RESUMEN
We present a comparative all-atom molecular dynamics simulation study of 18 biomembrane systems with lipid compositions corresponding to eukaryotic, bacterial, and archaebacterial membranes together with three single-component lipid bilayers. A total of 105 lipid types used in this study include diverse sterols and glycerol-based lipids with acyl chains of various lengths, unsaturation degrees, and branched or cyclic moieties. Our comparative analysis provides deeper insight into the influences of sterols and lipid unsaturation on the structural and mechanical properties of these biomembranes, including water permeation into the membrane hydrocarbon core. For sterol-containing membranes, sterol fraction is correlated with the membrane thickness, the area compressibility modulus, and lipid order but anticorrelated with the area per lipid and sterol tilt angles. Similarly, for all 18 biomembranes, lipid order is correlated with the membrane thickness and area compressibility modulus. Sterols and lipid unsaturation produce opposite effects on membrane thickness, but only sterols influence water permeation into the membrane. All membrane systems are accessible for public use in CHARMM-GUI Archive. They can be used as templates to expedite future modeling of realistic cell membranes with transmembrane and peripheral membrane proteins to study their structure, dynamics, molecular interactions, and function in a nativelike membrane environment.
Asunto(s)
Eucariontes , Simulación de Dinámica Molecular , Archaea/metabolismo , Membrana Celular/metabolismo , Membrana Dobles de Lípidos/químicaRESUMEN
Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
Asunto(s)
Envejecimiento/metabolismo , Disfunción Cognitiva/prevención & control , Células Mieloides/metabolismo , Adulto , Anciano , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Respiración de la Célula , Células Cultivadas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/genética , Dinoprostona/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Glucógeno/biosíntesis , Glucógeno/metabolismo , Humanos , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Mitocondrias/metabolismo , Células Mieloides/inmunología , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/deficiencia , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
Asunto(s)
Inmunidad Adaptativa , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Adaptadoras de Señalización CARD , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Caspasa 1/deficiencia , Caspasa 1/metabolismo , Diferenciación Celular , Proliferación Celular , Reprogramación Celular , Eliminación de Gen , Humanos , Terapia de Inmunosupresión , Ratones Endogámicos C57BL , Proteína Adaptadora de Señalización NOD2/metabolismo , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/patología , Linfocitos T/inmunología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-ß (Aß) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aß accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aß pathology.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Microglía/inmunología , Animales , Encéfalo/inmunología , HumanosRESUMEN
Nurses on an inpatient surgical unit were apprehensive in activating the Rapid Response Team (RRT). Nurse-led interdisciplinary solutions addressed perceived barriers and led to open communication and issue resolution with physician colleagues.
Asunto(s)
Actitud del Personal de Salud , Equipo Hospitalario de Respuesta Rápida , Personal de Enfermería en Hospital , Defensa del Paciente , Seguridad del Paciente , Adulto , Comunicación , Toma de Decisiones , Educación Continua en Enfermería , Femenino , Humanos , Comunicación Interdisciplinaria , Masculino , Persona de Mediana Edad , Rol de la Enfermera , Personal de Enfermería en Hospital/educación , Rol del Médico , Solución de ProblemasRESUMEN
A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
Asunto(s)
Anexina A2/metabolismo , Depresión/fisiopatología , Interneuronas/metabolismo , Núcleo Accumbens/metabolismo , Proteínas S100/metabolismo , Acetilcolina/metabolismo , Animales , Antidepresivos/farmacología , Conducta Animal , Depresión/metabolismo , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Chaperonas Moleculares/metabolismo , Neuronas/metabolismo , Neurotransmisores/metabolismo , Fenotipo , Receptores Colinérgicos/metabolismoRESUMEN
Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17ß-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5 min after infusion. Phospho-p42 ERK levels were downregulated 15 min after infusion and returned to baseline 30 min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.