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1.
PLoS One ; 16(11): e0259410, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34731202

RESUMO

As teachers are responsible for responding instantaneously to students' statements and actions, the progress of the class, and their teaching purpose, they need to be able to engage in responsive teaching. Teachers obtain information about students' learning by observing them in the classroom, and subsequently make instructional decisions based on this information. Teachers need to be sensitive to student behaviors and respond accordingly, because there are students who follow the teacher's instructions and those who do not in every classroom. Skilled teachers may distribute their gaze over the entire class and discover off-task behaviors. So how does a teacher's visual processing and noticing ability develop? It is important to clarify this process for both experienced teachers and student teachers. Therefore, the purpose of this study was to investigate whether there is a difference in visual processing and the ability to notice off-task behaviors in class between teachers and student teachers through gaze analysis. Using an eye tracking device, 76 teachers and 147 student teachers were asked to watch a video, and gaze measurements were collected. In the video, students exhibiting off-task behaviors in class were prompted by their classroom teacher to participate in the lesson. After the video, the participants were asked if they could identify the students who had displayed off-task behaviors and whom the teachers had warned. The results showed that teachers gazed at students engaging in off-task behaviors in class more often and noticed them at a higher rate than student teachers did. These results may be attributed to differences in the experiences of visual processing of relevant information in the classroom between teachers and student teachers. Thus, the findings on teachers' visual processing by direct measurement of gaze will be able to contribute to teachers' development.

2.
Mol Ther Nucleic Acids ; 26: 957-969, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34760338

RESUMO

Antisense oligonucleotides (ASOs) containing bridged nucleic acids (BNAs) have been proven to be very powerful. However, ensuring a reliable discovery and translational development scheme for this class of ASOs with wider therapeutic windows remains a fundamental challenge. We here demonstrate the robustness of our scheme in the context of the selection of ASOs having two different BNA chemistries (2,'4'-BNA/locked nucleic acid [LNA] and amido-bridged nucleic acid [AmNA]) targeting human proprotein convertase subtilisin/kexin type 9 (PCSK9). The scheme features a two-step process, including (1) a unique and sensitive in vitro screening approach, called Ca2+ enrichment of medium (CEM) transfection, and (2) a ligand-targeted drug delivery approach to better reach target tissues, averting unintended accumulation of ASOs. Using CEM screening, we identified a candidate ASO that shows >70% cholesterol-lowering action in monkeys. An N-acetylgalactosamine (GalNAc) ligand then was appended to the candidate ASO to further broaden the therapeutic margin by altering the molecule's pharmacokinetics. The GalNAc conjugate, HsPCSK9-1811-LNA, was found to be at least ten times more potent in non-human primates (compared with the unconjugated counterpart), with reduced nephrotoxicity in rats. Overall, we successfully showed that our drug development scheme is better suited for selecting clinically relevant BNA-based ASOs, especially for the treatment of liver-associated diseases.

3.
Nucleic Acid Ther ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34468210

RESUMO

Ligand-targeted drug delivery (LTDD) has gained more attention in the field of nucleic acid therapeutics. To further elicit the potential of therapeutic oligonucleotides by means of LTDD, we newly developed (R)- and (S)-3-amino-1,2-propanediol (APD) manifold for ligand conjugation. N-acetylgalactosamine (GalNAc)/asialoglycoprotein receptor (ASGPr) system has been shown to be a powerful and robust paradigm of LTDD. Our novel APD-based GalNAc (GalNAcAPD) was shown to have intrinsic chemical instability that could play a role in better manipulation of active drug release. The APD manifold also enables facile production of conjugates through an on-support ligand cluster synthesis. We showed in a series of in vivo studies that while the knockdown activity of antisense oligonucleotides (ASOs) bearing 5'-GalNAcAPD was comparable to the conventional hydroxy-L-prolinol-linked GalNAc (GalNAcHP), 3'-GalNAcAPD elicited ASO activity by more than twice as much as the conventional 3'-GalNAcHP. This was ascribed partly to the GalNAcAPD's ideal susceptibility to nucleolytic digestion, which is expected to facilitate cytosolic internalization of ASO drugs. Moreover, an in vivo/ex vivo imaging study visualized the enhancement effect of monoantennary GalNAcAPD on liver localization of ASOs. This versatile manifold with chemical and biological instability would benefit therapeutic oligonucleotides that target both the liver and extrahepatic tissues.

4.
Cancers (Basel) ; 13(15)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34359781

RESUMO

With the development of new anticancer medicines, novel modalities are being explored for cancer treatment. For many years, conventional modalities, such as small chemical drugs and antibody drugs, have worked by "inhibiting the function" of target proteins. In recent years, however, nucleic acid drugs, such as ASOs and siRNAs, have attracted attention as a new modality for cancer treatment because nucleic acid drugs can directly promote the "loss of function" of target genes. Recently, nucleic acid drugs for use in cancer therapy have been extensively developed and some of them have currently been under investigation in clinical trials. To develop novel nucleic acid drugs for cancer treatment, it is imperative that cancer researchers, including ourselves, cover and understand those latest findings. In this review, we introduce and provide an overview of various DDSs and ligand modification technologies that are being employed to improve the success and development of nucleic acid drugs, then we also discuss the future of nucleic acid drug developments for cancer therapy. It is our belief this review will increase the awareness of nucleic acid drugs worldwide and build momentum for the future development of new cancer-targeted versions of these drugs.

5.
J Phys Condens Matter ; 33(39)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34237717

RESUMO

We investigate heat transport through an assembly consisting of a two-level system coupled between two harmonic oscillators, which is described by the quantum Rabi model, as a prototype of nanoscale heat devices using controllable multi-level systems. Using the noninteracting-blip approximation, we find that the linear thermal conductance shows a characteristic temperature dependence with a two-peak structure. We also show that heat transport is sensitive to model parameters for weak system-bath coupling and strong hybridization between the two-level system and the harmonic oscillators. This property characteristic of the multi-level system is advantageous for applications such as a heat transistor, and can be examined in superconducting circuits.

6.
Pharmaceutics ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072682

RESUMO

The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called "tiny LNA (tiny Locked Nucleic Acid)" is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300-500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5' terminus rather than its 3' end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy.

7.
Neonatology ; 118(3): 310-316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33744873

RESUMO

INTRODUCTION: We aimed to evaluate the risk factors for mortality and neurodevelopmental impairment (NDI) among infants of 22-23 weeks' gestational age, which currently remain unclear. METHODS: This retrospective case-control study included 104 infants delivered at 22-23 weeks' gestation at Kagoshima City Hospital from 2006 to 2015. We compared 65 and 34 cases of survival to discharge and postnatal in-hospital death (5 excluded), respectively, and 26 and 35 cases with and without NDI, respectively, using maternal, prenatal, and postnatal records. A high rate of survivors' follow-up (61/65) was achieved in this study. RESULTS: The survival rate was 75.0% (21/28) and 62.0% (44/71) among infants born at 22 and 23 weeks' gestation, respectively. Infants who died weighed less (525.5 vs. 578 g, p = 0.04) and their intrauterine growth retardation (IUGR) rate (<5th percentile) was higher (14.7 vs. 1.5%, p = 0.02). Mortality was associated with an increased incidence of bradycardia on fetal heart rate monitoring (11.8 vs. 1.5%, p = 0.046), periventricular hemorrhagic infarction (PVHI; 32.4 vs. 6.2%, p = 0.001), necrotizing enterocolitis (NEC, surgery or drain tube; 14.7 vs. 0.0%, p = 0.004), and tension pneumothorax (29.4 vs. 6.2%, p = 0.004). There were significant differences in the proportion of PVHI (15.4 vs. 0%, p = 0.03) between infants with and without NDI. CONCLUSIONS: IUGR, bradycardia, PVHI, NEC, and tension pneumothorax were associated with neonatal mortality among infants born at 22-23 weeks' gestation. NDI at 36-42 months' chronological age was associated with PVHI.


Assuntos
Mortalidade Infantil , Doenças do Prematuro , Estudos de Casos e Controles , Feminino , Idade Gestacional , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Gravidez , Estudos Retrospectivos , Fatores de Risco
8.
Pharmaceutics ; 13(2)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530309

RESUMO

Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.

9.
Pediatr Int ; 63(4): 415-422, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32688450

RESUMO

BACKGROUND: In Japan, 44.3% of neonates are delivered in private clinics without an attending pediatrician. Obstetricians in the clinics must resuscitate asphyxiated neonates in unstable condition, such as respiratory failure, and they are frequently transferred to tertiary perinatal medical centers. There has been no study comparing the physiological status and prognosis of neonates transported by ambulance with those transported by helicopter. METHODS: Medical and transport records were used to compare the physiological status of neonates transported to Kagoshima City Hospital by land and those transported by air between January 1, 2013, and December 31, 2017. RESULTS: Data from 425 neonates transferred by land and 143 by air were analyzed. There were no significant differences between the two groups in mean gestational age, mean birthweight, fetal blood pH, Apgar score, or the Score for Neonatal Acute Physiology with Perinatal Extension-II (SNAPPE-II) on arrival to the tertiary center (16.3 ± 15.4 [95% confidence interval (CI): 13.2-17.7] vs 16.4 ± 15.4 [95% CI: 13.9-19.0], respectively; P = 0.999); both groups had SNAPPE-II score 10-19, indicating no difference in mortality risk. The times to starting first aid and to admission to the intensive care unit were significantly reduced in neonates transported by air than by land. In subgroup analysis of patients of a gestational age ≤28 weeks, all cases of severe intraventricular hemorrhage (IVH) were observed in the land transportation group. CONCLUSIONS: Neonatal transportation by air is as safe as land transportation, and time to first aid and intensive care are significantly reduced by transportation by air than by land. Air transport could also contribute to the prevention of IVH in neonatal transportation.


Assuntos
Ambulâncias , Hemorragia Cerebral , Índice de Apgar , Peso ao Nascer , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Gravidez , Transporte de Pacientes
11.
J Obstet Gynaecol Res ; 46(11): 2383-2389, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32924259

RESUMO

AIM: Periventricular leukomalacia (PVL) is an important cause of cerebral palsy in premature infants, and cystic PVL is the most serious form of the disease. The risk factors for cystic PVL in singleton fetuses at a gestational age of <35 weeks are unclear. METHODS: This study included 2013 singleton birth infants delivered at a gestational age of <35 weeks in Kagoshima City Hospital between 2006 and 2017. The findings for 30 infants with cystic PVL were compared with those for 63 matched control infants by gestational age and birth weight. RESULTS: The cystic PVL was associated with increased incidence of recurrent late deceleration (L/D) (43.4% vs. 15.9%, P = 0.004) and loss of variability (LOV) (10.0% vs. 0.0%, P = 0.03) in fetal heart rate monitoring and late-onset circulatory dysfunction (LCD) (33.3% vs. 11.1%, P = 0.02). Logistic regression analysis revealed that recurrent L/D (odds ratio [OR] = 3.57, 95% confidence interval [CI]: 1.29-10.15, P = 0.01) and LCD (OR = 3.41, 95% CI: 1.09-11.04, P = 0.03) were risk factors associated with cystic PVL. LOV was not included in the multivariate analysis as there were too few cases in both the cystic PVL and control groups. CONCLUSION: Recurrent L/D, LOV and LCD are strongly associated with cystic PVL. In cases of fetal acidosis related to recurrent L/D or loss of variability, cystic PVL may occur.


Assuntos
Leucomalácia Periventricular , Peso ao Nascer , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Leucomalácia Periventricular/epidemiologia , Gravidez , Fatores de Risco
12.
Methods Mol Biol ; 2176: 141-154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865788

RESUMO

Oligonucleotide drugs (ODs) have gained increasing attention owing to their promising therapeutic potential. One major obstacle that ODs have been facing is the lack of appropriate in vitro validation systems that can predict in vivo activity and toxicity. We have devised a transfection method called CEM (Ca2+-enrichment method), where the simple enrichment of calcium ion with calcium chloride in culture medium potentiates the activity of various types of naked oligonucleotides including gapmers, siRNA, and phosphorodiamidate morpholino antisense oligonucleotides (PMO) in many cultured cell lines with limited cytotoxicity. We here describe a precise procedure of the method. Besides the benefit of the CEM's predictive power to accurately estimate in vivo activity of ODs of your interest in drug discovery and development settings, this cost-efficient, easy-to-access method can be a robust laboratory technique to modulate gene expressions with ODs with a variety of mechanisms of action.


Assuntos
Cálcio/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Oligonucleotídeos/química , Oligonucleotídeos/genética , Transfecção/métodos , Células A549 , Animais , Sequência de Bases/fisiologia , Técnicas de Cultura de Células , Linhagem Celular , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinos/química , Morfolinos/genética , Morfolinos/farmacocinética , Conformação de Ácido Nucleico/efeitos dos fármacos , Oligonucleotídeos/farmacocinética , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacocinética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
13.
Pharmaceutics ; 12(6)2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545479

RESUMO

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody-anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells. We found that ExomiR-Tracker bound to the exosomes, and then the complexes were introduced into the recipient cells. We also found that anti-miR oligonucleotides introduced into the recipient cells can exhibit inhibitory effects on exosomal miRNA functions in vitro and in vivo. We believe that our strategy would be a promising one for targeting exosomal miRNAs.

14.
Nucleosides Nucleotides Nucleic Acids ; 39(1-3): 109-118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31617782

RESUMO

The asialoglycoprotein receptor (ASGPr) and N-acetylgalactosamine (GalNAc) is one of the most reliable receptor-ligand combinations for delivering antisense oligonucleotides (ASOs) to the liver. Here, we show that a modular GalNAc conjugation strategy allows us to reinforce the activity of the parent, naked 2',4'-BNA/LNA gapmer targeting apolipoprotein B. The conjugation partly reduced a possible hepatotoxicity of the parent ASO. The structure-activity study revealed the significance of the metabolic susceptibility of the GalNAc moiety to nucleolytic cleavage that results in exposure of the parent gapmer. The broad usefulness of our delivery strategy of ASOs to the liver has been demonstrated.


Assuntos
Acetilgalactosamina , Oligonucleotídeos Antissenso , Acetilgalactosamina/química , Animais , Receptor de Asialoglicoproteína , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Ligantes , Fígado , Masculino , Camundongos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/química , Ligação Proteica
15.
Ann Vasc Surg ; 64: 116-123, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31629849

RESUMO

BACKGROUND: Although endovascular repair (EVAR) is the first-line treatment for abdominal aortic aneurysm, type 2 endoleak (EL), which is associated with late sac enlargement or rupture, remains a concern. The present study aimed to assess the influence of type 2 EL on long-term outcomes after EVAR. METHODS: Among 550 patients who underwent EVAR between 2007 and 2013 at 14 Japanese national hospitals, 135 patients had type 2 EL diagnosed on follow-up computed tomography (CT) within 12 months after EVAR (EL2[+] group) and 415 patients did not have EL within 12 months (EL2[-] group). The cumulative incidences of sac enlargement, late intervention, and aneurysm-related death after EVAR were estimated using the cumulative incidence function method, and prognostic factors were investigated using the Fine-Gray hazard model. RESULTS: The median follow-up period was 5 years, and the 5-year cumulative incidence rates of sac enlargement, late intervention, and aneurysm-related death were 30.7% ± 4.4%, 25.3% ± 4.1%, and 2.6% ± 1.4%, respectively, in the EL2(+) group, and 8.7% ± 1.6%, 7.6% ± 1.4%, and 0.3% ± 0.3%, respectively, in the EL2(-) group. The cumulative incidence rates of sac enlargement (P = 0.002), late intervention (P < 0.001), and aneurysm-related death (P = 0.015) were significantly different between the 2 groups. As the first-line treatment for sac enlargement with type 2 EL, transcatheter coil embolization was performed in 30 patients. Information about sac behavior on CT after coil embolization was available in 20 of the 30 patients. Among these patients, no patients experienced sac shrinkage, and the aneurysmal sac dilated after coil embolization in 18 patients. CONCLUSIONS: Type 2 EL affects the long-term outcomes after EVAR. It is not recommended to observe large aneurysmal sacs conservatively as they tend to dilate in the presence of type 2 EL.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Endoleak/epidemiologia , Procedimentos Endovasculares/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/mortalidade , Implante de Prótese Vascular/mortalidade , Embolização Terapêutica , Endoleak/diagnóstico por imagem , Endoleak/mortalidade , Endoleak/terapia , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
Nucleosides Nucleotides Nucleic Acids ; 39(1-3): 119-130, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31645189

RESUMO

Point mutations are well characterized activators of oncogenes but are often indistinguishable using common gene technologies. In general, the precise sites of point-mutated oncogenes are difficult to distinguish under physiological conditions primarily because single nucleotide mismatch do not affect the annealing temperatures of DNA probes sufficiently. To address this limitation, we developed photo-responsive oligodeoxyribonucleotides containing 2'-O-[N-(4,5',8-trimethylpsoralen-4'-ylmethylcarbamoyl)]adenosine (Ps-amd-Oligo), which can be used to selectively manipulate and identify genes with point mutations. Here we present time course analyses of the photo-cross-linking efficiency of Ps-amd-Oligo with DNA and RNA and show promising selectivity for the oncogene H-ras.


Assuntos
Adenosina/análogos & derivados , Adenosina/química , DNA , Mutação , Oligodesoxirribonucleotídeos/química , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenosina/síntese química , Reagentes para Ligações Cruzadas , DNA/química , DNA/genética , Estrutura Molecular , Oligodesoxirribonucleotídeos/genética , Mutação Puntual , Raios Ultravioleta
17.
Gen Thorac Cardiovasc Surg ; 68(2): 185-189, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31041726

RESUMO

Relapsing polychondritis is a rare multi-system disease characterized by inflammation in cartilaginous structures and other connective tissues. Cardiovascular complications occur in 10-51% of the patients. We report a case of concomitant aortic valve replacement, mitral valve replacement, and coronary artery bypass grafting in a patient with relapsing polychondritis. A 71-year-old female with relapsing polychondritis on prednisolone (5 mg/day) for 15 years presented at our hospital for further evaluation of valvular disease. Severe aortic stenosis and severe mitral regurgitation were diagnosed. We performed aortic and mitral valve replacement. During surgery, we found connective tissue surrounding the intima of the sinus of Valsalva and stenosis of the right coronary artery ostium, which was not noted on preoperative coronary angiography. We removed the tissue and performed bypass grafting to the right coronary artery. Postoperative recovery was uneventful, and she was discharged 27 days after surgery.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Ponte de Artéria Coronária , Insuficiência da Valva Mitral/cirurgia , Valva Mitral/cirurgia , Policondrite Recidivante/cirurgia , Idoso , Angiografia Coronária , Feminino , Próteses Valvulares Cardíacas , Implante de Prótese de Valva Cardíaca , Humanos , Insuficiência da Valva Mitral/diagnóstico por imagem , Policondrite Recidivante/diagnóstico por imagem
18.
Opt Express ; 27(22): 32058-32068, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31684425

RESUMO

Graphene is widely recognized as an outstanding and multi-functional material in various application fields such as electronics, photonics, mechanics, and life sciences. We propose a neurotransmitter sensor with ultra-small volume for detecting the photonic light-matter response. Such detection can be achieved using surface-activated monolayer graphene sheets and CMOS-compatible silicon-photonic circuits. Patterned pieces of CVD-grown graphene are integrated on the top of a silicon micro-ring resonator, which induce the adsorption of catecholamine molecules originated from the π-stacking effect. We used dopamine to demonstrate such detection and examine the sensitivity of graphene-dopamine coupling. To avoid high optical insertion loss and degradation of resonance characteristics caused by a graphene's extremely high optical absorption coefficient in the near infrared region, a ring resonator with adjusted coupling design is used to compensate for the drawbacks. Owing to the advanced nano-sensing platform and measurement system, an activated graphene-sensing surface of only ∼30 µm2/ch enables π coupling to dopamine with enough sensitivity to detect less than 10-µM solution concentration. The detection mechanism through the surface reaction is also verified by optical simulation and atomic force microscopy measurement, revealing that the flowing dopamine molecules can only occupy the outermost surface of graphene. We expect this sensor to contribute to the development of an innovative label-free and disposable bio-sensing platform with accurate, sensitive, and fast response.

19.
Curr Protoc Nucleic Acid Chem ; 78(1): e99, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31529782

RESUMO

Ligand-targeted drug delivery (LTDD) has emerged as an attractive option in the field of oligonucleotide drugs following the great success of N-acetylgalactosamine (GalNAc)-conjugated siRNA and antisense oligonucleotides. GalNAc is a well-known ligand of the asialoglycoprotein receptor (ASGPR), and is classified as a C-type lectin associated with the metabolism of desialylated glycoproteins. This article describes the synthesis of a non-nucleosidic monovalent GalNAc phosphoramidite-a useful reagent for facilitating the conjugation of GalNAc epitopes into oligonucleotides using DNA synthesizers-together with some important caveats. The monomeric GalNAc consists of three parts: (1) a GalNAc moiety, (2) a linker moiety, and (3) a trans-4-hydroxyprolinol (tHP) branch point. The GalNAc moiety and the tHP moiety are coupled via a condensation reaction to prepare the monovalent GalNAc phosphoramidite. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Synthesis of N-acetylgalactosamine ligand Basic Protocol 2: Preparation of trans-4-hydroxyprolinol building block Basic Protocol 3: Preparation of GalNAc phosphoramidite.


Assuntos
Acetilgalactosamina/química , Fígado/efeitos dos fármacos , Oligonucleotídeos/farmacologia , Compostos Organofosforados/química , Sistemas de Liberação de Medicamentos , Ligantes , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/química
20.
Angew Chem Int Ed Engl ; 58(42): 15046-15050, 2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31418991

RESUMO

The skeletons of some classes of terpenoids are unusual in that they contain a larger number of Me groups (or their biosynthetic equivalents such as olefinic methylene groups, hydroxymethyl groups, aldehydes, or carboxylic acids and their derivatives) than provided by their oligoprenyl diphosphate precursor. This is sometimes the result of an oxidative ring-opening reaction at a terpene-cyclase-derived molecule containing the regular number of Me group equivalents, as observed for picrotoxan sesquiterpenes. In this study a sesquiterpene cyclase from Trichoderma spp. is described that can convert farnesyl diphosphate (FPP) directly via a remarkable skeletal rearrangement into trichobrasilenol, a new brasilane sesquiterpene with one additional Me group equivalent compared to FPP. A mechanistic hypothesis for the formation of the brasilane skeleton is supported by extensive isotopic labelling studies.


Assuntos
Carbono-Carbono Liases/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Sesquiterpenos/metabolismo , Trichoderma/metabolismo , Carbono-Carbono Liases/química , Carbono-Carbono Liases/genética , Estrutura Molecular , Fosfatos de Poli-Isoprenil/química , Sesquiterpenos/química , Estereoisomerismo , Trichoderma/enzimologia , Trichoderma/genética
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