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1.
Nat Methods ; 15(10): 805-815, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224673

RESUMO

Neuroscience is experiencing a revolution in which simultaneous recording of thousands of neurons is revealing population dynamics that are not apparent from single-neuron responses. This structure is typically extracted from data averaged across many trials, but deeper understanding requires studying phenomena detected in single trials, which is challenging due to incomplete sampling of the neural population, trial-to-trial variability, and fluctuations in action potential timing. We introduce latent factor analysis via dynamical systems, a deep learning method to infer latent dynamics from single-trial neural spiking data. When applied to a variety of macaque and human motor cortical datasets, latent factor analysis via dynamical systems accurately predicts observed behavioral variables, extracts precise firing rate estimates of neural dynamics on single trials, infers perturbations to those dynamics that correlate with behavioral choices, and combines data from non-overlapping recording sessions spanning months to improve inference of underlying dynamics.


Assuntos
Potenciais de Ação , Algoritmos , Modelos Neurológicos , Córtex Motor/fisiologia , Neurônios/fisiologia , Animais , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica Populacional , Primatas
2.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673007

RESUMO

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2-4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.


Assuntos
Antimaláricos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Plasmodium/efeitos dos fármacos , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Células Hep G2 , Humanos , Quinolinas/síntese química , Quinolinas/química
3.
Bioorg Med Chem Lett ; 30(14): 127217, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527539

RESUMO

The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.


Assuntos
Antiprotozoários/farmacologia , Cisteína Proteases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Sulfonas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Trypanosoma brucei brucei/crescimento & desenvolvimento , Trypanosoma brucei brucei/metabolismo
4.
Bioorg Med Chem Lett ; 28(9): 1647-1651, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29609908

RESUMO

A series of natural products-based phenyl sulfone derivative and their property-based analogues were investigated as potential growth inhibitors of Trypanosoma brucei. Trypanosoma brucei is a kinetoplastid protozoan parasite that causes trypanosomiasis. In this work, we found that nopol- and quinoline-based phenyl sulfone derivative were the most active and selective for T. brucei, and they were not reactive towards the active thiol of T. brucei's cysteine protease rhodesain. A thiol reactive variant of the quinoline-based phenyl sulfone was subsequently investigated and found to be a moderate inhibitor of rhodesain. The quinoline-based compound that is not reactive towards rhodesain can serve a template for phenotypic-based lead discovery while its thiol-active congener can serve as template for structure-based investigation of new antitrypanosomal agents.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Quinolinas/farmacologia , Sulfonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/química , Relação Estrutura-Atividade , Sulfonas/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
5.
Molecules ; 23(2)2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29419735

RESUMO

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl3 extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays.


Assuntos
Extratos Vegetais/química , Extratos Vegetais/farmacologia , Tabernaemontana/química , Triterpenos/química , Triterpenos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Testes de Sensibilidade Parasitária , Trypanosoma brucei brucei/efeitos dos fármacos
6.
J Comput Aided Mol Des ; 30(9): 761-771, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27592011

RESUMO

We assess the performance of several machine learning-based scoring methods at protein-ligand pose prediction, virtual screening, and binding affinity prediction. The methods and the manner in which they were trained make them sufficiently diverse to evaluate the utility of various strategies for training set curation and binding pose generation, but they share a novel approach to classification in the context of protein-ligand scoring. Rather than explicitly using structural data such as affinity values or information extracted from crystal binding poses for training, we instead exploit the abundance of data available from high-throughput screening to approach the problem as one of discriminating binders from non-binders. We evaluate the performance of our various scoring methods in the 2015 D3R Grand Challenge and find that although the merits of some features of our approach remain inconclusive, our scoring methods performed comparably to a state-of-the-art scoring function that was fit to binding affinity data.


Assuntos
Biologia Computacional/métodos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Proteínas/química , Algoritmos , Sítios de Ligação , Proteínas de Choque Térmico HSP90/química , Humanos , Ligantes , Estudos Prospectivos , Ligação Proteica
7.
New Dir Stud Leadersh ; 2021(171): 123-131, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34658174

RESUMO

This issue highlights leadership development approaches within institutional contexts that have not been well represented in leadership education research. As the first publication in the field to address racial equity through the lens of institutional type in this way, authors were given the challenging task of laying a conceptual, historical, and empirical foundation for readers in the absence of a robust body of literature. What follows is a synthesis of themes observed across each of the articles, concluding with implications for inclusive leadership research and practice.


Assuntos
Liderança , Humanos
8.
New Dir Stud Leadersh ; 2021(171): 15-22, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34658175

RESUMO

In this introductory article, we offer a theoretical overview of racial equity and provide the rationale for pursuing an issue related to racial equity in leadership education. We also make the case for examining marginalized institutional contexts as a step toward advancing racial equity in postsecondary leadership education.


Assuntos
Liderança , Humanos
9.
J Biomol Struct Dyn ; 39(17): 6810-6827, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795148

RESUMO

Due to an outbreak of COVID-19, the number of research papers devoted to in-silico drug discovery of potential antiviral drugs is increasing every day exponentially. Still, there is no specific drug to prevent or treat this novel coronavirus (SARS-CoV-2) disease. Thus, the screening for a potential remedy presents a global challenge for scientists. Up to date over a hundred crystallographic structures of SARS-CoV-2 Mpro have been deposited to Protein Data Bank. With many known proteins, the demand for a reliable target has become higher than ever, so as the choice of an efficient computational methods. Therefore, in this study comparative methods have been used for receptor-based virtual screening, targeting 9 selected structures of viral Mpro. Reliability analyses followed by re-docking of the specific co-crystallized ligand provided the best reproductivity for structures with PDB ID 6LU7, 6Y2G and 6Y2F. The influence of crystallographic water on an outcome of a virtual screening against selected targets was also investigated. Once the most reliable targets were selected, the library of easy purchasable natural compounds were retrieved from the MolPort database (10,305 compounds) and docked against the selected Mpro proteins. To ensure the efficiency of the selected compounds, binding energies for top-15 hit ligands were calculated using Molecular Mechanics as well as their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted. Based on predicted binding energies and toxicities, top-5 compounds were selected and subjected to Molecular Dynamics simulation and found to be stable in complex to act as possible inhibitors for SARS-CoV-2. Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Simulação de Dinâmica Molecular , Humanos , Simulação de Acoplamento Molecular , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Reprodutibilidade dos Testes , SARS-CoV-2
10.
New Dir Stud Leadersh ; 2017(155): 9-19, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28834315

RESUMO

Student organizations have existed for almost as long as educational institutions have. This chapter examines the historical role of student organizations in developing leadership capacity in students, as well as their current roles on high school and collegiate campuses in creating transformational environments for student leadership learning and growth.


Assuntos
Liderança , Organizações , Instituições Acadêmicas , Estudantes , Adolescente , Adulto , Humanos , Adulto Jovem
12.
Comput Biol Chem ; 64: 163-184, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27387412

RESUMO

Alphaviruses such as Chikungunya virus (CHIKV), O'Nyong-Nyong virus (ONNV), Ross River virus (RRV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that can cause fevers, rash, and rheumatic diseases (CHIKV, ONNV, RRV) or potentially fatal encephalitis (EEEV, VEEV, WEEV) in humans. These diseases are considered neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The alphavirus non-structural protein 2 (nsP2) contains a papain-like protease, which is considered to be a promising target for antiviral drug discovery. In this work, molecular docking analyses have been carried out on a library of 2174 plant-derived natural products (290 alkaloids, 664 terpenoids, 1060 polyphenolics, and 160 miscellaneous phytochemicals) with the nsP2 proteases of CHIKV, ONNV, RRV, EEEV, VEEV, WEEV, as well as Aura virus (AURV), Barmah Forest Virus (BFV), Semliki Forest virus (SFV), and Sindbis virus (SINV) in order to identity structural scaffolds for inhibitor design or discovery. Of the 2174 phytochemicals examined, a total of 127 showed promising docking affinities and poses to one or more of the nsP2 proteases, and this knowledge can be used to guide experimental investigation of potential inhibitors.


Assuntos
Alphavirus/química , Inibidores de Proteases/isolamento & purificação , Antivirais/química , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/química
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