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1.
Opt Express ; 32(7): 12982-12991, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38571104

RESUMO

Quantum dense metrology (QDM) performs high-precision measurements by a two-mode entangled state created by an optical parametric amplifier (PA), where one mode is a meter beam and the other is a reference beam. In practical applications, the photon losses of meter beam are unavoidable, resulting in a degradation of the sensitivity. Here, we employ coherent feedback that feeds the reference beam back into the PA by a beam splitter to enhance the sensitivity in a lossy environment. The results show that the sensitivity is enhanced significantly by adjusting the splitting ratio of the beam splitter. This method may find its potential applications in QDM. Furthermore, such a strategy that two non-commuting observables are simultaneous measurements could provide a new way to individually control the noise-induced random drift in phase or amplitude of the light field, which would be significant for stabilizing the system and long-term precision measurement.

2.
Biochemistry ; 62(5): 976-988, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36813261

RESUMO

Tau aggregate-bearing lesions are pathological markers and potential mediators of tauopathic neurodegenerative diseases, including Alzheimer's disease. The molecular chaperone DJ-1 colocalizes with tau pathology in these disorders, but it has been unclear what functional link exists between them. In this study, we examined the consequences of tau/DJ-1 interaction as isolated proteins in vitro. When added to full-length 2N4R tau under aggregation-promoting conditions, DJ-1 inhibited both the rate and extent of filament formation in a concentration-dependent manner. Inhibitory activity was low affinity, did not require ATP, and was not affected by substituting oxidation incompetent missense mutation C106A for wild-type DJ-1. In contrast, missense mutations previously linked to familial Parkinson's disease and loss of α-synuclein chaperone activity, M26I and E64D, displayed diminished tau chaperone activity relative to wild-type DJ-1. Although DJ-1 directly bound the isolated microtubule-binding repeat region of tau protein, exposure of preformed tau seeds to DJ-1 did not diminish seeding activity in a biosensor cell model. These data reveal DJ-1 to be a holdase chaperone capable of engaging tau as a client in addition to α-synuclein. Our findings support a role for DJ-1 as part of an endogenous defense against the aggregation of these intrinsically disordered proteins.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , alfa-Sinucleína/química , Doença de Parkinson/metabolismo , Proteínas tau/genética , Chaperonas Moleculares/genética , Proteína Desglicase DJ-1/genética
3.
Opt Express ; 31(4): 6499-6513, 2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36823904

RESUMO

We propose an alternative scheme for phase estimation in a Mach-Zehnder interferometer (MZI) with photon recycling. It is demonstrated that with the same coherent-state input and homodyne detection, our proposal possesses a phase sensitivity beyond the traditional MZI. For instance, it can achieve an enhancement factor of ∼9.32 in the phase sensitivity compared with the conventional scheme even with a photon loss of 10% on the photon-recycled arm. From another point of view, the quantum Cramér-Rao bound (QCRB) is also investigated. It is found that our scheme is able to achieve a lower QCRB than the traditional one. Intriguingly, the QCRB of our scheme is dependent of the phase shift ϕ while the traditional scheme has a constant QCRB regardless of the phase shift. Finally, we present the underlying mechanisms behind the enhanced phase sensitivity. We believe that our results provide another angle from which to enhance the phase sensitivity in a MZI via photon recycling.

4.
Phys Rev Lett ; 130(7): 073601, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36867793

RESUMO

Interferometers are crucial for precision measurements, including gravitational waves, laser ranging, radar, and imaging. The phase sensitivity, the core parameter, can be quantum-enhanced to break the standard quantum limit (SQL) using quantum states. However, quantum states are highly fragile and quickly degrade with losses. We design and demonstrate a quantum interferometer utilizing a beam splitter with a variable splitting ratio to protect the quantum resource against environmental impacts. The optimal phase sensitivity can reach the quantum Cramér-Rao bound of the system. This quantum interferometer can greatly reduce the quantum source requirements in quantum measurements. In theory, with a 66.6% loss rate, the sensitivity can break the SQL using only a 6.0 dB squeezed quantum resource with the current interferometer rather than a 24 dB squeezed quantum resource with a conventional squeezing-vacuum-injected Mach-Zehnder interferometer. In experiments, when using a 2.0 dB squeezed vacuum state, the sensitivity enhancement remains at ∼1.6 dB via optimizing the first splitting ratio when the loss rate changes from 0% to 90%, indicating that the quantum resource is excellently protected with the existence of losses in practical applications. This strategy could open a way to retain quantum advantages for quantum information processing and quantum precision measurement in lossy environments.

5.
Phys Rev Lett ; 131(15): 150804, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37897768

RESUMO

A quantum memory with the performances of low noise, high efficiency, and high bandwidth is of crucial importance for developing practical quantum information technologies. However, the excess noises generated during the highly efficient processing of quantum information inevitably destroy quantum state. Here, we present a quantum memory with built-in excess-noise eraser by integrating a photon-correlated quantum interferometry in quantum memory, where the memory efficiency can be enhanced and the excess noises can be suppressed to the vacuum level via destructive interference. This quantum memory is demonstrated in a rubidium vapor cell with a 10-ns-long photonics signal. We observe ∼80% noise suppression, the write-in efficiency enhancement from 87% to 96.2% without and with interferometry, and the corresponding memory efficiency excluding the noises from 70% to 77%. The fidelity is 93.7% at the single-photon level, significantly exceeding the no-cloning limit. Such interferometry-integrated quantum memory, the first expansion of quantum interference techniques to quantum information processing, simultaneously enables low noise, high bandwidth, high efficiency, and easy operation.

6.
J Biomol NMR ; 76(3): 49-57, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35389128

RESUMO

Rapid progress in machine learning offers new opportunities for the automated analysis of multidimensional NMR spectra ranging from protein NMR to metabolomics applications. Most recently, it has been demonstrated how deep neural networks (DNN) designed for spectral peak picking are capable of deconvoluting highly crowded NMR spectra rivaling the facilities of human experts. Superior DNN-based peak picking is one of a series of critical steps during NMR spectral processing, analysis, and interpretation where machine learning is expected to have a major impact. In this perspective, we lay out some of the unique strengths as well as challenges of machine learning approaches in this new era of automated NMR spectral analysis. Such a discussion seems timely and should help define common goals for the NMR community, the sharing of software tools, standardization of protocols, and calibrate expectations. It will also help prepare for an NMR future where machine learning and artificial intelligence tools will be common place.


Assuntos
Algoritmos , Inteligência Artificial , Humanos , Aprendizado de Máquina , Ressonância Magnética Nuclear Biomolecular/métodos , Software
7.
Opt Express ; 30(7): 11514-11523, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35473094

RESUMO

The SU (1,1)-type atom-light hybrid interferometer (SALHI) is a kind of interferometer that is sensitive to both the optical phase and atomic phase. However, the loss has been an unavoidable problem in practical applications and greatly limits the use of interferometers. Visibility is an important parameter to evaluate the performance of interferometers. Here, we experimentally demonstrate the mitigating effect of the loss on visibility of the SALHI via asymmetric gain optimization, where the maximum threshold of loss to visibility close to 100% is increased. Furthermore, we theoretically find that the optimal condition for the largest visibility is the same as that for the enhancement of signal-to-noise ratio (SNR) to the best value with the existence of the losses using the intensity detection, indicating that visibility can act as an experimental operational criterion for SNR improvement in practical applications. Improvement of the interference visibility means achievement of SNR enhancement. Our results provide a significant foundation for practical application of the SALHI in radar and ranging measurements.

8.
Phys Rev Lett ; 128(3): 033601, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35119880

RESUMO

We present experimental and theoretical results on a new interferometer topology that nests a SU(2) interferometer, e.g., a Mach-Zehnder or Michelson interferometer, inside a SU(1,1) interferometer, i.e., a Mach-Zehnder interferometer with parametric amplifiers in place of beam splitters. This SU(2)-in-SU(1,1) nested interferometer (SISNI) simultaneously achieves a high signal-to-noise ratio (SNR), sensitivity beyond the standard quantum limit (SQL) and tolerance to photon losses external to the interferometer, e.g., in detectors. We implement a SISNI using parametric amplification by four-wave mixing (FWM) in Rb vapor and a laser-fed Mach-Zehnder SU(2) interferometer. We observe path-length sensitivity with SNR 2.2 dB beyond the SQL at power levels (and thus SNR) 2 orders of magnitude beyond those of previous loss-tolerant interferometers. We find experimentally the optimal FWM gains and find agreement with a minimal quantum noise model for the FWM process. The results suggest ways to boost the in-practice sensitivity of high-power interferometers, e.g., gravitational wave interferometers, and may enable high-sensitivity, quantum-enhanced interferometry at wavelengths for which efficient detectors are not available.

9.
J Am Chem Soc ; 143(34): 13593-13604, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34428032

RESUMO

Amino-acid side-chain properties in proteins are key determinants of protein function. NMR spin relaxation of side chains is an important source of information about local protein dynamics and flexibility. However, traditional solution NMR relaxation methods are most sensitive to sub-nanosecond dynamics lacking information on slower ns-µs time-scale motions. Nanoparticle-assisted NMR spin relaxation (NASR) of methyl-side chains is introduced here as a window into these ns-µs dynamics. NASR utilizes the transient and nonspecific interactions between folded proteins and slowly tumbling spherical nanoparticles (NPs), whereby the increase of the relaxation rates reflects motions on time scales from ps all the way to the overall tumbling correlation time of the NPs ranging from hundreds of ns to µs. The observed motional amplitude of each methyl group can then be expressed by a model-free NASR S2 order parameter. The method is demonstrated for 2H-relaxation of CH2D methyl moieties and cross-correlated relaxation of CH3 groups for proteins Im7 and ubiquitin in the presence of anionic silica-nanoparticles. Both types of relaxation experiments, dominated by either quadrupolar or dipolar interactions, yield highly consistent results. Im7 shows additional dynamics on the intermediate time scales taking place in a functionally important loop, whereas ubiquitin visits the majority of its conformational substates on the sub-ns time scale. These experimental observations are in good agreement with 4-10 µs all-atom molecular dynamics trajectories. NASR probes side-chain dynamics on a much wider range of motional time scales than previously possible, thereby providing new insights into the interplay between protein structure, dynamics, and molecular interactions that govern protein function.


Assuntos
Nanopartículas/química , Ressonância Magnética Nuclear Biomolecular , Ubiquitina/química , Humanos , Metano/química , Simulação de Dinâmica Molecular , Dióxido de Silício/química
10.
J Nat Prod ; 84(5): 1638-1648, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33899471

RESUMO

While marine natural products have been investigated for anticancer drug discovery, they are barely screened against rare cancers. Thus, in our effort to discover potential drug leads against the rare cancer pseudomyxoma peritonei (PMP), which currently lacks effective drug treatments, we screened extracts of marine actinomycete bacteria against the PMP cell line ABX023-1. This effort led to the isolation of nine rearranged angucyclines from Streptomyces sp. CNZ-748, including five new analogues, namely, grincamycins P-T (1-5). The chemical structures of these compounds were unambiguously established based on spectroscopic and chemical analyses. Particularly, grincamycin R (3) possesses an S-containing α-l-methylthio-aculose residue, which was discovered in nature for the first time. All of the isolated compounds were evaluated against four PMP cell lines and some exhibited low micromolar inhibitory activities. To identify a candidate biosynthetic gene cluster (BGC) encoding the grincamycins, we sequenced the genome of the producing strain, Streptomyces sp. CNZ-748, and compared the BGCs detected with those linked to the production of angucyclines with different aglycon structures.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Pseudomixoma Peritoneal/tratamento farmacológico , Streptomyces/química , Antraquinonas/isolamento & purificação , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , California , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sedimentos Geológicos/microbiologia , Humanos , Estrutura Molecular , Família Multigênica , Streptomyces/genética
11.
BMC Pediatr ; 21(1): 465, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34674663

RESUMO

BACKGROUND: This retrospective study aimed to determine the epidemiological features of deaths caused by unintentional suffocation among infants in China. METHODS: The data used in this study were obtained from China's Under 5 Child Mortality Surveillance System (U5CMSS) from October 1, 2015, to September 30, 2016. A total of 377 children under 1 year of age who died from unintentional suffocation were included in the survey. Primary caregivers were interviewed individually using the Unintentional Suffocation Mortality among Children under 5 Questionnaire. EpiData was used to establish the database, and the results were analysed using SPSS 22.0. RESULTS: Most (85.9%) unintentional infant suffocations occurred in rural areas, and 67.5% occurred in infants 0 to 3 months old. Among the primary caregivers of the infants, most (82.7%) had a junior middle school education or below, and 83.1% of them lacked unintentional suffocation first aid skills. Of the 377 unintentional suffocated-infant deaths, the causes of death were accidental suffocation and strangulation in bed (ASSB) (193, 51.2%), inhalation suffocation (154, 40.8%), other unintentional suffocation (6, 1.6%), and unknown (24, 6.4%). Among the infant deaths due to ASSB, overlaying (88.6%) was the most frequently reported circumstance. A total of 93.8% of cases reported occurred during co-sleeping/bed sharing with parents, and in 72.8% of the cases, the infants were covered with the same quilt as their parents. In our study, most inhalation suffocation deaths (88.3%) involved liquid food (such as breast milk and formula milk). A total of 80.5% of infant deaths reportedly occurred after eating; in 28.2% of those cases, the infants were held upright and patted by their caregivers, and 57.2% of them were laid down to sleep immediately after eating. CONCLUSIONS: To reduce the occurrence of unintentional suffocation, local government should strengthen knowledge and awareness of unintentional suffocation prevention and safety among parents and caregivers. Additionally, health care providers should educate parents and caregivers about safety issues of unintentional suffocation, and relevant policies should be introduced to provide environments and activities that reduce the risk of suffocation, such as promoting the Safe to Sleep Campaign. It is important to enhance the focus on infant unintentional suffocation as a health issue.


Assuntos
Equipamentos para Lactente , Morte Súbita do Lactente , Asfixia/epidemiologia , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Fatores de Risco , Morte Súbita do Lactente/epidemiologia , Morte Súbita do Lactente/etiologia
12.
Bioorg Med Chem ; 28(20): 115711, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069067

RESUMO

Cyclic peptides are capable of binding to challenging targets (e.g., proteins involved in protein-protein interactions) with high affinity and specificity, but generally cannot gain access to intracellular targets because of poor membrane permeability. In this work, we discovered a conformationally constrained cyclic cell-penetrating peptide (CPP) containing a d-Pro-l-Pro motif, cyclo(AFΦrpPRRFQ) (where Φ is l-naphthylalanine, r is d-arginine, and p is d-proline). The structural constraints provided by cyclization and the d-Pro-l-Pro motif permitted the rational design of cell-permeable cyclic peptides of large ring sizes (up to 16 amino acids). This strategy was applied to design a potent, cell-permeable, and biologically active cyclic peptidyl inhibitor, cyclo(YpVNFΦrpPRR) (where Yp is l-phosphotyrosine), against the Grb2 SH2 domain. Multidimensional NMR spectroscopic and circular dichroism analyses revealed that the cyclic CPP as well as the Grb2 SH2 inhibitor assume a predominantly random coil structure but have significant ß-hairpin character surrounding the d-Pro-l-Pro motif. These results demonstrate cyclo(AFΦrpPRRFQ) as an effective CPP for endocyclic (insertion of cargo into the CPP ring) or exocyclic delivery of biological cargos (attachment of cargo to the Gln side chain).


Assuntos
Peptídeos Penetradores de Células/farmacologia , Dipeptídeos/farmacologia , Desenho de Fármacos , Proteína Adaptadora GRB2/antagonistas & inibidores , Peptídeos Cíclicos/farmacologia , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Proteína Adaptadora GRB2/isolamento & purificação , Proteína Adaptadora GRB2/metabolismo , Humanos , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Domínios de Homologia de src/efeitos dos fármacos
13.
Bioorg Med Chem ; 28(4): 115301, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953129

RESUMO

A new non-cytotoxic [(+)-17ß-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glicosídeos Cardíacos/farmacologia , Inibidores Enzimáticos/farmacologia , Moraceae/química , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Glicosídeos Cardíacos/química , Glicosídeos Cardíacos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flores/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Folhas de Planta/química , Caules de Planta/química , ATPase Trocadora de Sódio-Potássio/metabolismo , Relação Estrutura-Atividade
14.
Proc Natl Acad Sci U S A ; 113(8): 2086-91, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26858406

RESUMO

The bromodomain and extraterminal domain (BET) protein family are promising therapeutic targets for a range of diseases linked to transcriptional activation, cancer, viral latency, and viral integration. Tandem bromodomains selectively tether BET proteins to chromatin by engaging cognate acetylated histone marks, and the extraterminal (ET) domain is the focal point for recruiting a range of cellular and viral proteins. BET proteins guide γ-retroviral integration to transcription start sites and enhancers through bimodal interaction with chromatin and the γ-retroviral integrase (IN). We report the NMR-derived solution structure of the Brd4 ET domain bound to a conserved peptide sequence from the C terminus of murine leukemia virus (MLV) IN. The complex reveals a protein-protein interaction governed by the binding-coupled folding of disordered regions in both interacting partners to form a well-structured intermolecular three-stranded ß sheet. In addition, we show that a peptide comprising the ET binding motif (EBM) of MLV IN can disrupt the cognate interaction of Brd4 with NSD3, and that substitutions of Brd4 ET residues essential for binding MLV IN also impair interaction of Brd4 with a number of cellular partners involved in transcriptional regulation and chromatin remodeling. This suggests that γ-retroviruses have evolved the EBM to mimic a cognate interaction motif to achieve effective integration in host chromatin. Collectively, our findings identify key structural features of the ET domain of Brd4 that allow for interactions with both cellular and viral proteins.


Assuntos
Integrases/química , Vírus da Leucemia Murina/enzimologia , Proteínas Nucleares/química , Dobramento de Proteína , Fatores de Transcrição/química , Proteínas Virais/química , Motivos de Aminoácidos , Proteínas de Ciclo Celular , Humanos , Integrases/genética , Integrases/metabolismo , Vírus da Leucemia Murina/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
15.
Biochemistry ; 57(34): 5096-5104, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29898361

RESUMO

The Na+/Ca2+ exchanger (NCX) is a ubiquitous single-chain membrane protein that plays a major role in regulating the intracellular Ca2+ homeostasis by the counter transport of Na+ and Ca2+ across the cell membrane. Other than its prokaryotic counterpart, which contains only the transmembrane domain and is self-sufficient as an active ion transporter, the eukaryotic NCX protein possesses in addition a large intracellular loop that senses intracellular calcium signals and controls the activation of ion transport across the membrane. This provides a necessary layer of regulation for the more complex function of eukaryotic cells. The Ca2+ sensor in the intracellular loop is known as the Ca2+-binding domain (CBD12). However, how the signaling of the allosteric intracellular Ca2+ binding propagates and results in transmembrane ion transportation still lacks a detailed explanation. Further structural and dynamics characterization of the intracellular loop flanking both sides of CBD12 is therefore imperative. Here, we report the identification and characterization of another structured domain that is N-terminal to CBD12 in the intracellular loop using solution nuclear magnetic resonance (NMR) spectroscopy. The atomistic structure of this domain reveals that two tandem long α-helices, connected by a short linker, form a stable crossover two-helix bundle (THB), resembling an "awareness ribbon". Considering the highly conserved amino acid sequence of the THB domain, the detailed structural and dynamics properties of the THB domain will be common among NCXs from different species and will contribute toward the understanding of the regulatory mechanism of eukaryotic Na+/Ca2+ exchangers.


Assuntos
Cálcio/metabolismo , Trocador de Sódio e Cálcio/química , Trocador de Sódio e Cálcio/metabolismo , Sódio/metabolismo , Regulação Alostérica , Sequência de Aminoácidos , Animais , Cães , Transporte de Íons , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Homologia de Sequência , Transdução de Sinais
16.
Toxicol Appl Pharmacol ; 360: 109-119, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30282042

RESUMO

Nux vomica has been effectively used in Traditional Chinese Medicine. The processing of Nux vomica is necessary to reduce toxicity before it can be used in clinical practice. However, the mechanism for processing detoxification is unclear. hERG channels have been subjected to a routine test for compound cardiac toxicity in the drug development process. Therefore, we examined the effects and mechanisms of strychnine and brucine, two main ingredients of Nux vomica, and their N-oxides on hERG channels. Strychnine and brucine exhibited concentration-dependent inhibition of hERG channels with IC50 values of 25.9 µM and 44.18 µM, respectively. However, their nitrogen oxidative derivatives produced by processing of Nux vomica, strychnine N-oxide and brucine N-oxide, lost their activity on hERG channels. Compared to their parent compounds, only an oxygen atom was introduced in the nitrogen oxidative isoforms to compensate for the N+ - charge, suggesting that the protonated nitrogen is the key group for strychnine and brucine binding to hERG channel. Alanine-mutagenesis identified Y652 is the most important residue for strychnine and brucine binding to hERG channel. Y652A mutation increased the IC50 for strychnine and brucine by 21.64-fold and 29.78-fold that of WT IhERG, respectively. Docking simulations suggested that the protonated nitrogen of strychnine and brucine formed a cation-π interaction with the aromatic ring of Y652. This study suggests that introduction of an oxygen to compensate for the N+ - charge could be a useful strategy for reducing hERG potency and increasing the safety margin of alkaloid-type compounds in drug development.


Assuntos
Oxigênio/metabolismo , Canais de Potássio/metabolismo , Estricnina/análogos & derivados , Estricnina/metabolismo , Alcaloides/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Medicina Tradicional Chinesa/métodos , Nitrogênio/metabolismo , Sódio/metabolismo , Relação Estrutura-Atividade , Strychnos nux-vomica/química , Regulador Transcricional ERG/metabolismo
17.
Bioorg Med Chem ; 26(15): 4452-4460, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30057155

RESUMO

Syzygium is a large genus of flowering plants, with several species, including the clove tree, used as important resources in the food and pharmaceutical industries. In our continuing search for anticancer agents from higher plants, a chloroform extract of the leaves and twigs of Syzygium corticosum collected in Vietnam was found to be active toward the HT-29 human colon cancer cell line. Separation of this extract guided by HT-29 cells and nuclear factor-kappa B (NF-κB) inhibition yielded 19 known natural products, including seven triterpenoids, three ellagic acid derivatives, two methylated flavonoids, a cyclohexanone, four megastigmanes, a small lactone, and an aromatic aldehyde. The full stereochemistry of (+)-fouquierol (2) was defined for the first time. Biological investigations showed that (+)-ursolic acid (1) is the major cytotoxic component of S. corticosum, which exhibited also potent activities in the NF-κB and mitochondrial transmembrane potential (MTP) inhibition assays conducted, with IC50 values of 31 nM and 3.5 µM, respectively. Several analogues of (+)-ursolic acid (1) were synthesized, and a preliminary structure-activity relationship (SAR) study indicated that the C-3 hydroxy and C-28 carboxylic acid groups and 19,20-dimethyl substitution are all essential in the mediation of the bioactivities observed for this triterpenoid.


Assuntos
Antineoplásicos Fitogênicos/síntese química , NF-kappa B/metabolismo , Syzygium/química , Triterpenos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Conformação Molecular , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Relação Estrutura-Atividade , Syzygium/metabolismo , Triterpenos/síntese química , Triterpenos/farmacologia , Ácido Ursólico
18.
Opt Lett ; 42(19): 4024-4027, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28957188

RESUMO

We demonstrate a new phase-matching geometry for four-wave mixing processes in hot Rb85 vapor, in which all four fields propagate in different directions but two of them are degenerate in frequency. When used as a parametric amplifier with an injected seed, two types of quantum mechanically correlated twin-beam states, either frequency degenerate or nondegenerate, can be generated. The quantum noise reduction in the intensity difference is almost 7 dB for the nondegenerate type and nearly 5 dB for the degenerate type. The spatial nondegeneracy of the four waves allows a variety of configurations of parametric processes, leading to flexible control for both phase insensitive and sensitive parametric amplification. The spatially nondegenerate but frequency degenerate four-wave mixing process will find wide applications in quantum metrology, quantum communication, and quantum information of continuous variables.

19.
Opt Lett ; 42(9): 1752-1755, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28454152

RESUMO

In studying quantum correlation and quantum memory of continuous variables of light fields and atoms, a crucial step is the retrieval of the quantum fields by converting an atomic spin wave to light, and retrieval efficiency is a crucial parameter. In this Letter, we implement a double-pass Raman scheme in Rb87 by incorporating coherent feedback. We find that the transfer efficiency from an atomic spin wave, which is generated from a Raman process in a high gain regime, to light fields is enhanced by the double-pass scheme as compared to the commonly used single-pass scheme. An atomic spin wave as high as 88% is read out, limited only by decoherence of the atomic spin waves. Our analysis shows that the enhancement effect is because a double-pass scheme introduced the coherent feedback mechanism which selects the spatial mode of an atomic spin wave via the correlated optical field and enhances the coupling efficiency between the atom and light. The correlations between the write-in and readout signals generated in such a two-pass Raman process are also better than the single-pass case. We believe such a two-pass scheme with feedback mechanism should be useful for studying continuous variables in quantum systems.

20.
Appl Environ Microbiol ; 82(9): 2763-2772, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26921428

RESUMO

A new environmental bacterial strain exhibited strong antimicrobial characteristics against methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of Enterococcus faecalis and Lactobacillus plantarum, and other Gram-positive bacteria. The producer strain, designated OSY-I1, was determined to be Brevibacillus laterosporusvia morphological, biochemical, and genetic analyses. The antimicrobial agent was extracted from cells of OSY-I1 with isopropanol, purified by high-performance liquid chromatography, and structurally analyzed using mass spectrometry (MS) and nuclear magnetic resonance (NMR). The MS and NMR results, taken together, uncovered a linear lipopeptide consisting of 13 amino acids and an N-terminal C6 fatty acid (FA) chain, 2-hydroxy-3-methylpentanoic acid. The lipopeptide (FA-Dhb-Leu-Orn-Ile-Ile-Val-Lys-Val-Val-Lys-Tyr-Leu-valinol, where Dhb is α,ß-didehydrobutyric acid and valinol is 2-amino-3-methyl-1-butanol) has a molecular mass of 1,583.0794 Da and contains three modified amino acid residues: α,ß-didehydrobutyric acid, ornithine, and valinol. The compound, designated brevibacillin, was determined to be a member of a cationic lipopeptide antibiotic family. In addition to its potency against drug-resistant bacteria, brevibacillin also exhibited low MICs (1 to 8 µg/ml) against selected foodborne pathogenic and spoilage bacteria, such as Listeria monocytogenes,Bacillus cereus, and Alicyclobacillus acidoterrestris Purified brevibacillin showed no sign of degradation when it was held at 80 °C for 60 min, and it retained at least 50% of its antimicrobial activity when it was held for 22 h under acidic or alkaline conditions. On the basis of these findings, brevibacillin is a potent antimicrobial lipopeptide which is potentially useful to combat drug-resistant bacterial pathogens and foodborne pathogenic and spoilage bacteria.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Brevibacillus/química , Brevibacillus/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Infecciosos/isolamento & purificação , Brevibacillus/genética , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Lactobacillus plantarum/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ácidos Pentanoicos/química , Valina/análogos & derivados , Valina/química , Enterococos Resistentes à Vancomicina/efeitos dos fármacos
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