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Transcription factors have a pivotal role in synaptic plasticity and the associated modification of neuronal networks required for memory formation and consolidation. The nuclear receptors subfamily 4 group A (Nr4a) have emerged as possible modulators of hippocampal synaptic plasticity and cognitive functions. However, the molecular and cellular mechanisms underlying Nr4a2-mediated hippocampal synaptic plasticity are not completely known. Here, we report that neuronal activity enhances Nr4a2 expression and function in cultured mouse hippocampal neurons (both sexes) by an ionotropic glutamate receptor/Ca2+/cAMP response element-binding protein/CREB-regulated transcription factor 1 (iGluR/Ca2+/CREB/CRTC1) pathway. Nr4a2 activation mediates BDNF production and increases expression of iGluRs, thereby affecting LTD at CA3-CA1 synapses in acute mouse hippocampal slices (both sexes). Together, our results indicate that the iGluR/Ca2+/CREB/CRTC1 pathway mediates activity-dependent expression of Nr4a2, which is involved in glutamatergic synaptic plasticity by increasing BDNF and synaptic GluA1-AMPARs. Therefore, Nr4a2 activation could be a therapeutic approach for brain disorders associated with dysregulated synaptic plasticity.SIGNIFICANCE STATEMENTA major factor that regulates fast excitatory synaptic transmission and plasticity is the modulation of synaptic AMPARs. However, despite decades of research, the underlying mechanisms of this modulation remain poorly understood. Our study identified a molecular pathway that links neuronal activity with AMPAR modulation and hippocampal synaptic plasticity through the activation of Nr4a2, a member of the nuclear receptor subfamily 4. Since several compounds have been described to activate Nr4a2, our study not only provides mechanistic insights into the molecular pathways related to hippocampal synaptic plasticity and learning, but also identifies Nr4a2 as a potential therapeutic target for pathologic conditions associated with dysregulation of glutamatergic synaptic function.

Este estudio analiza el concepto de alto cargo desde el punto de vista de la normativa sobre buen gobierno y altos cargos dictada en los últimos años en el ámbito estatal, autonómico y local. La realidad es que el legislador ha hecho de la noción de alto cargo un concepto impreciso e inacabado. Esta cuestión no es de importancia menor, pues de ello dependerá el régimen jurídico del desempeño del cargo y a quiénes se puede exigir la responsabilidad administrativa a que se refieren dichas normas.

Hilar mossy cells (MCs) are principal excitatory neurons of the dentate gyrus (DG) that play critical roles in hippocampal function and have been implicated in brain disorders such as anxiety and epilepsy. However, the mechanisms by which MCs contribute to DG function and disease are poorly understood. Expression from the dopamine D2 receptor (D2R) gene (Drd2) promoter is a defining feature of MCs, and previous work indicates a key role for dopaminergic signaling in the DG. Additionally, the involvement of D2R signaling in cognition and neuropsychiatric conditions is well-known. Surprisingly, though, the function of MC D2Rs remain largely unexplored. In this study, we show that selective and conditional removal ofDrd2from MCs of adult mice impaired spatial memory, promoted anxiety-like behavior and was proconvulsant. To determine the subcellular expression of D2Rs in MCs, we used a D2R knockin mouse which revealed that D2Rs are enriched in the inner molecular layer of the DG, where MCs establish synaptic contacts with granule cells. D2R activation by exogenous and endogenous dopamine reduced MC to dentate granule cells (GC) synaptic transmission, most likely by a presynaptic mechanism. In contrast, removingDrd2from MCs had no significant impact on MC excitatory inputs and passive and active properties. Our findings support that MC D2Rs are essential for proper DG function by reducing MC excitatory drive onto GCs. Lastly, impairment of MC D2R signaling could promote anxiety and epilepsy, therefore highlighting a potential therapeutic target.SIGNIFICANCEGrowing evidence indicates that hilar mossy cells (MCs) of the dentate gyrus play critical but incompletely understood roles in memory and brain disorders, including anxiety and epilepsy. Dopamine D2 receptors (D2Rs), implicated in cognition and several psychiatric and neurological disorders, are considered to be characteristically expressed by MCs. Still, the subcellular localization and function of MC D2Rs are largely unknown. We report that removing theDrd2gene specifically from MCs of adult mice impaired spatial memory and was anxiogenic and proconvulsant. We also found that D2Rs are enriched where MCs synaptically contact dentate granule cells (GC) and reduce MC-GC transmission. This work uncovered the functional significance of MC D2Rs, thus highlighting their therapeutic potential in D2R- and MC-associated pathologies.

The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.

Mossy cells (MCs) of the dentate gyrus (DG) are key components of an excitatory associative circuit established by reciprocal connections with dentate granule cells (GCs). MCs are implicated in place field encoding, pattern separation and novelty detection, as well as in brain disorders such as temporal lobe epilepsy and depression. Despite their functional relevance, little is known about the determinants that control MC activity. Here, we examined whether MCs express functional kainate receptors (KARs), a subtype of glutamate receptors involved in neuronal development, synaptic transmission and epilepsy. Using mouse hippocampal slices, we found that bath application of submicromolar and micromolar concentrations of the KAR agonist kainic acid induced inward currents and robust MC firing. These effects were abolished in GluK2 KO mice, indicating the presence of functional GluK2-containing KARs in MCs. In contrast to CA3 pyramidal cells, which are structurally and functionally similar to MCs, and express synaptic KARs at mossy fiber (MF) inputs (i.e., GC axons), we found no evidence for KAR-mediated transmission at MF-MC synapses, indicating that most KARs at MCs are extrasynaptic. Immunofluorescence and immunoelectron microscopy analyses confirmed the extrasynaptic localization of GluK2-containing KARs in MCs. Finally, blocking glutamate transporters, a manipulation that increases extracellular levels of endogenous glutamate, was sufficient to induce KAR-mediated inward currents in MCs, suggesting that MC-KARs can be activated by increases in ambient glutamate. Our findings provide the first direct evidence of functional extrasynaptic KARs at a critical excitatory neuron of the hippocampus.Significance StatementHilar mossy cells (MCs) are an understudied population of hippocampal neurons that form an excitatory loop with dentate granule cells. MCs have been implicated in pattern separation, spatial navigation, and epilepsy. Despite their importance in hippocampal function and disease, little is known about how MC activity is recruited. Here, we show for the first time that MCs express extrasynaptic kainate receptors (KARs), a subtype of glutamate receptors critically involved in neuronal function and epilepsy. While we found no evidence for synaptic KARs in MCs, KAR activation induced strong action potential firing of MCs, raising the possibility that extracellular KARs regulate MC excitability in vivo and may also promote dentate gyrus hyperexcitability and epileptogenesis.

Fragile X messenger ribonucleoprotein (FMRP) is an RNA-binding protein that can form granules within neurons. Although FMRP-containing Fragile X granules have been extensively characterized, visualizing changes in granule structure in relation to function has been difficult. We used high-resolution imaging to detect discrete differences in puncta size, intensity, and contrast in our mouse FMRP and serine 499 (S499) phospho-mutant reporters. Tracking analyses of FMRP particles showed that phospho-mutant granules traveled at rates consistent with active transport within dendrites. In addition, GFP-FMRP exhibited a wide range of speeds owing to its ability to oligomerize when overexpressed. Recent work suggested that FMRP granules could be phase separated structures that may function as hubs for local protein synthesis. To test this idea, we performed fluorescence recovery after photobleaching (FRAP) on individual FMRP granules. Intriguingly, we observed only a partial recovery that occurred over minutes and was dependent on translation. Moreover, the phospho-mutants displayed differences in recovery kinetics reflecting the labile (S499A) or preferential (S499D) nature of their interaction with granules containing stalled ribosomes. Our high-resolution approach reveals that the phosphorylation-state of FMRP can modulate the clustering of FMRP granules and thereby regulate local protein synthesis at the level of individual granules.

The ability of neurons to process and store salient environmental features underlies information processing in the brain. Long-term information storage requires synaptic plasticity and regulation of gene expression. While distinct patterns of activity have been linked to synaptic plasticity, their impact on immediate early gene (IEG) expression remains poorly understood. The activity regulated cytoskeleton associated (

Background Cervical cytology is essential for the early detection of cervical cancer. However, in Colombia during 2019, 50% of women with health insurance for poor people (subsidized regime) were screened, compared to 100% of women with health insurance for people with capacity to pay a contribution (contributive regime); these differences reflect significant barriers to face. The objective of this study was to identify the barriers and facilitators of adherence to the cytology exam in low-income women affiliated to the subsidized regime in a public primary care network in the city of Cali, Colombia from 2014 to 2018. Methods In a qualitative case study, the experience of women and health care and administrative personnel was recovered. Forty-seven women participated in seven focus group discussions; Five other women using the program participated in in-depth interviews; Finally, we interviewed eight people from the healthcare area and the health services administration. Results Women describe living conditions, fear, shame, and fears of the procedure as barriers. As facilitators, they recognize agile attention, ease of consulting services, and having social support. However, the health care and administration personnel consider the lack of up-to-date information on women a significant barrier, challenging recruiting and following up. Conclusions complex interventions are required to be adapted to the social conditions, culture, and social processes of the women affiliated with the subsidized health insurance. This might facilitate adherence in groups of non-adherent women with low adherence.

We present a detailed structural and optical analysis of dopant occupancy in Dy-doped Gd2O3 NPs not previously reported.

MUSCAT is a new large-format 1.1 mm continuum camera for local and extra-galactic astronomy currently being installed at the 50 m Large Millimetre Telescope Alfonso Serrano, LMT. The focal plane is populated with 1458 feedhorn coupled Aluminium LEKIDs, cooled to 130 mk, and read out with 6 frequency division multiplexed RF readout chains, each with a 500 MHz bandwidth. The nominal mux ratio is $$\sim$$ ∼ 250 resonators per chain with an average spacing of 2 MHz between resonators. In each RF chain, the multiplexed waveform generation/decomposition is performed with the BLAST-TNG firmware on a ROACH2 FPGA board with a MUSIC DAC/ADC. The quadrature modulated IF signals are mixed to and from the LEKID readout band on a custom card that houses IQ mixers, a programmable synthesizer, and additional programmable input and output gain control and filtering. Within the cryostat, the RF signals are attenuated prior to reaching the focal plane array and then amplified at 4K. A novel software system controls all the programmable hardware and handles instructions from the LMT instrument control system to record and store observation data, as well as performing automated resonator retuning and providing results of quick look analysis to the telescope operators. In this paper, we present the detailed design and in-lab performance of the cryogenic and room temperature electronics, and the software control system.

Two oxoiron(IV) isomers (R2a and R2b) of general formula [FeIV(O)(RPyNMe3)(CH3CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.

Introduction: Adipose-derived stem cells (ASCs) show some membrane markers that enable cell identification by flow cytometry. One of them which is essential during the angiogenesis process is CD105 (Endoglin). This is very important for various pathologies where it is required angiogenesis to regenerate tissues or organs affected by various acquired or congenital noxae. To determine the phenotypic expression, CD105 angiogenesis factor, of ASCs obtain Objective: ed by Selective Tissue Engineering Photostimulation (STEP ) with infrared light of 1210 nm compared to those obtained by TM Gold Standard Suction assisted lipectomy/conventional liposuction technique (SAL). ASCs obtained by Results: STEP™ technique with 1210 nm laser were found to be highly viable (> 97%) and showed increased CD105 expression (90%) and only