A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

α7 nicotinic acetylcholine receptor in memory processing.

Information storage in the brain involves different memory types and stages that are processed by several brain regions. Cholinergic pathways through acetylcholine receptors actively participate on memory modulation, and their disfunction is associated with cognitive decline in several neurological disorders. During the last decade, the role of α7 subtype of nicotinic acetylcholine receptors in different memory stages has been studied. However, the information about their role in memory processing is still scarce. In this review, we attempt to identify brain areas where α7 nicotinic receptors have an essential role in different memory types and stages. In addition, we discuss recent work implicating-or not-α7 nicotinic receptors as promising pharmacological targets for memory impairment associated with neurological disorders.

Disparities in breast cancer mortality among Latin American women: trends and predictions for 2030.

BACKGROUND: Breast cancer is among the leading cause of cancer-related mortality among Latin American and Caribbean (LAC) women, but a comprehensive and updated analysis of mortality trends is lacking. The objective of this study was to determine the breast cancer mortality rates between 1997 and 2017 for LAC countries and predict mortality until 2030. METHODS: We retrieved breast cancer deaths across 17 LAC countries from the World Health Organization mortality database. Age-standardized mortality rates per 100,000 women-years were estimated. Mortality trends were evaluated with Joinpoint regression analyses by country and age group (all ages, < 50 years, and ≥ 50 years). By 2030, we predict number of deaths, mortality rates, changes in population structure and size, and the risk of death from breast cancer. RESULTS: Argentina, Uruguay, and Venezuela reported the highest mortality rates throughout the study period. Guatemala, El Salvador, and Nicaragua reported the largest increases (from 2.4 to 2.8% annually), whereas Argentina, Chile, and Uruguay reported downward trends (from - 1.0 to - 1.6% annually). In women < 50y, six countries presented downward trends and five countries showed increasing trends. In women ≥ 50y, three countries had decreased trends and ten showed increased trends. In 2030, increases in mortality are expected in the LAC region, mainly in Guatemala (+ 63.0%), Nicaragua (+ 47.3), El Salvador (+ 46.2%), Ecuador (+ 38.5%) and Venezuela (+ 29.9%). CONCLUSION: Our findings suggest considerable differences in breast cancer mortality across LAC countries by age group. To achieve the 2030 sustainable developmental goals, LAC countries should implement public health strategies to reduce mortality by breast cancer.

Regional disparities of prostate cancer mortality in Ecuador: an examination of trends and correlates from 2004 to 2019.

BACKGROUND: Prostate cancer is the leading cause of cancer death in Ecuadorian men. However, there is a lack of information regarding the evolution of prostate cancer mortality rates in Ecuador and its regions in the last few decades. OBJECTIVE: The aim of this study was to report prostate cancer mortality rates in Ecuador and its geographical areas and observe the evolution of these rates between 2004 and 2019. METHODS: An observational ecological study was conducted, analysing data for prostate cancer deaths from 2004 to 2019 in Ecuador. Age standardized mortality rates (ASMR) were calculated per 100,000 men using the world standard population with the direct method proposed by SEGI. Joinpoint regression analysis was performed to examine mortality trends. We used a Cluster Map to explore relationships among regions between 2015 and 2019. RESULTS: Ecuador reported 13,419 deaths by prostate cancer between 2004 and 2019, with the Coastal region accounting for 49.8% of the total deaths. The mean age at death was 79 years (± 10 years), 91.7% were elderly (more than 65 years old) and had primary education (53%). Deaths by prostate cancer were more frequently reported among mestizos (81.4%). There were no significant variations in these percentages in Ecuador and its regions during the study period. Carchi province had the highest mortality rate in 2005 and 2019 (> 13 deaths per 100,000). Heterogeneity in the evolution of mortality rates was reported among the provinces of Ecuador. Azuay decreased in the first few years, and then increased from 2010 to 2019, whereas Guayas and Pichincha decreased throughout the whole period. CONCLUSION: Although prostate cancer mortality rates in Ecuador have remained stable over the past few decades, there are significant disparities among the different regions. These findings suggest the need for the development of national and provincial registration measures, integrated healthcare actions, and targeted interventions to reduce the burden of prostate cancer in the Ecuadorian population.

Toll-Like Receptor 3 (TLR3) Is Engaged in the Intracellular Survival of the Protozoan Parasite Leishmania (Leishmania) amazonensis.

The protozoan parasite Leishmania (L.) amazonensis infects and replicates inside host macrophages due to subversion of the innate host cell response. In the present study, we demonstrate that TLR3 is required for the intracellular growth of L. (L.) amazonensis. We observed restricted intracellular infection of TLR3-/- mouse macrophages, reduced levels of IFN1ß and IL-10, and increased levels of IL-12 upon L. (L.) amazonensis infection, compared with their wild-type counterparts. Accordingly, in vivo infection of TLR3-/- mice with L. (L.) amazonensis displayed a significant reduction in lesion size. Leishmania (L.) amazonensis infection induced TLR3 proteolytic cleavage, which is a process required for TLR3 signaling. The chemical inhibition of TLR3 cleavage or infection by CPB-deficient mutant L. (L.) mexicana resulted in reduced parasite load and restricted the expression of IFN1ß and IL-10. Furthermore, we show that the dsRNA sensor molecule PKR (dsRNA-activated protein kinase) cooperates with TLR3 signaling to potentiate the expression of IL-10 and IFN1ß and parasite survival. Altogether, our results show that TLR3 signaling is engaged during L. (L.) amazonensis infection and this component of innate immunity modulates the host cell response.

Cervical cancer mortality among young women in Latin America and the Caribbean: trend analysis from 1997 to 2030.

BACKGROUND: Cervical cancer continues to show a high burden among young women worldwide, particularly in low- and middle-income countries. Limited data is available describing cervical cancer mortality among young women in Latin America and the Caribbean (LAC). The purpose of this study was to examine the mortality trends of cervical cancer among young women in LAC and predict mortality rates to 2030. METHODS: Deaths from cervical cancer were obtained from the World Health Organization mortality database. Age-standardized mortality rates per 100,000 women-years were estimated in women aged 20-44 years using the world standard population for 16 countries (and territories) in LAC from 1997 to 2017. We estimated the average mortality rates for the last 4 years (2014-2017). Joinpoint regression models were used to identify significant changes in mortality trends. Nordpred method was used for the prediction of the mortality rates to 2030. RESULTS: Between 2014 and 2017, Paraguay and Venezuela had the highest mortality rates of cervical cancer, whereas Puerto Rico had the lowest rates. Overall, most of the LAC countries showed downward trends of cervical cancer mortality over the entire period. Significant decreases were observed in Chile (Average annual percent change [AAPC]: - 2.4%), Colombia (AAPC: - 2.0%), Cuba (AAPC: - 3.6%), El Salvador (AAPC: - 3.1%), Mexico (AAPC: - 3.9%), Nicaragua (AAPC: - 1.7%), Panama (AAPC: - 1.7%), and Peru (AAPC: - 2.2%). In contrast, Brazil (AAPC: + 0.8%) and Paraguay (AAPC: + 3.7%) showed significant upward trends. By 2030, mortality rates are not predicted to further decrease in some LAC countries, including Argentina, Paraguay, and Venezuela. CONCLUSIONS: Mortality trends of cervical cancer among young women have large variability in LAC countries. Cervical cancer screening programs have a high priority for the region. Primary and secondary prevention in the community are necessary to accelerate a reduction of cervical cancer mortality by 2030.

Medial prefrontal cortical control of reward- and aversion-based behavioral output: Bottom-up modulation.

How does the brain guide our actions? This is a complex issue, where the medial prefrontal cortex (mPFC) plays a crucial role. The mPFC is essential for cognitive flexibility and decision making. These functions are related to reward- and aversion-based learning, which ultimately drive behavior. Though, cortical projections and modulatory systems that may regulate those processes in the mPFC are less understood. How does the mPFC regulate approach-avoidance behavior in the case of conflicting aversive and appetitive stimuli? This is likely dependent on the bottom-up neuromodulation of the mPFC projection neurons. In this review, we integrate behavioral-, pharmacological-, and viral-based circuit manipulation data showing the involvement of mPFC dopaminergic, noradrenergic, cholinergic, and serotoninergic inputs in reward and aversion processing. Given that an incorrect balance of reward and aversion value could be a key problem in mental diseases such as substance use disorders, we discuss outstanding questions for future research on the role of mPFC modulation in reward and aversion.

The late consolidation of an aversive memory is promoted by VTA dopamine release in the dorsal hippocampus.

The hippocampus has been implicated in the processing and storage of aversive memories but the precise mechanisms by which these memories persist in time remain elusive. We have demonstrated that dopaminergic neurotransmission in the dorsal hippocampus regulates the long-term storage of both appetitive and aversive memories at a critical time point known as "late consolidation" (12 hr after the learning experience). This modulation appears to have opposite effects depending on the valence of the stimuli, with hippocampal dopamine release peaking immediately and 13-17 hr after a rewarding experience. Here, we determined the release pattern of hippocampal dopamine following an aversive experience, in order to better understand this opposite modulation process. We observed significant increases in dopamine levels at several times (6-8, 11-12, and 15 hr) after subjecting rats to a conditioned place aversion (CPA) task with the aversive agent lithium chloride (LiCl). Early pharmacological blockade of hippocampal DA receptors impaired CPA memory consolidation. In addition and consistent with previous findings showing that late post-training infusions of dopaminergic agents into the hippocampus modulate the long-term storage of aversive memories, we found that the photostimulation of dopaminergic VTA fibers in the dorsal hippocampus 11-12 hr after CPA training was enough to transform a short-lasting long-term memory into a long-lasting one. The fact that the persistence of an aversive memory can still be affected several hours after the learning experience opens new avenues to develop behavioral and pharmacological strategies for the treatment of a variety of mental disorders.

Functional connectivity of anterior retrosplenial cortex in object recognition memory.

Recognition memory can rely on three components: "what", "where" and "when". Recently we demonstrated that the anterior retrosplenial cortex (aRSC), like the perirhinal cortex (PRH) and unlike the hippocampus (HP), is required for consolidation of the "what" component. Here, we aimed at studying which brain structures interact with the aRSC to process object recognition (OR) memory in rats. We studied the interaction of six brain structures that are connected to the aRSC during OR memory processing: PRH, medial prefrontal cortex (mPFC), anteromedial thalamic nuclei (AM), medial entorhinal cortex (MEC), anterior cingulate cortex (ACC) and the dorsal HP (dHP). We previously described the role of the PRH and dHP, so we first studied the participation of the mPFC, AM, MEC and ACC in OR memory consolidation by bilateral microinfusions of the GABAA receptor agonist muscimol. We observed an impairment in OR long-term memory (LTM) when inactivating the mPFC, the AM and the MEC, but not the ACC. Then, we studied the functional connections by unilateral inactivation of the aRSC and each one of the six structures in the same (ipsilateral) or the opposite (contralateral) hemisphere. Our results showed an amnesic LTM effect in rats with ipsilateral inactivations of aRSC-PRH, aRSC-mPFC, aRSC-AM, or aRSC-MEC. On the other hand, we observed memory impairment when aRSC-ACC were inactivated in opposite hemispheres, and no effect when the aRSC-dHP connection was inactivated. Thus, our ipsilateral inactivation findings reveal that the aRSC and, at least one brain region required in OR LTM processing are essential to consolidate OR memory. In conclusion, our results show that several cortico-cortical and cortico-thalamic pathways are important for OR memory consolidation.

Cervical cancer mortality in Peru: regional trend analysis from 2008-2017.

BACKGROUND: Cervical cancer is the third leading cause of cancer-related death among Latin American women. Peru has the sixth highest mortality rate for cervical cancer in the region with regional variations. We aimed to determine overall and regional cervical cancer mortality rates and trends in Peru between 2008 and 2017. METHODS: We performed an ecological study on the number of deaths by cervical cancer in Peru. Deaths were extracted from the Peruvian Ministry of Health mortality database. Age-standardized mortality rates (ASMR) were estimated per 100,000 women-years using the world standard Segi population. We computed mortality trends using the Joinpoint regression program, estimating the annual percent change (APC). For spatial analysis, GeoDA software was used. RESULTS: Peru showed downward trends in the last decade (from 11.62 in 2008 to 9.69 in 2017 (APC = - 2.2, 95% CI: - 4.3, - 0.1, p < 0.05). According to regional-specific analysis, the highest ASMR was in the rainforest region, although this declined from 34.16 in 2008 to 17.98 in 2017 (APC = - 4.3, 95% CI: - 7.2, - 1.3, p < 0.01). Concerning spatial analysis and clustering, the mortality rates from 2008 to 2017 showed a positive spatial autocorrelation and significant clustering (Moran's I: 0.35, p < 0.001) predominantly in the neighboring North-East departments (Loreto, Ucayali, and San Martin). CONCLUSIONS: Although mortality trends in the entire population are decreasing, mortality rates remain very high, mainly in the rainforest region. Our results encourage a need for further development and improvement of the current health care delivery system in Peru.

Payments for environmental services supported social capital while increasing land management.

Payments for environmental services (PES) programs incentivize landowners to protect or improve natural resources. Many conservationists fear that introducing compensation for actions previously offered voluntarily will reduce social capital (the institutions, relationships, attitudes, and values that govern human interactions), yet little rigorous research has investigated this concern. We examined the land cover management and communal social capital impacts of Mexico's federal conservation payments program, which is a key example for other countries committed to reducing deforestation, protecting watersheds, and conserving biodiversity. We used a regression discontinuity (RD) methodology to identify causal program effects, comparing outcomes for PES participants and similar rejected applicants close to scoring cutoffs. We found that payments increased land cover management activities, such as patrolling for illegal activity, building fire breaks, controlling pests, or promoting soil conservation, by ∼50%. Importantly, increases in paid activities as a result of PES did not crowd out unpaid contributions to land management or other prosocial work. Community social capital increased by ∼8-9%, and household-level measures of trust were not affected by the program. These findings demonstrate that major environmental conditional cash transfer programs can support both land management and the attitudes and institutions underpinning prosocial behavior. Rigorous empirical research on this question can proceed only country by country because of methodological limitations, but will be an important line of inquiry as PES continues to expand worldwide.

Effects of three biochars on copper immobilization and soil microbial communities in a metal-contaminated soil using a metallophyte and two agricultural plants.

Biochar (BC) is a porous, carbonaceous material produced by slow pyrolysis of biomass under oxygen-limited conditions. BC production has been attracting research interest because it modifies soil physicochemical characteristics and improves the growth of plants in problem soils. These benefits may be best actualized for soils contaminated by metals, where remediation is hampered by metal toxicity to both plants and soil microbial communities. The objectives of this study were to evaluate the impact of the addition of chicken manure biochar (CMB), oat hull biochar (OHB), or pine bark biochar (PBB) on copper (Cu) bioavailability in a Cu-contaminated soil, the effectiveness of these BCs promoting plant growth, and its effects on soil microbial communities supporting these plants. A sandy soil (338 mg Cu kg-1) was amended with CMB, OHB, and PBB, and the metallophyte Oenothera picensis or the agricultural species Solanum lycopersicum and Lolium perenne were grown for 3 months. The BCs produced an increase in soil pH, reduced the exchangeable Cu, and increased Cu bound to organic matter and residual fractions. All BCs enhanced the quality of contaminated soil and increased the plant biomass production, notably for S. lycopersicum, which grew until 12 times more than plants in non-amended soil. While BC addition reduced the concentration of Cu in soil pore water, the amendment did not reduce the concentrations of Cu in shoot tissues. BC additions also stimulated soil microorganisms, increasing basal respiration and DHA activity and modifying microbial communities, especially in soils supporting L. perenne. These results indicate that BCs represent an effective tool to remediate Cu-contaminated sandy soils.

Breast cancer mortality trends in Peruvian women.

BACKGROUND: Breast cancer (BC) is the most common malignancy in Latin American women, but with a wide variability with respect to their mortality. This study aims to estimate the mortality rates from BC in Peruvian women and to assess mortality trends over 15 years. METHODS: We calculated BC age-standardized mortality rate (ASMR) per 100,000 women-years using the world standard SEGI population. We estimated joinpoint regression models for BC in Peru and its geographical areas. The spatial analysis was performed using the Moran's I statistic. RESULTS: In a 15-year period, Peru had a mortality rate of 9.97 per 100,000 women-years. The coastal region had the highest mortality rate (12.15 per 100,000 women-years), followed by the highlands region (4.71 per 100,000 women-years). In 2003, the highest ASMR for BC were in the provinces of Lima, Arequipa, and La Libertad (above 8.0 per 100,000 women-years), whereas in 2017, the highest ASMR were in Tumbes, Callao, and Moquegua (above 13.0 per women-years). The mortality trend for BC has been declining in the coastal region since 2005 (APC = - 1.35, p < 0.05), whereas the highlands region experienced an upward trend throughout the study period (APC = 4.26, p < 0.05). The rainforest region had a stable trend. Spatial analysis showed a Local Indicator of Spatial Association of 0.26 (p < 0.05). CONCLUSION: We found regional differences in the mortality trends over 15 years. Although the coastal region experienced a downward trend, the highlands had an upward mortality trend in the entire study period. It is necessary to implement tailored public health interventions to reduce BC mortality in Peru.

A Gesture Elicitation Study of Nose-Based Gestures.

Presently, miniaturized sensors can be embedded in any small-size wearable to recognize movements on some parts of the human body. For example, an electrooculography-based sensor in smart glasses recognizes finger movements on the nose. To explore the interaction capabilities, this paper conducts a gesture elicitation study as a between-subjects experiment involving one group of 12 females and one group of 12 males, expressing their preferred nose-based gestures on 19 Internet-of-Things tasks. Based on classification criteria, the 912 elicited gestures are clustered into 53 unique gestures resulting in 23 categories, to form a taxonomy and a consensus set of 38 final gestures, providing researchers and practitioners with a larger base with six design guidelines. To test whether the measurement method impacts these results, the agreement scores and rates, computed for determining the most agreed gestures upon participants, are compared with the Condorcet and the de Borda count methods to observe that the results remain consistent, sometimes with a slightly different order. To test whether the results are sensitive to gender, inferential statistics suggest that no significant difference exists between males and females for agreement scores and rates.

Influence of inorganic additives on wheat straw composting: Characterization and structural composition of organic matter derived from the process.

Metallic oxides and clay minerals have gained increasing interest as additives of composting due to their influence in greenhouse gas emissions reduction and their effectivity in the stabilization of carbon both in compost and soils, leading to a cleaner compost production and potentially C sequestrant amendments. In this study, wheat straw (WS) was co-composted with iron oxide and allophanic soil and their influence on WS composting and composition of the end-products was evaluated. WS compost and their humic like-substances (HS) fraction were characterized by chemical and spectroscopic analyzes. After 126 days of process, the elemental composition showed slight differences of the N content for compost and HS, where the C/N atomic ratio tended to decrease relative to the initial material (WS; ~130). This trend was more pronounced in the HS from co-composted treatments (<30). The addition of inorganic materials increased the total acidity and phenolic-OH group contents (~15 and 14 mEq g-1 respectively, iron oxide treatment) relative to the treatment without inorganic additives. Nevertheless, the FTIR and solid-state 13CNMR spectroscopy barely support the wet chemical analysis and revealed a similar final composition between all the studied compost treatments. These results suggest that the incorporation of these materials as compost additives had no major effect on the spectroscopic features of the end-products, however, critical changes of the properties such as the extractability, functionality and composition of HS were revealed by traditional methods. In conclusion, the supply of metal oxides and clays could impact the aerobic composting of WS favorizing the stabilization of certain C pools and adsorptive properties of the end-products, that is of importance in production of amendments suitable for being used in degraded and contaminated soils. Nevertheless, under the experimental conditions of our research C stabilization apparently depends of other mechanisms that still need to be elucidate.

Influence of saprophytic fungi and inorganic additives on enzyme activities and chemical properties of the biodegradation process of wheat straw for the production of organo-mineral amendments.

Cellulose and lignin as main components of crop residues have a significant influence on composting operations and composition of the final products. Both are strongly associated, and lignin can be considered an important barrier during the biodegradation process of lignocellulosic materials. Saprophytic fungi are efficient lignin degraders due to their complex enzymatic system. Therefore, the influence of the inoculation of saprophytic fungi (Coriolopsis rigida, Pleurotus ostreatus, Trichoderma harzianum and Trametes versicolor) and the supply of inorganic additives (Al2O3, Fe2O3 and allophanic soil) that promote the stabilization of carbon (C), were analyzed in the biodegradation of wheat straw (WS). The activity of Laccase (LAC), manganese peroxidase (MnP) and ß-glucosidase and changes in temperature, pH and E4/E6 ratio were analyzed in a biodegradation process of 126 days. The activity of LAC, MnP and the E4/E6 ratio were significantly influenced and increased (enzymes) by fungi species, inorganic additives, and time of inorganic material addition, as well as their interactions (p < 0.05). The WS inoculated with T. versicolor showed the highest average activities for LAC, MnP and ß-glucosidase (2000, 220 UL-1 and 400 µmol pNP g-1 h-1 respectively). Furthermore, the addition of Al2O3 and Fe2O3 increased all the activities regarded to the decomposition of WS and influenced the changes associated with the stabilization of OM in composted WS. In conclusion, the inoculation of WS with T. versicolor in combination with metal oxides improved the enzyme related to the biodegradation process of WS favorizing its stabilization in the medium time, which is of importance in the composting of residues with high C/N ratio.

Selection of the Activated Carbon Type for the Treatment of Landfill Leachate by Fenton-Adsorption Process.

Sanitary landfill leachates usually have characteristics that depend on the region where they are generated and according to the age of the landfill, which is why a unique treatment for their sanitation has not been found. However, the adsorption preceded by the Fenton process has been proven to be highly efficient at removing contaminants. In this study, the adsorptive capacity of two types of activated carbon, granular and powdered, was analyzed to determine which was more efficient in the adsorption stage in the Fenton-adsorption process. Likewise, its behavior was analyzed using three isotherm models (Langmuir, Freundlich and Temkin), testing the raw leachate and the Fenton-treated one with both carbons. The adsorption that is carried out on the carbons is better adjusted to the Freundlich and Temkin models. It concludes that multilayers, through the physical adsorption, carry out the adsorption of pollutants on the surface of the carbons. The results show that, statistically, granular activated carbon is more efficient at removing chemical oxygen demand (COD), and powdered activated carbon removes color better. Finally, an adsorption column was designed for the Fenton-adsorption process that was able to remove 21.68 kgCOD/kg carbon. Removal efficiencies for color and COD were >99%.

The Immunopathologic Effects of Mycoplasma pneumoniae and Community-acquired Respiratory Distress Syndrome Toxin. A Primate Model.

Mycoplasma pneumoniae infection has been linked to poor asthma outcomes. M. pneumoniae produces an ADP-ribosylating and vacuolating toxin called community-acquired respiratory distress syndrome (CARDS) toxin that has a major role in inflammation and airway dysfunction. The objective was to evaluate the immunopathological effects in primates exposed to M. pneumoniae or CARDS toxin. A total of 13 baboons were exposed to M. pneumoniae or CARDS toxin. At Days 7 and 14, BAL fluid was collected and analyzed for cell count, percent of each type of cell, CARDS toxin by PCR, CARDS toxin by antigen capture, eosinophilic cationic protein, and cytokine profiles. Serum IgM, IgG, and IgE responses to CARDS toxin were measured. All animals had a necropsy for analysis of the histopathological changes on lungs. No animal developed signs of infection. The serological responses to CARDS toxin were variable. At Day 14, four of seven animals exposed to M. pneumoniae and all four animals exposed to CARDS toxin developed histological "asthma-like" changes. T cell intracellular cytokine analysis revealed an increasing ratio of IL-4/IFN-γ over time. Both M. pneumoniae and CARDS toxin exposure resulted in similar histopathological pulmonary changes, suggesting that CARDS toxin plays a major role in the inflammatory response.

The CCAAT box in the proximal SERCA2 gene promoter regulates basal and stress-induced transcription in cardiomyocytes.

The cardiac sarco/endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) is vital for the correct handling of calcium concentration in cardiomyocytes. Recent studies showed that the induction of endoplasmic reticulum (ER) stress (ERS) with the SERCA2 inhibitor Thapsigargin (Tg) increases the mRNA and protein levels of SERCA2a. The SERCA2 gene promoter contains an ERS response element (ERSE) at position -78 bp that is conserved among species and might transcriptionally regulate SERCA2 gene expression. However, its involvement in SERCA2 basal and calcium-mediated transcriptional activation has not been elucidated. In this work, we show that in cellular cultures of neonatal rat ventricular myocytes, the treatment with Tg or the calcium ionophore A23187 increases the SERCA2a mRNA and protein abundance, as well as the transcriptional activity of two chimeric human SERCA2 gene constructs, containing -254 and -2579 bp of 5'-regulatory region cloned in the pGL3-basic vector and transiently transfected in cultured cardiomyocytes. We found that the ERSE present in the SERCA2 proximal promoter contains a CCAAT box that is involved in basal and ERS-mediated hSERCA2 transcriptional activation. The EMSA results showed that the CCAAT box present in the ERSE recruits the NF-Y transcription factor. Additionally, by ChIP assays, we confirmed in vivo binding of NF-Y and C/EBPß transcription factors to the SERCA2 gene proximal promoter.

Requirement of an Early Activation of BDNF/c-Fos Cascade in the Retrosplenial Cortex for the Persistence of a Long-Lasting Aversive Memory.

During the past few years, there has been growing interest in the role of the retrosplenial cortex (RSC) in memory processing. However, little is known about the molecular changes that take place in this brain region during memory formation. In the present work, we studied the early post-training participation of RSC in the formation of a long-lasting memory in rats. We found an increase in c-Fos levels in the anterior part of the RSC (aRSC) after inhibitory avoidance (IA) training. Interestingly, this increase was associated with memory durability, since blocking c-Fos expression using specific antisense oligonucleotides (ASO) impaired long-lasting retention 7 days after training without affecting memory expression 2 days after training. In addition, we showed that BDNF is one of the upstream signals for c-Fos expression required for memory persistence, since blocking BDNF synthesis prevents IA training-induced increase in c-Fos levels in aRSC and affects memory persistence. In addition, we found that injection of BDNF into aRSC around training was sufficient to establish a persistent memory and that this effect was prevented by c-fos ASO infusion into the same structure. These findings reveal an early post-training involvement of aRSC in the processing of a long-lasting aversive memory.