Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats.

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID.

Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review analyzed the compounds used in hepatotoxicity assays and established a list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from COST Action ProEuroDILI Network (CA17112). METHODS: Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'. RESULTS: 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on the drug concentrations. CONCLUSIONS: The extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating in vitro models for improving preclinical drug safety testing regimes. IMPACT AND IMPLICATIONS: Prediction of human toxicity early in the drug development process remains a major challenge. For this, human in vitro models are becoming increasingly important, however, the development of more physiologically relevant liver models and careful selection of control DILI+ and DILI- drugs are requisites to better predict DILI liability of new drug candidates. Thus, this systematic study holds critical implications for standardizing validation of new in vitro models for studying drug-induced liver injury (DILI). By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. The results are of paramount importance to all the actors involved in the drug development process, offering a standardized approach to assess hepatotoxic risks. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment.

Plasmodium falciparum alters the trophoblastic barrier and stroma villi organization of human placental villi explants.

BACKGROUND: The sequestration of Plasmodium falciparum infected erythrocytes in the placenta, and the resulting inflammatory response affects maternal and child health. Despite existing information, little is known about the direct impact of P. falciparum on the placental barrier formed by trophoblast and villous stroma. This study aimed to assess placental tissue damage caused by P. falciparum in human placental explants (HPEs). METHODS: HPEs from chorionic villi obtained of human term placentas (n = 9) from normal pregnancies were exposed to P. falciparum-infected erythrocytes (IE) for 24 h. HPEs were embedded in paraffin blocks and used to study tissue damage through histopathological and histochemical analysis and apoptosis using TUNEL staining. Culture supernatants were collected to measure cytokine and angiogenic factors and to determine LDH activity as a marker of cytotoxicity. A subset of archived human term placenta paraffin-embedded blocks from pregnant women with malaria were used to confirm ex vivo findings. RESULTS: Plasmodium falciparum-IE significantly damages the trophoblast layer and the villous stroma of the chorionic villi. The increased LDH activity and pathological findings such as syncytial knots, fibrin deposits, infarction, trophoblast detachment, and collagen disorganization supported these findings. The specific damage to the trophoblast and the thickening of the subjacent basal lamina were more pronounced in the ex vivo infection. In contrast, apoptosis was higher in the in vivo infection. This disparity could be attributed to the duration of exposure to the infection, which significantly varied between individuals naturally exposed over time and the 24-h exposure in the ex vivo HPE model. CONCLUSION: Exposure to P. falciparum-IE induces a detachment of the syncytiotrophoblast, disorganization of the stroma villi, and an increase in apoptosis, alterations that may be associated with adverse results such as intrauterine growth restriction and low birth weight.

Cell competition promotes metastatic intestinal cancer through a multistage process.

Cell competition plays an instrumental role in quality control during tissue development and homeostasis. Nevertheless, cancer cells can exploit this process for their own proliferative advantage. In our study, we generated mixed murine organoids and microtissues to explore the impact of cell competition on liver metastasis. Unlike competition at the primary site, the initial effect on liver progenitor cells does not involve the induction of apoptosis. Instead, metastatic competition manifests as a multistage process. Initially, liver progenitors undergo compaction, which is followed by cell-cycle arrest, ultimately forcing differentiation. Subsequently, the newly differentiated liver cells exhibit reduced cellular fitness, rendering them more susceptible to outcompetition by intestinal cancer cells. Notably, cancer cells leverage different interactions with different epithelial populations in the liver, using them as scaffolds to facilitate their growth. Consequently, tissue-specific mechanisms of cell competition are fundamental in driving metastatic intestinal cancer.

Enhancing BIM implementation in Spanish public procurement: A framework approach.

The European Union supports the use of technology to improve public procurement, acknowledging Building Information Modeling (BIM) as a catalyst for cost-effective public works and innovation. The purpose of this paper is to evaluate BIM implementation practices in Spanish public procurement. The methodology used in this study is a mixed research method involving a questionnaire survey and semi-structured expert interviews. The findings reveal market maturity as a barrier to BIM adoption in Spanish public procurement throughout the asset lifecycle. Selecting the right instrument for implementation proves challenging for public organizations. This study has contributed to the development of more practical and effective strategies to ensure full adoption of BIM within the public procurement sector of Spain. It proposes a framework approach for the pre-contractual phase, helping contracting authorities to make the optimal instrument selection. Two criteria are considered: the maturity of the public client and sector, and the economic value classification of tenders.

Daphnia magna model for the study of mycotoxins present in food: Gliotoxin, ochratoxin A and its combination.

Mycotoxins are low molecular weight compounds present in food and feed. Although their effects on human health have been widely described, their mechanisms of action are still undefined. Gliotoxin (GTX) and ochratoxin A (OTA) are among the most dangerous mycotoxins produced by Aspergillus spp. Therefore, their toxicity was studied in the Daphnia magna model, which has high capacity to predict cytotoxicity and assess ecotoxicity, comparable to mammalian models. The study consisted of a series of tests to evaluate the effects of mycotoxins GTX, OTA and their combinations at different dilutions on Daphnia magna that were conducted according to standardized OECD 202 and 211 guidelines. The following assays were carried out: acute toxicity test, heartbeat, delayed toxicity test, reproduction, growth rate test. Reproducibility was determined by observing the offspring after 21 days of GTX exposure. In acute and delayed toxicity transcript levels of genes involved in xenobiotic metabolism (mox, gst, abcb1, and abcc5), and oxidative stress (vtg-SOD) were analyzed by qPCR. GTX showed acute toxicity and decreased heart rate in D. magna compared to OTA. On the other hand, OTA showed a delayed effect as evidenced by the immobility test. Both mycotoxins showed to increase genes involved in xenobiotic metabolism, while only the mycotoxin mixture increased oxidative stress. These results suggest that the mycotoxins tested could have negative impact on the environment and human health.

The family myth in nursing care for children in psychological distress.

This is a theoretical study aimed at reflecting on the contribution of the concept of family myth to nursing care for children in psychological distress. It is methodologically structured around three topics: the importance of the family in caring for children; the perspective of family-centered nursing care for children in psychological distress; and the contribution of the understanding of family myth to nursing care for children in psychological distress. The following dialectic is considered: the family, considered by current literature to be a harmonious unit, also triggers family conflicts that can be the cause of psychological suffering. The concept of family myth emerges as a possible theoretical anchor for nursing care for children in psychological distress, as it allows nurses to consider the signifiers that mark the child's psychological structure and construct their symptoms. Uncovering the place that the family assigns to the child enables nurses to help them construct and elaborate their own place as a subject in their subjectivity.

The Perceived Quality of Life of Older People in Spain Who Care for Grandchildren and Related Variables: A Mixed Methods Study.

Grandparental care of grandchildren is a prevalent social phenomenon. This study explores the perceptions of health-related quality of life of grandparents caring for their grandchildren. A mixed methods design was developed. In the first phase, participants were interviewed using a baseline questionnaire. The second phase consisted of focus groups with 19 of the 100 participants in the quantitative phase. The scores obtained from the quantitative analysis are in line with the qualitative data; they reflect that grandparent carers who are more involved in the care of their grandchildren have more symptoms of depression and stress and have poorer perceptions of physical health-related quality of life. What may at first appear to be a positive aspect, keeping grandparent carers active, can become negative when it comes to shared care and when the grandparents' willingness to provide care is abused.

[Health and well-being of healthcare workers: employment and working conditions beyond the pandemic]. / Salud y bienestar del personal sanitario: condiciones de empleo y de trabajo más allá de la pandemia. Informe SESPAS 2024.

Healthcare workers are people who work in health activities, whether or not they have direct contact with citizens. Currently, around 1.3 million people (70% women) work in healthcare activities in Spain. This represents around 10% of the active population, having increased by 33% since 2008, especially the number of women, which has doubled. Healthcare organizations, especially hospitals, are extremely complex workplaces, with precarious working and employment conditions, especially in more hierarchical occupations, exposing healthcare workers to numerous occupational hazards, mainly from ergonomic and psychosocial conditions. These causes frequent musculoskeletal and mental disorders, highlighting burnout, which is estimated at 40% in some services such as intensive care units. This high morbidity is reflected in a high frequency of absences due to illness, around 9% after the pandemic. The pandemic, and its consequences in the last three years, has put extreme pressure on the health system and has clearly shown its deficiencies in relation to working and employment conditions. The hundreds of occupational health professionals, technicians and healthcare workers, who are part of the structures of health organizations, constitute very valuable resources to increase the resilience of the NHS. We recommend the strengthening in resources and institutionally of the occupational health services of health centers and the creation of an Observatory of working, employment and health conditions in the National Health Service, as an instrument for monitoring changes and proposing solutions.

Exploring Psychedelics for Alleviating Existential and Spiritual Suffering in People With Serious Illnesses: Links to the Theory of Self-Transcendence.

The fields of palliative and holistic Nursing are dedicated to providing comprehensive care for the person, emphasizing special attention to the existential and spiritual aspects of care. Psychedelic-assisted therapy has emerged as a promising approach for symptom management in individuals with serious illnesses, particularly those of existential and spiritual origin. People who undergo challenging experiences, as is the case with serious illnesses, often undergo an identity crisis and question the purpose of their lives. Psychedelic therapy, when conducted properly by trained professionals, can facilitate self-exploration and self-transcendence, opening doors to states of expanded consciousness and fostering a profound connection with oneself. This experience can help patients develop a greater sense of self-awareness and a deeper understanding of their existential and spiritual issues, enabling them to find meaning and inner peace. The Theory of Self-Transcendence theory provides a Nursing framework for understanding how psychedelic-assisted therapy can facilitate, through self-transcendence, the journey of spiritual and existential healing, offering the possibility of achieving wellbecoming from a state of vulnerability.

Structure and dynamics of Li1.24K0.76CO3 molten carbonate electrolyte from molecular simulations with explicit polarization.

Molten carbonate electrolysis cells represent a key technology for harnessing surplus energy from renewable sources and converting it into gaseous energy carriers. To optimize their efficiency, a comprehensive understanding of each step in the operational process is essential. Here, we focus on the electrolyte of choice in molten carbonate cells: the Li1.24K0.76CO3 melt. Utilizing molecular dynamics with explicit polarization, we demonstrate that the structure of this molten mixture is characterized by a dense network of lithium-carbonate complexes, with K+ ions loosely embedded within this network. This structural insight enables us to rationalize from an atomistic perspective the conductivity trends observed experimentally in molten carbonates. Moreover, our work highlights the importance of including polarization for the simulations of dense liquid carbonates. It also acts as a foundational step towards more advanced theoretical studies for elucidating the role of the electrolyte in these devices.

Interactions between TNFAIP3, PTPN22, and TRAF1-C5 gene polymorphisms in patients with primary Sjögren's syndrome.

Objectives: The aim of our study was to investigate whether TNFAIP3, PTPN22, and TRAF1-5 single nucleotide polymorphisms (SNPs) are associated with susceptibility, severity, or serological markers in primary Sjögren's syndrome (pSS). Patients and methods: The cases and controls study was conducted between December 2021 and June 2022. TNFAIP3 rs10499194C/T, rs6920220G/A, and rs2230926T/G, PTPN22 rs2476601C/T and rs33996649G/A, and TRAF1-C5 rs10818488G/A polymorphisms were genotyped in 154 female pSS patients (mean age: 45.2±6.8 years) and 313 female control subjects (mean age: 50.3±7.5 years) using the TaqMan® SNP genotyping assay. An association analysis between TNFAIP3, PTPN22, and TRAF1-C5 SNPs and susceptibility, clinical characteristics, and serological markers of pSS was performed. Interactions between TNFAIP3, PTPN22, and TRAF1-C5 SNPs were also evaluated in patients and controls. Results: The genotype and allele frequencies showed no association with susceptibility, severity, or serological markers of pSS. Nevertheless, several interactions between TNFAIP3 and TRAF1-C5 or TNFAIP3, PTPN22, and TRAF1-C5 genotypes were associated with susceptibility to pSS (p<0.01). Conclusion: Individual TNFAIP3, PTPN22, and TRAF1-C5 SNPs are not associated with susceptibility, severity, or serological markers of pSS. However, genetic interactions between TRAF1-C5 and TNFAIP3 or TNFAIP3, PTPN22, and TRAF1-C5 SNPs are risk factors for pSS.

Effective prediction of SnO2 conduction band edge potential: The key role of surface oxygen vacancies.

Several theoretical studies at different levels of theory have attempted to calculate the absolute position of the SnO2 conduction band, whose knowledge is key for its effective application in optoelectronic devices such us, for example, perovskite solar cells. However, the predicted band edges fall outside the experimentally measured range. In this work, we introduce a computational scheme designed to calculate the conduction band minimum values of SnO2, yielding results aligned with experiments. Our analysis points out the fundamental role of encompassing surface oxygen vacancies to properly describe the electronic profile of this material. We explore the impact of both bridge and in-plane oxygen vacancy defects on the structural and electronic properties of SnO2, explaining from an atomistic perspective the experimental observables. The results underscore the importance of simulating both types of defects to accurately predict SnO2 features and provide new fundamental insights that can guide future studies concerning design and optimization of SnO2-based materials and functional interfaces.

Influence of support materials on the electroactive behavior, structure and gene expression of wild type and GSU1771-deficient mutant of Geobacter sulfurreducens biofilms.

Geobacter sulfurreducens DL1 is a metal-reducing dissimilatory bacterium frequently used to produce electricity in bioelectrochemical systems (BES). The biofilm formed on electrodes is one of the most important factors for efficient electron transfer; this is possible due to the production of type IV pili and c-type cytochromes that allow it to carry out extracellular electron transfer (EET) to final acceptors. In this study, we analyzed the biofilm formed on different support materials (glass, hematite (Fe2O3) on glass, fluorine-doped tin oxide (FTO) semiconductor glass, Fe2O3 on FTO, graphite, and stainless steel) by G. sulfurreducens DL1 (WT) and GSU1771-deficient strain mutant (Δgsu1771). GSU1771 is a transcriptional regulator that controls the expression of several genes involved in electron transfer. Different approaches and experimental tests were carried out with the biofilms grown on the different support materials including structure analysis by confocal laser scanning microscopy (CLSM), characterization of electrochemical activity, and quantification of relative gene expression by RT-qPCR. The gene expression of selected genes involved in EET was analyzed, observing an overexpression of pgcA, omcS, omcM, and omcF from Δgsu1771 biofilms compared to those from WT, also the overexpression of the epsH gene, which is involved in exopolysaccharide synthesis. Although we observed that for the Δgsu1771 mutant strain, the associated redox processes are similar to the WT strain, and more current is produced, we think that this could be associated with a higher relative expression of certain genes involved in EET and in the production of exopolysaccharides despite the chemical environment where the biofilm develops. This study supports that G. sulfurreducens is capable of adapting to the electrochemical environment where it grows.

Metal Ions Trigger the Gelation of Cysteine-Containing Peptide-Appended Coordination Cages.

We report a series of coordination cages that incorporate peptide chains at their vertices, prepared through subcomponent self-assembly. Three distinct heterochiral tripeptide subcomponents were incorporated, each exhibiting an L-D-L stereoconfiguration. Through this approach, we prepared and characterized three tetrahedral metal-peptide cages that incorporate thiol and methylthio groups. The gelation of these cages wasprobed through the binding of additional metal ions, with the metal-peptide cages acting as junctions, owing to the presence of sulfur atoms on the peripheral peptides. Gels were obtained with cages bearing cysteine at the C-terminus. Our strategy for developing functional metal-coordinated supramolecular gels with a modular design may result in the development of materials useful for chemical separations or drug delivery.