Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory

Inclusive Urban Gateways: Towards Socially Just and Open Urban Systems

Received 27 June 2024. Accepted 23 February 2025. Published online 30 April 2025.This article reimagines the concept of urban gateways, highlighting their potential to promote social equity and inform policy decisions in urban development. The research explores how urban gateways can be adapted to meet contemporary needs, focusing on their evolving forms, functions, and conceptualizations. Using grounded theory, a case study of Shiraz’s Qur’an Gate illustrates how the concept of a gateway can be reinterpreted as a cultural entity that remains relevant in urban planning. The analysis identifies five primary categories that define urban gateways: spatial, functional, environmental, social, and perceptual. These categories emphasize the potential for gateways to contribute to balanced urban development strategies that promote social justice. The research advocates for a transition from closed to open spatial systems in gateway design, driven by cultural, economic, and political considerations. This shift can lead to policies that foster social and economic balance, urban decentralization, and a more inclusive urban environment. By examining gateways as thresholds and nodes within urban networks, the research investigates their ability to connect local, regional, and even global scales. The concept of projective and topological spatial performance is introduced, suggesting ways in which gateways can be designed to redefine their roles within the evolving urban landscape. Ultimately, this article emphasizes the importance of reconceptualizing urban gateways as tools for promoting social equity and shaping policies toward more just and open urban systems

Novel flow cytometry approach to identify bronchial epithelial cells from healthy human airways

Sampling various compartments within the lower airways to examine human bronchial epithelial cells (HBEC) is essential for understanding numerous lung diseases. Conventional methods to identify HBEC in bronchoalveolar lavage (BAL) and wash (BW) have throughput limitations in terms of efficiency and ensuring adequate cell numbers for quantification. Flow cytometry can provide high-throughput quantification of cell number and function in BAL and BW samples, while requiring low cell numbers. To date, a flow cytometric method to identify HBEC recovered from lower human airway samples is unavailable. In this study we present a flow cytometric method identifying HBEC as CD45 negative, EpCAM/pan-cytokeratin (pan-CK) double-positive population after excluding debris, doublets and dead cells from the analysis. For validation, the HBEC panel was applied to primary HBEC resulting in 98.6% of live cells. In healthy volunteers, HBEC recovered from BAL (2.3% of live cells), BW (32.5%) and bronchial brushing samples (88.9%) correlated significantly (p = 0.0001) with the manual microscopy counts with an overall Pearson correlation of 0.96 across the three sample types. We therefore have developed, validated, and applied a flow cytometric method that will be useful to interrogate the role of the respiratory epithelium in multiple lung diseases

Assessment of non-classical lymphocyte populations in patients with advanced lung cancer treated with Biomodulina T following platinum-based chemotherapy

Aim: Currently, malignant diseases represent a health issue worldwide. Among these, lung cancer is of growing importance, due to its high incidence and mortality. Chemotherapy, one of the most frequently used treatments, has shown its ability to induce accelerated immunosenescence in classic and as well non-classic lymphocyte compartments, being less described in the latter. The immune restoration strategies have demonstrated their ability to reverse immunosenescence and exhaustion markers in conventional lymphocyte subpopulations after chemotherapy. However, the possible immunorestorative effect on non-classical lymphocytes has not been widely reported. The aim of this study was to evaluate the effect of chemotherapy and the administration of a thymic polypeptide factor on non-classical lymphocyte populations in patients with advanced lung cancer. Methods: Eighteen patients with advanced lung cancer, were evaluated at baseline before and after platinum-based chemotherapy (4–6 cycles). All patients could complete treatment with a thymic polypeptide factor [Biomodulina T (BT)] at the end of chemotherapy. Blood from patients was collected by venipuncture in heparinized tubes before and after chemotherapy and at the end of BT treatment to analyze the frequencies of non-classical immune subpopulations by flow cytometry. Results: Natural killer (NK), natural killer T cells (NKT), and double-positive T lymphocyte (DPT) proportions reached normal values in patients diagnosed with advanced lung cancer before receiving cytotoxic treatment. Chemotherapy did not induce modifications in the total percent of NK, NKT, and DPT populations in these patients. However, the administration of BT decreased DPTs and NK cells expressing the cluster of differentiation (CD)57 molecule, which is considered a marker of immunosenescence. Conclusions: These results suggest a lower influence of platinum-based chemotherapy on non-classical lymphocytes and the potential to generate a reconstitution of lymphocyte subpopulations in patients with advanced lung cancer by using the thymic factor BT, which reveals a new possibility for improving the response to cancer immunotherapies [Cuban Public Registry of Clinical Trial (RPCEC, https://rpcec.sld.cu/en/trials/RPCEC00000358-En) identifier: RPCEC00000358]

Light Intensity and Nitrogen Concentration Impact on the Biomass and Phycoerythrin Production by Porphyridium purpureum

Several factors have the potential to influence microalgae growth. In the present study, nitrogen concentration and light intensity were evaluated in order to obtain high biomass production and high phycoerythrin accumulation from Porphyridium purpureum. The range of nitrogen concentrations evaluated in the culture medium was 0.075–0.450 g L−1 and light intensities ranged between 30 and 100 μmol m−2 s−1. Surprisingly, low nitrogen concentration and high light intensity resulted in high biomass yield and phycoerythrin accumulation. Thus, the best biomass productivity (0.386 g L−1 d−1) and biomass yield (5.403 g L−1) were achieved with NaNO3 at 0.075 g L−1 and 100 μmol m−2 s−1. In addition, phycoerythrin production was improved to obtain a concentration of 14.66 mg L−1 (2.71 mg g−1 of phycoerythrin over dry weight). The results of the present study indicate that it is possible to significantly improve biomass and pigment production in Porphyridium purpureum by limiting nitrogen concentration and light intensity

Safety and effectiveness of CIMAvax-EGF administered in community polyclinics

In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients’ burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition.Clinical trial registrationhttps://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205

Does Liability under the Equal Pay Act Automatically Lead to Title VII Liability?—\u3ci\u3eFallon v. State of Illinois\u3c/i\u3e, 882 F.2d 1206 (7th Cir. 1989)

This Note examines the reasoning behind the several circuit courts\u27 (Tenth, Ninth, Eighth, and Sixth) differing answers to the question of whether a violation of the Equal Pay Act will automatically lead to Title VII liability and the effect the different answers have on the allocation of the burden of proof under a Title VII claim. Finally, a critical analysis is done to determine which rule—the equivalence or no equivalence —is based upon better reasoning

Desigualdades, discapacidad e interseccionalidad : análisis del contexto cubano 2008-2018

A partir de una perspectiva multidimensional, compleja y contextualizada de las desigualdades, y de una pluralidad de referentes disciplinares e institucionales, en la presente Colección se analizan las principales desigualdades e inequidades sociales existentes en la sociedad cubana actual en diferentes grupos sociales -género, color de la piel, etarios, socioclasista, discapacidad, territorio, ruralidad- y ámbitos -económico, vivienda/hábitat, participación social y cultural-, las intersecciones entre ellas, los fenómenos de pobreza, vulnerabilidad y marginación, así como los efectos de las políticas públicas en estos fenómenos. Como aspecto novedoso, desde el enfoque interseccional se analizan las desigualdades en grupos y ámbitos específicos y, además, se formulan propuestas de políticas de promoción de equidad y justicia social

Desigualdades etarias e interseccionalidad : análisis del contexto cubano 2008-2018

A partir de una perspectiva multidimensional, compleja y contextualizada de las desigualdades, y de una pluralidad de referentes disciplinares e institucionales, en la presente Colección se analizan las principales desigualdades e inequidades sociales existentes en la sociedad cubana actual en diferentes grupos sociales -género, color de la piel, etarios, socioclasista, discapacidad, territorio, ruralidad- y ámbitos -económico, vivienda/hábitat, participación social y cultural-, las intersecciones entre ellas, los fenómenos de pobreza, vulnerabilidad y marginación, así como los efectos de las políticas públicas en estos fenómenos. Como aspecto novedoso, desde el enfoque interseccional se analizan las desigualdades en grupos y ámbitos específicos y, además, se formulan propuestas de políticas de promoción de equidad y justicia social

Comparison of laboratory and field evaluation of alkali- silica reaction in large dams

Peer reviewed: YesNRC publication: Ye