinas/farmacología , Opsinas de Bastones/genética , Potenciales Sinápticos/fisiología , Triazoles/farmacología , Xantenos/farmacología
15.
J Biol Chem ; 294(11): 3806-3821, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30610117

RESUMEN

Channelrhodopsins (ChRs) are light-gated ion channels in widespread use in neuroscience for mediating the genetically targetable optical control of neurons (optogenetics). ChRs pass multiple kinds of ions, and although nonspecific ChR-mediated conductance is not an issue in many neuroscience studies, conductance of calcium and protons, which can mediate diverse cellular signals, may be undesirable in some instances. Here, we turned our attention to the creation of ChRs that have high cation photocurrent but pass fewer calcium ions and protons. We developed an automated, time-resolved screening method capable of rapidly phenotyping channelrhodopsin-2 (ChR2) variants. We found substitution mutations throughout ChR2 that could boost current while altering ion selectivity and observed that the mutations that reduced calcium or proton conductance have additive effects. By combining four mutations, we obtained a ChR, ChromeQ, with improved photocurrent that possesses order-of-magnitude reductions in calcium and proton conductance and high fidelity in driving repetitive action potentials in neurons. The approach presented here offers a viable pathway toward customization of complex physiological properties of optogenetic tools. We propose that our screening method not only enables elucidation of new ChR variants that affect microbial opsin performance but may also reveal new principles of optogenetic protein engineering.


Asunto(s)
Calcio/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Conductividad Eléctrica , Variación Genética , Protones , Animales , Clonación Molecular , Fluorescencia , Variación Genética/genética , Células HEK293 , Humanos , Oxidación-Reducción , Fenotipo , Procesos Fotoquímicos
16.
Lung ; 195(5): 563-569, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28474108

RESUMEN

INTRODUCTION: Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Recurrent respiratory tract infections in young children, especially viral infections, are the major cause of acute asthmatic exacerbations and contribute to development of asthma. Bacterial extracts have been used to improve the immune defenses of the respiratory tract. However, seldom studies have examined the effect of bacterial lysates on childhood asthma. In this study, we examined whether bacterial lysates (OM-85) will improve symptoms of asthmatic mice via modulation of the immune response. METHODS: Asthmatic mice models were established with OVA challenge and treated with oral administration of Broncho-Vaxom (OM-85). Next, infiltrations of inflammatory cells including eosinophil and neutrophils were examined. Pulmonary tissues in asthmatic mice models were analyzed by hematoxylin and eosin (HE) staining. The levels of Th1/Th2-typed cytokines in bronchoalveolar lavage fluid (BALF) of asthmatic mice models were examined by enzyme-linked immunosorbent assay. RESULTS: Compared to control group, we found significant reduction of airway wall thickness, luminal stenosis, and mucus plug formation in asthmatic mice models after oral administration of OM-85. The infiltrations of eosinophil were also significantly decreased in BALF in asthmatic mice models. Oral administration of OM-85 was shown to suppress Th2-type cytokine levels. CONCLUSION: Our findings provide evidence that oral administration of OM-85 is capable of attenuating airway inflammation in asthmatic mice models. Oral administration of OM-85 may have a positive impact in terms of asthma severity.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Asma/tratamiento farmacológico , Extractos Celulares/farmacología , Citocinas/efectos de los fármacos , Pulmón/efectos de los fármacos , Administración Oral , Animales , Asma/inmunología , Bronquios/efectos de los fármacos , Bronquios/inmunología , Bronquios/patología , Líquido del Lavado Bronquioalveolar , Citocinas/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Femenino , Inmunoterapia , Pulmón/inmunología , Pulmón/patología , Ratones , Moco/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología
17.
Mar Drugs ; 15(4)2017 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-28353633

RESUMEN

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS² runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM.


Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Pirroliminoquinonas/química , Pirroliminoquinonas/farmacología , Animales , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética/métodos , Poríferos/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Relación Estructura-Actividad
18.
Inorg Chem ; 56(6): 3475-3482, 2017 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-28240880

RESUMEN

Copper-doped (Tb0.861Mn0.121)MnO3-δ has been synthesized by the conventional solid state reaction method. X-ray, neutron, and electron diffraction data indicate that they crystallize in Pnma space group at room temperature. Two magnetic orderings are found for this series by neutron diffraction. One is the ICAM (incommensurate canted antiferromagnetic) ordering of Mn with a wave vector qMn = (∼0.283, 0, 0) with a ≈ 5.73 Å, b ≈ 5.31 Å, and c ≈ 7.41 Å, and the other is the CAM (canted antiferromagnetic) ordering of both Tb and Mn in the magnetic space group Pn'a21' with a ≈ 5.73 Å, b ≈ 5.31 Å, and c ≈ 7.41 Å. A dielectric peak around 40 K is found for the samples doped with Cu, which is higher than that for orthorhombic TbMnO3.

19.
Cell ; 166(6): 1564-1571.e6, 2016 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-27610576

RESUMEN

Optogenetic studies in mice have revealed new relationships between well-defined neurons and brain functions. However, there are currently no means to achieve the same cell-type specificity in monkeys, which possess an expanded behavioral repertoire and closer anatomical homology to humans. Here, we present a resource for cell-type-specific channelrhodopsin expression in Rhesus monkeys and apply this technique to modulate dopamine activity and monkey choice behavior. These data show that two viral vectors label dopamine neurons with greater than 95% specificity. Infected neurons were activated by light pulses, indicating functional expression. The addition of optical stimulation to reward outcomes promoted the learning of reward-predicting stimuli at the neuronal and behavioral level. Together, these results demonstrate the feasibility of effective and selective stimulation of dopamine neurons in non-human primates and a resource that could be applied to other cell types in the monkey brain.


Asunto(s)
Conducta de Elección/fisiología , Neuronas Dopaminérgicas/metabolismo , Optogenética/métodos , Animales , Dependovirus/genética , Dopamina/metabolismo , Regulación de la Expresión Génica , Vectores Genéticos/genética , Macaca mulatta , Regiones Promotoras Genéticas/genética , Rodopsina/genética
20.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(4): 324-8, 2016 Apr.
Artículo en Chino | MEDLINE | ID: mdl-27097577

RESUMEN

OBJECTIVE: To investigate ORMDL3 polymorphisms in children with asthma in Hunan, China, and to determine the relationship between ORMDL3 polymorphisms and serum osteopontin (OPN) and transforming growth factor-ß1 (TGF-ß1) levels. METHODS: Peripheral blood samples were collected in children with asthma (n=98; astma group) or without asthma (n=30; control group) from Hunan, China. The asthma group was subdivided into atopic (n=62) and non-atopic (n=36) subgroups. Single nucleotide polymorphism (SNP) analysis was performed, and serum OPN and TGF-ß1 levels were measured. RESULTS: There were no significant differences in genotype and allele frequencies of rs7216389 of the ORMDL3 gene between the asthma and control groups. The serum level of OPN in the asthma group was significantly higher than in the control group (P<0.05). Both the atopic and non-atopic subgroups showed increased serum levels of OPN compared with the control group (P<0.05). The serum level of TGF-ß1 in the atopic subgroup was significantly higher than in the control group (P<0.05). The serum levels of OPN and TGF-ß1 showed no significant differences in asthmatic children with different genotypes. The serum levels of OPN and TGF-ß1 were in a positive linear correlation in the asthma group (r=0.620; P<0.01) and its two subgroups (r=0.734, 0.649 respectively; P<0.01). CONCLUSIONS: In children from Hunan, China, the SNP (rs7216389) of ORMDL3 is not related to asthma susceptibility. OPN and TGF-ß1 may be involved in the development of asthma, and they are in a positive linear correlation. The SNP (rs7216389) of ORMDL3 does not influence the expression of OPN and TGF-ß1, suggesting that it may not be associated with airway remodeling.


Asunto(s)
Asma/genética , Proteínas de la Membrana/genética , Osteopontina/sangre , Polimorfismo de Nucleótido Simple , Factor de Crecimiento Transformador beta1/sangre , Remodelación de las Vías Aéreas (Respiratorias) , Asma/sangre , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino
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