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1.
BMJ Open ; 14(10): e087189, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39389597

RESUMEN

OBJECTIVES: This study aims to describe the prevalence, characteristics and longitudinal changes in frailty among outpatient chronic kidney disease (CKD) and haemodialysis (HD) populations and their impact on survival. DESIGN: Prospective observational cohort study. SETTING: Single-centre ambulatory tertiary care setting, metropolitan Australian teaching hospital. PARTICIPANTS: Adult patients with advanced CKD (defined as estimated glomerular filtration rate <20 mL/min) or undergoing maintenance HD. Consent model was informed opt-out consent. INTERVENTIONS: Fried frailty assessment at baseline, 6 months and 12 months of longitudinal follow-up. PRIMARY OUTCOMES: All-cause mortality and kidney transplantation events. RESULTS: Frailty was identified in 36.3% of the 256 participants, while an additional 46.5% exhibited prefrailty. Frailty was equally common among CKD and HD cohorts. Frailty outperformed age, comorbidity and laboratory parameters in predicting mortality risk with HR 2.83 (95% CI 1.44 to 5.56, p<0.001). Frailty also substantially reduced access to transplantation. While most participants exhibited static Fried phenotype over longitudinal assessment, improvements in frailty were observed as frequently as frailty progression. Female gender and symptom burden predicted frailty progression. CONCLUSIONS: Frailty is highly prevalent and closely aligned with survival outcomes. Frailty among patients attending routine outpatient care may demonstrate responsiveness to intervention with subsequent improvements in mortality and other patient-level outcomes.


Asunto(s)
Fragilidad , Diálisis Renal , Insuficiencia Renal Crónica , Humanos , Femenino , Masculino , Fragilidad/mortalidad , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/terapia , Australia/epidemiología , Trasplante de Riñón , Estudios Longitudinales , Prevalencia , Tasa de Filtración Glomerular
2.
BMC Nephrol ; 25(1): 304, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39272062

RESUMEN

BACKGROUND: Understanding the patient perspective of frailty is critical to offering holistic patient-centred care. Rehabilitation strategies for patients with advanced chronic kidney disease (CKD) and frailty are limited in their ability to overcome patient-perceived barriers to participation, resulting in high rates of drop-out and non-adherence. The aim of this study was to explore patient perspectives and preferences regarding experiences with rehabilitation to inform a CKD/Frailty rehabilitation model. METHODS: This qualitative study involved two focus groups, six individual semi-structured interviews and three caregiver semi-structured interviews with lived experience of advanced kidney disease and frailty. Interviews were recorded, transcribed, and coded for meaningful concepts and analysed using inductive thematic analysis using constant comparative method of data analysis employing Social Cognitive Theory. RESULTS: Six major themes emerged including accommodating frailty is an act of resilience, exercise is endorsed for rehabilitation but existing programs have failed to meet end-users' needs. Rehabilitation goals were framed around return to normative behaviours and rehabilitation should have a social dimension, offering understanding for "people like us". Participants reported on barriers and disruptors to frailty rehabilitation in the CKD context. Participants valued peer-to-peer education, the camaraderie of socialisation and the benefit of feedback for maintaining motivation. Patients undertaking dialysis described the commodity of time and the burden of unresolved symptoms as barriers to participation. Participants reported difficulty envisioning strategies for frailty rehabilitation, maintaining a focus on the immediate and avoidance of future uncertainty. CONCLUSIONS: Frailty rehabilitation efforts in CKD should leverage shared experiences, address comorbidity and symptom burden and focus on goals with normative value.


Asunto(s)
Grupos Focales , Fragilidad , Prioridad del Paciente , Investigación Cualitativa , Insuficiencia Renal Crónica , Humanos , Femenino , Masculino , Anciano , Insuficiencia Renal Crónica/rehabilitación , Insuficiencia Renal Crónica/psicología , Fragilidad/rehabilitación , Fragilidad/psicología , Anciano de 80 o más Años , Persona de Mediana Edad
3.
J Med Educ Curric Dev ; 10: 23821205231177862, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37275656

RESUMEN

Problem-based learning (PBL) utilizes a self-directed strategy. This process relies on group participation to succeed. Students without a background in biology or medicine can feel overwhelmed by the complexity of the subject matter and unable to participate in the group learning process. We incorporated curated educational videos in the PBL curriculum to help address this situation. First year medical students participated in this study in the form of a typical PBL session. They were then assessed on basic and clinical science knowledge and their learning experience. Student basic science and clinical knowledge were similar between the student groups. However, the students given a list of suggested videos scored higher in their learning experience, perception of feeling prepared, and participating in the group PBL experience than students who were not given the video list. Results from this study indicate that videos can be utilized to enhance the PBL process.

4.
Biochem Biophys Rep ; 32: 101341, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36120492

RESUMEN

Up to 70 million people around the world suffer from rheumatoid arthritis. Current treatment options have varied efficacy and can cause unwanted side effects. New approaches are needed to treat this condition. Sialic acid modifications on chondrocyte receptors have been associated with arthritic inflammation and joint destruction. For example, the transmembrane mucin receptor protein podoplanin (PDPN) has been identified as a functionally relevant receptor that presents extracellular sialic acid motifs. PDPN signaling promotes inflammation and invasion associated with arthritis and, therefore, has emerged as a target that can be used to inhibit arthritic inflammation. Maackia amurensis seed lectin (MASL) can target PDPN on chondrocytes to decrease inflammatory signaling cascades and reduce cartilage destruction in a lipopolysaccharide induced osteoarthritis mouse model. Here, we investigated the effects of MASL on rheumatoid arthritis progression in a TNFα transgenic (TNF-Tg) mouse model. Results from this study indicate that MASL can be administered orally to ameliorate joint malformation and increase velocity of movement exhibited by these TNF-Tg mice. These data support the consideration of MASL as a potential treatment for rheumatoid arthritis.

5.
Exp Cell Res ; 403(1): 112594, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33823179

RESUMEN

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 125 million confirmed COVID-19 cases that have caused over 2.7 million deaths worldwide as of March 2021. COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 presents a surface "spike" protein that binds to the ACE2 receptor to infect host cells. In addition to the respiratory tract, SARS-Cov-2 can also infect cells of the oral mucosa, which also express the ACE2 receptor. The spike and ACE2 proteins are highly glycosylated with sialic acid modifications that direct viral-host interactions and infection. Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins and can be used as an antiviral agent. Here, we report that MASL targets the ACE2 receptor, decreases ACE2 expression and glycosylation, suppresses binding of the SARS-CoV-2 spike protein, and decreases expression of inflammatory mediators by oral epithelial cells that cause ARDS in COVID-19 patients. In addition, we report that MASL also inhibits SARS-CoV-2 infection of kidney epithelial cells in culture. This work identifies MASL as an agent with potential to inhibit SARS-CoV-2 infection and COVID-19 related inflammatory syndromes.


Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Lectinas/farmacología , Boca/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/efectos de los fármacos , Progresión de la Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Interacciones Microbiota-Huesped/efectos de los fármacos , Humanos , Maackia/metabolismo , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/metabolismo
6.
J Cancer Res Clin Oncol ; 147(2): 445-457, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33205348

RESUMEN

PURPOSE: Oral cancer causes over 120,000 deaths annually and affects the quality of life for survivors. Over 90% of oral cancers are derived from oral squamous cell carcinoma cells (OSCCs) which are generally resistant to standard cytotoxic chemotherapy agents. OSCC cells often exhibit increased TGFß and PDPN receptor activity compared to nontransformed oral epithelial cells. Maackia amurensis seed lectin (MASL) can target the PDPN receptor and has been identified as a novel agent that can be used to treat oral cancer. However, mechanisms by which MASL inhibits OSCC progression are not yet clearly defined. METHODS: Here, we performed cell migration and cytotoxicity assays to assess the effects of MASL on OSCC motility and viability at physiologically relevant concentrations. We then performed comprehensive transcriptome analysis combined with transcription factor reporter assays to investigate the how MASL affects OSCC gene expression at these concentration. Key data were then confirmed by western blotting to evaluate the effects of MASL on gene expression and kinase signaling activity at the protein level. RESULTS: MASL significantly affected the expression of about 27% of approximately 15,000 genes found to be expressed by HSC-2 cells used to model OSCC cells in this study. These genes affected by MASL include members of the TGFß-SMAD, JAK-STAT, and Wnt-ßCTN signaling pathways. In particular, MASL decreased expression of PDPN, SOX2, and SMAD5 at the RNA and protein levels. MASL also inhibited SMAD and MAPK activity, and exhibited potential for combination therapy with doxorubicin and 5-fluorouracil. CONCLUSIONS: Taken together, results from this study indicate that MASL decreases activity of JAK-STAT, TGFß-SMAD, and Wnt-ßCTN signaling pathways to inhibit OSCC growth and motility. These data suggest that further studies should be undertaken to determine how MASL may also be used alone and in combination with other agents to treat oral cancer.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Maackia/química , Neoplasias de la Boca/tratamiento farmacológico , Lectinas de Plantas/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Humanos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Lectinas de Plantas/uso terapéutico , Factores de Transcripción SOXB1/genética , Transducción de Señal/efectos de los fármacos , Proteínas Smad/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Transcripción Genética/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos
7.
Res Sq ; 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33106801

RESUMEN

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 23 million confirmed COVID-19 cases that have cause over 800 thousand deaths worldwide as of August 19th, 2020. COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 presents a surface "spike" protein that binds to the ACE2 receptor to infect host cells. In addition to the respiratory tract, SARS-Cov-2 can also infect cells of the oral mucosa, which also express the ACE2 receptor. The spike and ACE2 proteins are highly glycosylated with sialic acid modifications that direct viral-host interactions and infection. Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins and can be used as an antiviral agent. Here, we report that MASL targets the ACE2 receptor, decreases ACE2 expression and glycosylation, suppresses binding of the SARS-CoV-2 spike protein, and decreases expression of inflammatory mediators by oral epithelial cells that cause ARDS in COVID-19 patients. This work identifies MASL as an agent with potential to inhibit SARS-CoV-2 infection and COVID-19 related inflammatory syndromes.

8.
Curr Opin Biomed Eng ; 14: 18-24, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32548365

RESUMEN

Traumatic brain injury often leads to progressive alterations at the molecular to circuit levels resulting in epilepsy and memory impairments. Ex vivo and in vitro models have provided a powerful platform for investigating the multimodal alteration after trauma. Recent ex vivo analyses using voltage sensitive dye imaging, optogenetics, and glutamate uncaging have revealed circuit abnormalities following in vivo brain injury. In vitro injury models have enabled examination of early and progressive changes in activity while development of three-dimensional organoids derived from human induced pluripotent stem cells have opened novel avenues for injury research. Here, we highlight recent advances in ex vivo and in vitro systems, focusing on their potential for advancing mechanistic understandings, possible limitations, and implications for therapeutics.

9.
J Lesbian Stud ; 23(2): 144-168, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30632906

RESUMEN

We introduce a theoretical framework of lesbian disclosure of sexual orientation in workplace contexts. Existing empirical research suggests (1) that disclosing one's sexual orientation results in positive, negative, and neutral workplace outcomes; and (2) that scholarship focused specifically on lesbian disclosure in workplace contexts is relatively limited. We extend this literature by introducing new theory that suggests that reactions to disclosure of lesbian identities will vary as a function of self-presentation. Specifically, we suggest that the extent of stereotypical gender expression (embodying stereotypically masculine vs. feminine traits or behaviors) will impact both the decision to disclose and the outcomes of disclosure in workplace contexts. We describe a conceptual model that includes intrapersonal, interpersonal, organizational, and societal considerations related to lesbian disclosure and present eight specific research propositions to advance this literature.


Asunto(s)
Homosexualidad Femenina , Autorrevelación , Mujeres Trabajadoras , Lugar de Trabajo , Femenino , Identidad de Género , Homofobia , Homosexualidad Femenina/psicología , Humanos , Modelos Psicológicos , Estereotipo , Mujeres Trabajadoras/psicología
10.
PLoS One ; 13(5): e0196223, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29715265

RESUMEN

Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post-synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability. Increased CA1 neuronal excitability was not associated with increased seizure severity as Bhlhe40 KO relative to +/+ (WT) control mice injected with the convulsant kainic acid. However, significant reductions in long term potentiation and long term depression at CA1 synapses were observed in Bhlhe40 KO mice, indicating impaired hippocampal synaptic plasticity. Behavioral testing for spatial learning and memory on the Morris Water Maze (MWM) revealed that while Bhlhe40 KO mice performed similarly to WT controls initially, when the hidden platform was moved to the opposite quadrant Bhlhe40 KO mice showed impairments in relearning, consistent with decreased hippocampal synaptic plasticity. To investigate possible mechanisms for increased neuronal excitability and decreased synaptic plasticity, a whole genome mRNA expression profile of Bhlhe40 KO hippocampus was performed followed by a chromatin immunoprecipitation sequencing (ChIP-Seq) screen of the validated candidate genes for Bhlhe40 protein-DNA interactions consistent with transcriptional regulation. Of the validated genes identified from mRNA expression analysis, insulin degrading enzyme (Ide) had the most significantly altered expression in hippocampus and was significantly downregulated on the RNA and protein levels; although Bhlhe40 did not occupy the Ide gene by ChIP-Seq. Together, these findings support a role for Bhlhe40 in regulating neuronal excitability and synaptic plasticity in the hippocampus and that indirect regulation of Ide transcription may be involved in these phenotypes.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiopatología , Proteínas de Homeodominio/fisiología , Plasticidad Neuronal , Neuronas/fisiología , Convulsiones/fisiopatología , Animales , Femenino , Perfilación de la Expresión Génica , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología
11.
Brain Res ; 1671: 1-13, 2017 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-28666957

RESUMEN

Neural circuits in mammalian brains consist of large numbers of different cell types having different functional properties. To better understand the separate roles of individual neuron types in specific aspects of spatial learning and memory, we perturbed the function of principal neurons in vivo during maze performance or in hippocampal slices during recording of evoked excitatory synaptic potentials. Transgenic mice expressing the Drosophila allatostatin receptor (AlstR) in cortical and hippocampal pyramidal cells were tested on an elevated plus maze, in a Y-maze, and in the Morris water maze. Relative to a control cohort, AlstR-positive mice treated with allatostatin exhibited no difference in open arm dwell time on the elevated plus maze or total number of arm entries in a Y-maze, but displayed reduced spontaneous alternation. When animals received massed or spaced training trials in the Morris water maze, and the peptide was delivered prior to an immediate probe, no effects on performance were observed. When the peptide was delivered during a probe trial performed 24h after seven days of spaced training, allatostatin delivery to AlstR positive mice enhanced direct navigation to the escape platform. Combined, these results suggest that cortical and hippocampal pyramidal neurons are required during spatial decision-making in a novel environment and compete with other neural systems after extended training in a long-term reference memory task. In hippocampal slices collected from AlstR positive animals, allatostatin delivery produced frequency dependent alterations in the Schaffer collateral fiber volley (attenuated accommodation at 100Hz) and excitatory postsynaptic potential (attenuated facilitation at 5Hz). Combined, the neural and behavioral discoveries support the involvement of short-term plasticity of Schaffer collateral axons and synapses during exploration of a novel environment and during initial orientation to a goal in a well-learned setting.


Asunto(s)
Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiología , Aprendizaje/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Receptores de Neuropéptido/metabolismo , Receptores de Neuropéptido/fisiología , Memoria Espacial/fisiología , Animales , Axones/fisiología , Drosophila/anatomía & histología , Drosophila/metabolismo , Potenciales Postsinápticos Excitadores , Hipocampo/metabolismo , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Memoria a Largo Plazo/fisiología , Ratones , Ratones Transgénicos , Neuronas/fisiología , Neuropéptidos/metabolismo , Neuropéptidos/fisiología , Prosencéfalo/metabolismo , Prosencéfalo/fisiología , Células Piramidales/fisiología , Transmisión Sináptica/fisiología
12.
PLoS One ; 11(10): e0165141, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27760193

RESUMEN

Memory consolidation benefits from post-training sleep. However, recent studies suggest that sleep does not uniformly benefit all memory, but instead prioritizes information that is important to the individual. Here, we examined the effect of test expectation on memory consolidation across sleep and wakefulness. Following reports that information with strong "future relevance" is preferentially consolidated during sleep, we hypothesized that test expectation would enhance memory consolidation across a period of sleep, but not across wakefulness. To the contrary, we found that expectation of a future test enhanced memory for both spatial and motor learning, but that this effect was equivalent across both wake and sleep retention intervals. These observations differ from those of least two prior studies, and fail to support the hypothesis that the "future relevance" of learned material moderates its consolidation selectively during sleep.


Asunto(s)
Consolidación de la Memoria/fisiología , Sueño/fisiología , Vigilia/fisiología , Adolescente , Femenino , Humanos , Masculino , Recuerdo Mental , Pruebas Neuropsicológicas , Aprendizaje Espacial , Adulto Joven
13.
Neurobiol Learn Mem ; 130: 17-25, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26802698

RESUMEN

Numerous studies demonstrate that post-training sleep benefits human memory. At the same time, emerging data suggest that other resting states may similarly facilitate consolidation. In order to identify the conditions under which non-sleep resting states benefit memory, we conducted an EEG (electroencephalographic) study of verbal memory retention across 15min of eyes-closed rest. Participants (n=26) listened to a short story and then either rested with their eyes closed, or else completed a distractor task for 15min. A delayed recall test was administered immediately following the rest period. We found, first, that quiet rest enhanced memory for the short story. Improved memory was associated with a particular EEG signature of increased slow oscillatory activity (<1Hz), in concert with reduced alpha (8-12Hz) activity. Mindwandering during the retention interval was also associated with improved memory. These observations suggest that a short period of quiet rest can facilitate memory, and that this may occur via an active process of consolidation supported by slow oscillatory EEG activity and characterized by decreased attention to the external environment. Slow oscillatory EEG rhythms are proposed to facilitate memory consolidation during sleep by promoting hippocampal-cortical communication. Our findings suggest that EEG slow oscillations could play a significant role in memory consolidation during other resting states as well.


Asunto(s)
Encéfalo/fisiología , Consolidación de la Memoria/fisiología , Recuerdo Mental/fisiología , Descanso/fisiología , Sueño/fisiología , Electroencefalografía , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Adulto Joven
14.
Crit Care Nurse ; 35(2): 82-4, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25834013

RESUMEN

Incidence and characteristics of patient falls and fall prevention programs have been a topic of interest in the literature; however, few articles on fall reduction strategies written by staff nurses have been published. Falls in hospitalized patients are serious threats to patient safety. According to Morse, sequelae of falls are the second leading cause of death in the United States. Costs resulting from falls alone have been reported at between 0.85% and 1.5% of the total health care expenses within the United States, Australia, the European Union, and the United Kingdom. A fall is the most reported safety incident in inpatients and occurs in all adult clinical areas. Accidental falls are among the most common incidents reported in hospitals and occur in approximately 2% of all hospital stays. Growing evidence indicates that falls occurring in the hospital can be reduced with planning and intervention techniques


Asunto(s)
Accidentes por Caídas/prevención & control , Enfermería de Cuidados Críticos/métodos , Medicina Basada en la Evidencia/métodos , Sistemas de Atención de Punto/organización & administración , Prevención de Accidentes/métodos , Anciano , Anciano de 80 o más Años , Cuidados Críticos/métodos , Femenino , Humanos , Pacientes Internos/estadística & datos numéricos , Masculino , Seguridad del Paciente
15.
Pharm Res ; 31(12): 3445-60, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24980206

RESUMEN

PURPOSE: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs. METHODS: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics. RESULTS: Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose. In vitro analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and in vivo POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing. CONCLUSIONS: Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure in vivo.


Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Técnicas de Silenciamiento del Gen/métodos , ARN Interferente Pequeño/farmacología , Animales , Química Farmacéutica , Diclofenaco/metabolismo , Técnicas In Vitro , Masculino , Microsomas/efectos de los fármacos , Microsomas/enzimología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Midazolam/metabolismo , Nanopartículas , Unión Proteica , Ratas
16.
Front Neurosci ; 6: 49, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22536169

RESUMEN

The importance of neuronal morphology has been recognized from the early days of neuroscience. Elucidating the functional roles of axonal and dendritic arbors in synaptic integration, signal transmission, network connectivity, and circuit dynamics requires quantitative analyses of digital three-dimensional reconstructions. We extensively searched the scientific literature for all original reports describing reconstructions of neuronal morphology since the advent of this technique three decades ago. From almost 50,000 titles, 30,000 abstracts, and more than 10,000 full-text articles, we identified 902 publications describing ∼44,000 digital reconstructions. Reviewing the growth of this field exposed general research trends on specific animal species, brain regions, neuron types, and experimental approaches. The entire bibliography, annotated with relevant metadata and (wherever available) direct links to the underlying digital data, is accessible at NeuroMorpho.Org.

17.
Bioorg Med Chem Lett ; 22(7): 2609-12, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22374217

RESUMEN

Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.


Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/química , Piridinas/síntesis química , Tiazoles/síntesis química , Amidas/química , Antineoplásicos/farmacología , Sitios de Unión , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Diseño de Fármacos , Etilenodiaminas/química , Humanos , Enlace de Hidrógeno , Cinética , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Piridinas/farmacología , Relación Estructura-Actividad , Tiazoles/farmacología , Agua/química
18.
Bioorg Med Chem Lett ; 22(7): 2613-9, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22365762

RESUMEN

Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.


Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/química , Piridinas/síntesis química , Tiazoles/síntesis química , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Diseño de Fármacos , Halogenación , Humanos , Cinética , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Piridinas/farmacología , Relación Estructura-Actividad , Tiazoles/farmacología , Quinasa Activadora de Quinasas Ciclina-Dependientes
19.
J Neurosci ; 30(5): 1712-20, 2010 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-20130180

RESUMEN

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-beta-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-beta-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, and spatial memory. These data demonstrate the ability of neuroprotective gene expression limited to a specific cell population to both locally and trans-synaptically offset neurophysiological disruptions produced by prolonged increases in circulating stress hormones. This report supplies the first physiological explanation for previously demonstrated cognitive sparing by anti-stress gene therapy approaches and lends additional insight into the hippocampal processes that are important for memory.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Corticosterona/metabolismo , Terapia Genética , Hipocampo/metabolismo , Memoria/fisiología , Plasticidad Neuronal/genética , Células Piramidales/fisiología , Animales , Corticosterona/farmacología , Giro Dentado/enzimología , Expresión Génica , Hipocampo/citología , Masculino , Trastornos de la Memoria/fisiopatología , Ratas , Ratas Sprague-Dawley , Percepción Espacial/fisiología , Sinapsis/fisiología
20.
Arch Biochem Biophys ; 484(1): 1-7, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19467625

RESUMEN

A number of inhibitors of kinesin spindle protein (KSP) have been described, which are known from X-ray crystallography studies to bind to an induced fit pocket defined by the L5 loop. We describe the characterization of eight mutant forms of KSP in which six residues that line this pocket have been altered. Mutants were analyzed by measuring rates of enzyme catalysis, in the presence and absence of six KSP inhibitors of four diverse structural classes and of varied ATP-competition status. Our analysis was in agreement with the model of binding established by the structural studies and suggests that binding energy is well distributed across functional groups in these molecules. The majority of the mutants retained significant enzymatic activity while diminishing inhibitor binding, indicating potential for the development of drug resistance. These data provide detailed information on interactions between inhibitor and binding pocket at the functional group level and enable the development of novel KSP inhibitors.


Asunto(s)
Cinesinas/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Unión Competitiva , Biocatálisis , Cristalografía por Rayos X , Humanos , Cinesinas/química , Cinesinas/genética , Cinesinas/metabolismo , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Conformación Proteica , Homología de Secuencia de Aminoácido
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