RESUMEN
How memories are organized in the brain influences whether they are remembered discretely versus linked with other experiences or whether generalized information is applied to entirely novel situations. Here, we used scFLARE2 (single-chain fast light- and activity-regulated expression 2), a temporally precise tagging system, to manipulate mouse lateral amygdala neurons active during one of two 3 min threat experiences occurring close (3 h) or further apart (27 h) in time. Silencing scFLARE2-tagged neurons showed that two threat experiences occurring at distal times are dis-allocated to orthogonal engram ensembles and remembered discretely, whereas the same two threat experiences occurring in close temporal proximity are linked via co-allocation to overlapping engram ensembles. Moreover, we found that co-allocation mediates memory generalization applied to a completely novel stimulus. These results indicate that endogenous temporal evolution of engram ensemble neuronal excitability determines how memories are organized and remembered and that this would not be possible using conventional immediate-early gene-based tagging methods.
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Miedo , Memoria , Ratones , Animales , Memoria/fisiología , Miedo/fisiología , Neuronas/fisiología , Encéfalo/fisiología , Recuerdo Mental/fisiologíaRESUMEN
Understanding how local traffic congestion spreads in urban traffic networks is fundamental to solving congestion problems in cities. In this work, by analyzing the high-resolution data of traffic velocity in Seoul, we empirically investigate the spreading patterns and cluster formation of traffic congestion in a real-world urban traffic network. To do this, we propose a congestion identification method suitable for various types of interacting traffic flows in urban traffic networks. Our method reveals that congestion spreading in Seoul may be characterized by a treelike structure during the morning rush hour but a more persistent loop structure during the evening rush hour. Our findings suggest that diffusion and stacking processes of local congestion play a major role in the formation of urban traffic congestion.
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Making the connection between the function and structure of networked systems is one of the fundamental issues in complex systems and network science. Urban traffic flows are related to various problems in cities and can be represented as a network of local traffic flows. To identify an empirical relation between the function and network structure of urban traffic flows, we construct a time-varying traffic flow network of a megacity, Seoul, and analyze its global efficiency with a percolation-based approach. Comparing the real-world traffic flow network with its corresponding null-model network having a randomized structure, we show that the real-world network is less efficient than its null-model network during rush hour, yet more efficient during non-rush hour. We observe that in the real-world network, links with the highest betweenness tend to have lower quality during rush hour compared to links with lower betweenness, but higher quality during non-rush hour. Since the top betweenness links tend to be the bridges that connect the network together, their congestion has a stronger impact on the network's global efficiency. Our results suggest that the spatial structure of traffic flow networks is important to understand their function.
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According to the encoding specificity hypothesis, memory is best recalled by retrieval cues that overlap with training cues. Human studies generally support this hypothesis. However, memories are thought to be stored in neuronal ensembles (engrams), and retrieval cues are thought to reactivate neurons in an engram to induce memory recall. Here, we visualized engrams in mice to test whether retrieval cues that overlap with training cues produce maximal memory recall via high engram reactivation (engram encoding specificity hypothesis). Using variations of cued threat conditioning (pairing conditioned stimulus [CS] with footshock), we manipulated encoding and retrieval conditions along multiple domains, including pharmacological state, external sensory cue, and internal optogenetic cue. Maximal engram reactivation and memory recall occurred when retrieval conditions closely matched training conditions. These findings provide a biological basis for the encoding specificity hypothesis and highlight the important interaction between stored information (engram) and cues available at memory retrieval (ecphory).
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Memoria , Recuerdo Mental , Ratones , Humanos , Animales , Memoria/fisiología , Recuerdo Mental/fisiología , Condicionamiento Clásico/fisiología , Neuronas/fisiología , Señales (Psicología)RESUMEN
The dissipation patterns of chlorfenapyr, cyenopyrafen, indoxacarb, and spirotetramat on strawberries and the effects of different household washing methods were investigated. A risk assessment was also conducted by monitoring the insecticide residues detected. The concentrations ranged from 0.011 to 0.27 mg/kg for chlorfenapyr, 0.064 to 0.99 mg/kg for cyenopyrafen, 0.042 to 0.53 mg/kg for indoxacarb, and from 0.25 to 1.3 mg/kg for spirotetramat, which were all below the maximum residue limits (MRLs) reported. Soaking the fruit in solution and then rinsing with running water (B) led to better residue removal (40.9 ± 23.7%) than only soaking in solution (A) (24.7 ± 22.5%). However, neither method decreased chlorfenapyr concentrations, suggesting that the physical-chemical properties of chlorfenapyr could also affect its removal on strawberries. Regarding the different washing solutions in method B, 3% vinegar (removal efficiency: 48.7%) and 3% salt (45.7%) were the most efficient, followed by 3% green tea (38.9%), and tap water only (24.6%). Additionally, the estimated risk quotients (RQs) for strawberry consumption for women were about 1.5 times higher than those observed for men, but both were lower than 1, suggesting minimal risk to humans.
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Memories of past experiences guide future behaviour. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Neurons involved in a particular engram ("engram neurons") are necessary for subsequent memory expression as memory retrieval is thought to be initiated by an external sensory cue reactivating engram neurons. However, conditions or environments are dynamic, such that future behaviour should be flexible. The role of engrams in mediating flexible behaviour is not understood. Here we examined this question using one type of flexible behaviour, extinction of a threat response. An initially neutral tone is first paired with an aversive footshock such that the tone alone induces defensive freezing. After subsequent repeated tone presentations without the footshock, rodents no longer freeze to the tone. Because the tone cue is thought to reactivate the engram to induce memory retrieval, we examined whether it is possible to induce an extinction-like behavioural effect by optogenetically reactivating the lateral amygdala component of the engram alone (without tone re-exposure). Similar to tone-induced extinction, mice showed decreased freezing to optogenetic stimulation of the lateral amygdala engram in the "extinction training" session. Moreover, "opto-extinguished" mice showed decreased freezing to the tone when subsequently tested for retrieval of the extinction training in the same context, suggesting that the opto-extinction transferred to the actual sensory stimulus. However, unlike tone extinction, in which mice showed renewal of tone-induced freezing when tested in a novel context, opto-extinguished mice continued to show a deficit in tone-induced freezing. Extinction has been characterized as new learning that inhibits the original memory or a phenomenon in which the original memory is "unlearned". Our findings suggest that opto-extinction may silence the original engram to "unlearn" the original memory.
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Miedo , Memoria , Animales , Ratones , Amígdala del Cerebelo/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Memoria/fisiología , Neuronas/metabolismo , OptogenéticaRESUMEN
Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.
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Most individuals undergo traumatic stresses at some points in their life, but only a small proportion develop stress-related disorders such as anxiety diseases and posttraumatic stress disorder (PTSD). Although stress susceptibility is one determinant of mental disorders, the underlying mechanisms and functional implication remain unclear yet. We found that an increased amount of freezing that animals exhibited in the intertrial interval (ITI) of a stress-enhanced fear learning paradigm, predicts ensuing PTSD-like symptoms whereas resilient mice show ITI freezing comparable to that of unstressed mice. To examine the behavioral features, we developed a systematic analytical approach for ITI freezing and stress susceptibility. Thus, we provide a behavioral parameter for prognosis to stress susceptibility of individuals in the development of PTSD-like symptoms as well as a new mathematical means to scrutinize freezing behavior.
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Miedo/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Enfermedad Aguda , Animales , Ansiedad/fisiopatología , Conducta Animal/fisiología , Susceptibilidad a Enfermedades , Extinción Psicológica , Reacción Cataléptica de Congelación/fisiología , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
Exposure to fine particulate matter (PM) comprising toxic compounds arising from air pollution is a major human health concern. It is linked to increased mortality and incidence of various lung diseases. However, the mechanisms underlying the toxic effects of PM on lung fibroblasts have not been fully explored. We used targeted quantitative metabolomics and lipidomics analysis along with cytotoxicity studies to comprehensively characterize the alterations in the metabolite profiles of human lung fibroblasts (HEL 299) upon exposure to PM2.5 and PM10. This exposure at 50 µg/mL for 72 h induced an abnormally high apoptotic response via triggering intracellular reactive oxygen species (ROS) production and mitochondrial dysfunction through an imbalance between pro- and anti-apoptotic signaling pathways. The cytotoxic effects of PM2.5 were more severe than those of PM10. Metabolomics and lipidomics analyses revealed that PM exposure triggered substantial changes in the cellular metabolite profile, which involved reduced mitochondria-related metabolites such as tricarboxylic acid (TCA) cycle intermediates, amino acids, and free fatty acids as well as increased lysoglycerophospholipids (LPLs) containing polyunsaturated fatty acids. The decrease in mitochondria-related metabolites suggested that PM exposure led to reduced TCA cycle capacity and energy production. Apoptotic and inflammatory responses as well as mitochondrial dysfunction were likely to be accelerated because of excessive accumulation of LPLs, contributing to the disruption of membrane rafts and Ca2+ homeostasis and causing increased mitochondrial ROS formation. These results provide valuable insights regarding the toxic effects of PM exposure. Our study also provides a new direction for research on PM exposure-related health disorders using different cell lines.
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Contaminantes Atmosféricos/toxicidad , Fibroblastos/fisiología , Material Particulado/toxicidad , Fosfolípidos/metabolismo , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Apoptosis , Línea Celular , Fibroblastos/efectos de los fármacos , Homeostasis , Humanos , Lipidómica , Pulmón/efectos de los fármacos , Enfermedades Pulmonares , Metabolómica , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The internal representation of an experience is thought to be encoded by long-lasting physical changes to the brain ("engrams") . Previously, we and others showed within the lateral amygdala (LA), a region critical for auditory conditioned fear, eligible neurons compete against one other for allocation to an engram. Neurons with relatively higher function of the transcription factor CREB were more likely to be allocated to the engram. In these studies, though, CREB function was artificially increased for several days before training. Precisely when increased CREB function is important for allocation remains an unanswered question. Here, we took advantage of a novel optogenetic tool (opto-DN-CREB) to gain spatial and temporal control of CREB function in freely behaving mice. We found increasing CREB function in a small, random population of LA principal neurons in the minutes, but not 24 h, before training was sufficient to enhance memory, likely because these neurons were preferentially allocated to the underlying engram. However, similarly increasing CREB activity in a small population of random LA neurons immediately after training disrupted subsequent memory retrieval, likely by disrupting the precise spatial and temporal patterns of offline post-training neuronal activity and/or function required for consolidation. These findings reveal the importance of the timing of CREB activity in regulating allocation and subsequent memory retrieval, and further, highlight the potential of optogenetic approaches to control protein function with temporal specificity in behaving animals.
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Complejo Nuclear Basolateral , Optogenética , Animales , Miedo , Memoria , Ratones , NeuronasRESUMEN
Phosphatidylinositol-4,5-bisphosphate (PIP2), one of the key phospholipids, directly interacts with several membrane and cytosolic proteins at neuronal plasma membranes, leading to changes in neuronal properties including the feature and surface expression of ionotropic receptors. Although PIP2 is also concentrated at the dendritic spines, little is known about the direct physiological functions of PIP2 at postsynaptic as opposed to presynaptic sites. Most previous studies used genetic and pharmacological methods to modulate enzymes that alter PIP2 levels, making it difficult to delineate time- or region-specific roles of PIP2. We used chemically-induced dimerization to translocate inositol polyphosphate 5-phosphatase (Inp54p) to plasma membranes in the presence of rapamycin. Upon redistribution of Inp54p, long-term depression (LTD) induced by low-frequency stimulation was blocked in the mouse hippocampal CA3-CA1 pathway, but the catalytically-dead mutant did not affect LTD induction. Collectively, PIP2 is critically required for induction of LTD whereas translocation of Inp54p to plasma membranes has no effect on the intrinsic properties of the neurons, basal synaptic transmission, long-term potentiation or expression of LTD.
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Potenciación a Largo Plazo , Neuronas/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Sinapsis/metabolismo , Animales , Células Cultivadas , Células HEK293 , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Inositol Polifosfato 5-Fosfatasas/genética , Inositol Polifosfato 5-Fosfatasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Sinapsis/fisiologíaRESUMEN
O-GlcNAcylated proteins are abundant in the brain and are associated with neuronal functions and neurodegenerative diseases. Although several studies have reported the effects of aberrant regulation of O-GlcNAcylation on brain function, the roles of O-GlcNAcylation in synaptic function remain unclear. To understand the effect of aberrant O-GlcNAcylation on the brain, we used Oga+/- mice which have an increased level of O-GlcNAcylation, and found that Oga+/- mice exhibited impaired spatial learning and memory. Consistent with this result, Oga+/- mice showed a defect in hippocampal synaptic plasticity. Oga heterozygosity causes impairment of both long-term potentiation and long-term depression due to dysregulation of AMPA receptor phosphorylation. These results demonstrate a role for hyper-O-GlcNAcylation in learning and memory.
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Hipocampo/metabolismo , Hipocampo/fisiopatología , Memoria , Plasticidad Neuronal , Animales , Espinas Dendríticas/metabolismo , Neuronas GABAérgicas/metabolismo , Glicosilación , Hipocampo/patología , Ratones , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Aprendizaje Espacial , Memoria Espacial , Transmisión Sináptica , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
MicroRNAs (miRNAs) play critical roles in controlling various cellular processes, and the expression levels of individual miRNAs can be considerably altered in pathological conditions such as cancer. Accurate quantification of miRNA at the single-cell level will lead to a better understanding of miRNA function. Here, we present a direct and sensitive method for miRNA detection using atomic force microscopy (AFM). A hybrid binding domain (HBD)-tethered tip enabled mature miRNAs, but not premature miRNAs, to be located individually on an adhesion force map. By scanning several sections of a micrometer-sized DNA spot, we were able to quantify the copy number of miR-134 in a single neuron and demonstrate that the expression was increased upon cell activation. Moreover, we visualized individual miR-134s on fixed neurons after membrane removal and observed 2-4 miR-134s in the area of 1.0 × 1.0 µm(2) of soma. The number increased to 8-14 in stimulated neurons, and this change matches the ensemble-averaged increase in copy number. These findings indicate that miRNAs can be reliably quantified at the single cell level with AFM and that their distribution can be mapped at nanometric lateral resolution without modification or amplification. Furthermore, the analysis of miRNAs, mRNAs, and proteins in the same sample or region by scanning sequentially with different AFM tips would let us accurately understand the post-transcriptional regulation of biological processes.
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MicroARNs/metabolismo , Microscopía de Fuerza Atómica , Análisis de la Célula Individual , Animales , Línea Celular Tumoral , Ratones , MicroARNs/química , Conformación de Ácido NucleicoRESUMEN
BACKGROUND: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer's disease (AD)-associated amyloid ß-protein (Aß). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aß, the role of exosomes in regulating synaptic dysfunction induced by Aß has not been explored. RESULTS: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aß. Mechanistically, this effect involves sequestration of synaptotoxic Aß assemblies by exosomal surface proteins such as PrPC rather than Aß proteolysis. CONCLUSIONS: These data suggest that exosomes can counteract the inhibitory action of Aß, which contributes to perpetual capability for synaptic plasticity.
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Péptidos beta-Amiloides/toxicidad , Exosomas/metabolismo , Plasticidad Neuronal , Sinapsis/metabolismo , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Líquido Cefalorraquídeo/metabolismo , Difusión , Exosomas/efectos de los fármacos , Femenino , Humanos , Ligandos , Potenciación a Largo Plazo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Proteínas PrPC/metabolismo , Ratas , Ratas Wistar , Sinapsis/efectos de los fármacosRESUMEN
Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cis-interactions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.
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Moléculas de Adhesión Celular Neuronal/metabolismo , Plasticidad Neuronal/fisiología , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Análisis de Varianza , Animales , Western Blotting , Maleato de Dizocilpina , Inmunoprecipitación , Microscopía Confocal , Microscopía Inmunoelectrónica , Ratas , Estadísticas no ParamétricasRESUMEN
Various animal models of Alzheimer disease (AD) are characterized by deficits in spatial memory that are causally related to altered synaptic function and impairment of long-term potentiation (LTP) in the hippocampus. In Tg2576 AD mice, we compared LTP in 2 major hippocampal pathways, Schaffer collateral (SC) and mossy fiber (MF) pathways. Whereas LTP was completely abolished in the SC pathway of Tg2576 mice, we found no decrease in LTP induced by stimulation of the MF pathway. In fact, we found that in the MF pathway, LTP was slightly, but significantly, enhanced compared with that in the MF pathway of WT littermates. This pathway-specific impairment of LTP is not attributable to alterations in transmitter release, as indicated by an unaltered paired-pulse ratio. These results suggest that the spatial memory deficits normally seen in AD models arise primarily from LTP impairment at the SC pathway.
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Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Memoria , Fibras Musgosas del Hipocampo/metabolismo , Plasticidad Neuronal , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Humanos , Potenciación a Largo Plazo/genética , Memoria/fisiología , Trastornos de la Memoria/genética , Ratones , Ratones Transgénicos , Fibras Musgosas del Hipocampo/patología , Mutación/genética , Vías Nerviosas/fisiología , Plasticidad Neuronal/genética , Transmisión Sináptica/genéticaRESUMEN
Organic photovoltaic cells (OPVs) with a highly conductive poly 3,4-ethylenedioxythiophene:poly styrenesulfonate (PEDOT:PSS) layer as an anode and that were modified with the addition of some organic solvents such as sorbitol (So), dimethyl sulfoxide (DMSO), N-methyl-pyrrolidone (NMP), dimethylformamide (DMF), and ethylene glycol (EG) were fabricated without the use of transparent conducting oxide (TCO). The conductivity of the PEDOT:PSS film that was modified with each additive was enhanced by three orders of magnitude. According to the atomic force microscopy (AFM) study, the conductivity enhancement might have been related to the better connections between the conducting PEDOT chains. The TCO-free solar cells with a modified PEDOT:PSS layer and an active layer composed of poly (3-hexylthiophene) (P3HT) and phenyl [6, 6] C61 butyric acid methyl ester (PCBM) performed as well as the indium-tin-oxide (ITO)-based organic solar cells. The power conversion efficiency (PCE) of the organic solar cells with a DMSO-, So + DMSO-, and EG-modified PEDOT:PSS layer reached 3.51, 3.64, and 3.77%, respectively, under an illumination of AM 1.5 (100 mW/cm2).
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Despite considerable evidence for a critical role of neuroligin-1 in the specification of excitatory synapses, the cellular mechanisms and physiological roles of neuroligin-1 in mature neural circuits are poorly understood. In mutant mice deficient in neuroligin-1, or adult rats in which neuroligin-1 was depleted, we have found that neuroligin-1 stabilizes the NMDA receptors residing in the postsynaptic membrane of amygdala principal neurons, which allows for a normal range of NMDA receptor-mediated synaptic transmission. We observed marked decreases in NMDA receptor-mediated synaptic currents at afferent inputs to the amygdala of neuroligin-1 knockout mice. However, the knockout mice exhibited a significant impairment in spike-timing-dependent long-term potentiation (STD-LTP) at the thalamic but not the cortical inputs to the amygdala. Subsequent electrophysiological analyses indicated that STD-LTP in the cortical pathway is largely independent of activation of postsynaptic NMDA receptors. These findings suggest that neuroligin-1 can modulate, in a pathway-specific manner, synaptic plasticity in the amygdala circuits of adult animals, likely by regulating the abundance of postsynaptic NMDA receptors.