Immunomodulatory effects of inactivated Ligilactobacillus salivarius CECT 9609 on respiratory epithelial cells.

The microbiota in humans and animals play crucial roles in defense against pathogens and offer a promising natural source for immunomodulatory products. However, the development of physiologically relevant model systems and protocols for testing such products remains challenging. In this study, we present an experimental condition where various natural products derived from the registered lactic acid bacteria Ligilactobacillus salivarius CECT 9609, known for their immunomodulatory activity, were tested. These products included live and inactivated bacteria, as well as fermentation products at different concentrations and culture times. Using our established model system, we observed no morphological changes in the airway epithelium upon exposure to Pasteurella multocida, a common respiratory pathogen. However, early molecular changes associated with the innate immune response were detected through transcript analysis. By employing diverse methodologies ranging from microscopy to next-generation sequencing (NGS), we characterized the interaction of these natural products with the airway epithelium and their potential beneficial effects in the presence of P. multocida infection. In particular, our discovery highlights that among all Ligilactobacillus salivarius CECT 9609 products tested, only inactivated cells preserve the conformation and morphology of respiratory epithelial cells, while also reversing or altering the natural immune responses triggered by Pasteurella multocida. These findings lay the groundwork for further exploration into the protective role of these bacteria and their derivatives.

Transcriptional Regulation of Airway Epithelial Cell Differentiation: Insights into the Notch Pathway and Beyond.

The airway epithelium is a critical component of the respiratory system, serving as a barrier against inhaled pathogens and toxins. It is composed of various cell types, each with specific functions essential to proper airway function. Chronic respiratory diseases can disrupt the cellular composition of the airway epithelium, leading to a decrease in multiciliated cells (MCCs) and an increase in secretory cells (SCs). Basal cells (BCs) have been identified as the primary stem cells in the airway epithelium, capable of self-renewal and differentiation into MCCs and SCs. This review emphasizes the role of transcription factors in the differentiation process from BCs to MCCs and SCs. Recent advancements in single-cell RNA sequencing (scRNAseq) techniques have provided insights into the cellular composition of the airway epithelium, revealing specialized and rare cell types, including neuroendocrine cells, tuft cells, and ionocytes. Understanding the cellular composition and differentiation processes within the airway epithelium is crucial for developing targeted therapies for respiratory diseases. Additionally, the maintenance of BC populations and the involvement of Notch signaling in BC self-renewal and differentiation are discussed. Further research in these areas could provide valuable insights into the mechanisms underlying airway epithelial homeostasis and disease pathogenesis.

Sesamol prevents mitochondrial impairment and pro-inflammatory alterations in the human neuroblastoma SH-SY5Y cells: role for Nrf2.

Mitochondria are a primary source and a target of reactive oxygen species (ROS). Increased mitochondrial production of ROS is associated with bioenergetics decline, cell death, and inflammation. Here we investigated whether a pretreatment (for 24 h) with sesamol (SES; at 12.5-50 µM) would be efficient in preventing the mitochondrial collapse induced by hydrogen peroxide (H2O2, at 300 µM) in the human neuroblastoma SH-SY5Y cell line. We have found that a pretreatment with SES at 25 µM decreased the effects of H2O2 on lipid peroxidation, protein carbonylation, and protein nitration in membranes obtained from the mitochondria isolated from the SH-SY5Y cells. In this regard, SES pretreatment decreased the production of superoxide anion radical (O2-•) by the mitochondria of H2O2-treated cells. SES also prevented the mitochondrial dysfunction induced by H2O2, as assessed by analyzing the activity of the complexes I and V. The H2O2-induced reduction in the production of adenosine triphosphate (ATP) was also prevented by SES. The levels of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), as well as the activity of the transcription factor nuclear factor-κB (NF-κB) were downregulated by the SES pretreatment in the H2O2-challenged cells. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor abolished the protection induced by SES regarding mitochondrial function and inflammation. Thus, SES depends on Nrf2 to promote mitochondrial protection in cells facing redox impairment.

Proteomic Analysis of an Induced Pluripotent Stem Cell Model Reveals Strategies to Treat Juvenile Myelomonocytic Leukemia.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate, thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with an increased incidence of JMML. We report that the proteomic perturbations induced by the leukemia-associated PTPN11 mutations are associated with TP53 and NF-Kκb signaling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with an increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients, who develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive hematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.

Centriole positioning in epithelial cells and its intimate relationship with planar cell polarity.

Planar cell polarity (PCP)-signaling and associated tissue polarization are evolutionarily conserved. A well documented feature of PCP-signaling in vertebrates is its link to centriole/cilia positioning, although the relationship of PCP and ciliogenesis is still debated. A recent report in Drosophila established that Frizzled (Fz)-PCP core signaling has an instructive input to polarized centriole positioning in non-ciliated Drosophila wing epithelia as a PCP read-out. Here, we review the impact of this observation in the context of recent descriptions of the relationship(s) of core Fz-PCP signaling and cilia/centriole positioning in epithelial and non-epithelial cells. All existing data are consistent with a model where Fz-PCP signaling functions upstream of centriole/cilia positioning, independent of ciliogenesis. The combined data sets indicate that the Fz-Dsh PCP complex is instructive for centriole/ciliary positioning via an actin-based mechanism. Thereby, centriole/cilia/centrosome positioning can be considered an evolutionarily conserved readout and common downstream effect of PCP-signaling from flies to mammals.

Inhaled resveratrol treatments slow ageing-related degenerative changes in mouse lung.

BACKGROUND: Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc-/-) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally. Here, we tested whether inhaled RSL could protect young, terc-/- mice from accelerated ageing of the lung. METHODS: terc-/- mice aged 2 months inhaled 1 mg/kg RSL that was instilled intratracheally once per month for 3 months. One month after the last inhalation, whole lung function, structure and cellular DNA damage were evaluated and AEC2 survival was assessed by western blotting for survival pathway gene expression. RESULTS: RSL treatments delayed the loss of lung compliance (p<0.05), maintained lung structure (p<0.001) and blocked parenchymal cell DNA damage as measured by TdT Nick-End Labeling (TUNEL). RSL, a known agonist of deacetylase SIRT1, supported AEC2 survival by stimulating SIRT1 expression, promoting p53 destabilisation and decreasing Bax expression and by maintaining expression levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), activated p-Akt and p-Mdm2 and inactivated Phospho-Phosphatase and tensin homolog (p-PTEN). CONCLUSIONS: RSL prophylaxis by inhalation is a potential approach for slowing ageing-related deterioration of lung function and structure by maintaining AEC2 integrity.

Regeneration of the Aging Lung: A Mini-Review.

Natural lung aging is marked by molecular changes that occur during development, maturation, and late-life decline. At the cellular and whole organ level, degenerative changes that are a hallmark of natural aging (shorter telomeres, increased expression of cellular senescence markers, increased DNA damage, oxidative stress, and apoptosis, accompanied by diminished elasticity) reach pathological levels in aging humans in the form of chronic respiratory disease. Aging strongly correlates with the development and incidence of chronic respiratory diseases, including cancer and idiopathic pulmonary fibrosis, but is most strongly linked with development of chronic obstructive pulmonary disease. Lung failure due to aging can be traced to loss of lung stem cell regenerative capacity within the distinctive stem cell niches found within each compartment of the lung. Current knowledge about the identity and function of these stem cell compartments has been largely drawn from a variety of transgenic and spontaneously mutated mouse models that are characterized by rapid rates of aging or have been used to examine regeneration from injury in the context of natural or accelerated aging. While much work has focused on the failure of epithelial cell populations as a key component of the aging process, additional studies have shown that aging, as a global phenomenon in the lung, also impacts resident endothelial, mesenchymal, and immune cell populations. In this review, we examine aging as a process dependent on specific changes in molecular pathways within multiple lung cell populations.

Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair.

Type 2 alveolar epithelial cells (AEC2) are regarded as the progenitor population of the alveolus responsible for injury repair and homeostatic maintenance. Depletion of this population is hypothesized to underlie various lung pathologies. Current models of lung injury rely on either uncontrolled, nonspecific destruction of alveolar epithelia or on targeted, nontitratable levels of fixed AEC2 ablation. We hypothesized that discrete levels of AEC2 ablation would trigger stereotypical and informative patterns of repair. To this end, we created a transgenic mouse model in which the surfactant protein-C promoter drives expression of a mutant SR39TK herpes simplex virus-1 thymidine kinase specifically in AEC2. Because of the sensitivity of SR39TK, low doses of ganciclovir can be administered to these animals to induce dose-dependent AEC2 depletion ranging from mild (50%) to lethal (82%) levels. We demonstrate that specific levels of AEC2 depletion cause altered expression patterns of apoptosis and repair proteins in surviving AEC2 as well as distinct changes in distal lung morphology, pulmonary function, collagen deposition, and expression of remodeling proteins in whole lung that persist for up to 60 days. We believe SPCTK mice demonstrate the utility of cell-specific expression of the SR39TK transgene for exerting fine control of target cell depletion. Our data demonstrate, for the first time, that specific levels of type 2 alveolar epithelial cell depletion produce characteristic injury repair outcomes. Most importantly, use of these mice will contribute to a better understanding of the role of AEC2 in the initiation of, and response to, lung injury.

The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

"The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion.

p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications.

The TP53 gene is renowned as a tumor suppressor, playing a pivotal role in overseeing the cell cycle, apoptosis, and maintaining genomic stability. Dysregulation of p53 often contributes to the initiation and progression of various cancers, including lung cancer (LC) subtypes. The review explores the intricate relationship between p53 and its role in the development and progression of LC. p53, a crucial tumor suppressor protein, exists in various isoforms, and understanding their distinct functions in LC is essential for advancing our knowledge of this deadly disease. This review aims to provide a comprehensive literature overview of p53, its relevance to LC, and potential clinical applications.

Early Atf4 activity drives airway club and goblet cell differentiation.

Activating transcription factor 4 (Atf4), which is modulated by the protein kinase RNA-like ER kinase (PERK), is a stress-induced transcription factor responsible for controlling the expression of a wide range of adaptive genes, enabling cells to withstand stressful conditions. However, the impact of the Atf4 signaling pathway on airway regeneration remains poorly understood. In this study, we used mouse airway epithelial cell culture models to investigate the role of PERK/Atf4 in respiratory tract differentiation. Through pharmacological inhibition and silencing of ATF4, we uncovered the crucial involvement of PERK/Atf4 in the differentiation of basal stem cells, leading to a reduction in the number of secretory cells. ChIP-seq analysis revealed direct binding of ATF4 to regulatory elements of genes associated with osteoblast differentiation and secretory cell function. Our findings provide valuable insights into the role of ATF4 in airway epithelial differentiation and its potential involvement in innate immune responses and cellular adaptation to stress.

Next generation sequencing technologies to address aberrant mRNA translation in cancer.

In this review, we explore the transformative impact of next generation sequencing technologies in the realm of translatomics (the study of how translational machinery acts on a genome-wide scale). Despite the expectation of a direct correlation between mRNA and protein content, the complex regulatory mechanisms that affect this relationship remark the limitations of standard RNA-seq approaches. Then, the review characterizes crucial techniques such as polysome profiling, ribo-seq, trap-seq, proximity-specific ribosome profiling, rnc-seq, tcp-seq, qti-seq and scRibo-seq. All these methods are summarized within the context of cancer research, shedding light on their applications in deciphering aberrant translation in cancer cells. In addition, we encompass databases and bioinformatic tools essential for researchers that want to address translatome analysis in the context of cancer biology.

How to Manage the Suffering of the Patient and the Family in the Final Stage of Life: A Qualitative Study.

BACKGROUND: The end of life and death have changed from being issues managed within the family, assumed as part of life, to occur within health institutions for the majority of patients. The amount of patients dying at home has decreased, and the roles of families and communities in death and dying have become involuted, threatening related traditions and knowledge. As a result, a need to promote the end of life at home in this new self-serving society has arisen. In that context, the main objective of this study was to find out what patients and their families need during the end-of-life process in order to feel effectively accompanied at this time. METHODS: With that objective, a descriptive qualitative study was conducted via the content analysis of data from semi-structured interviews and focus groups. This research adhered to the COREQ guidelines. The sample consisted of 36 informants selected via intentional sampling of family members and patients integrated into the Comprehensive Palliative Care Process (PAI Paliativos). RESULTS: The results suggest the existence of several common needs such as communication and presence, including the conspiracy of silence as an important factor generating suffering for both. However, there are specific needs such as autonomy, dignity, and respect for patients, which must be taken into account. CONCLUSIONS: The results of this study will allow us to establish intervention strategies for effective accompaniment of patients' family members at the end of life and the avoidance of ethnocentrism in this process. This study was retrospectively registered with the (nursrep-1194226) on the (21 April 2023).

Holes in the Head. Double cranial surgery on an individual from the Chalcolithic burial site of Camino del Molino (SE Spain).

OBJECTIVE: This article analyses new prehistoric evidence of trepanation from a collective burial site in the south-eastern Iberian Peninsula. MATERIALS: The trepanned individual was documented in the Chalcolithic burial site of Camino del Molino, where 1348 individuals (30.7 % non-adults and 69.3 % adults) were deposited in two contiguous funerary phases, making it a reference site for the knowledge of Recent Prehistoric populations. METHODS: The individual has been sexed using traditional anthropological methods and ancient DNA. C14 dating has also been obtained. The lesion has been analysed macroscopically and microscopically using SEM. RESULTS: The skull under study belonged to an adult female deposited in the second burial phase (2566-2239 years cal BCE). It exhibits in the anterior region of the right temporal fossa two contiguous and partially overlapping holes that correspond to two trepanations performed using the scraping technique. CONCLUSIONS: It is a double cranial trepanation with signs of bone remodelling suggesting survival from surgery. No pathological signs were identified potentially associated with the intervention. SIGNIFICANCE: This is the second case of surgical interventions in the geographical area of study and one of the few evidences of this practice in women during prehistoric times. LIMITATIONS: So far only the articulated skeletons from this burial have been thoroughly analysed. SUGGESTIONS FOR FURTHER RESEARCH: Further intensive review of skull collection is advised to learn more about these surgical interventions in Copper Age and to go deeper into the causes that motivated their execution.

Critical digital ischemia and biliary cholangitis related to graft versus host disease: A case report and systematic literature review.

RATIONALE: Chronic graft versus host disease (cGVHD) is a systemic immune-mediated complication that occurs in approximately half of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT), and remains the leading cause of late morbidity and mortality. cGVHD involves a heterogeneous group of organic manifestations, many of which mimic autoimmune diseases such as scleroderma, primary biliary cholangitis, Sjögren syndrome and polymyositis. PATIENT CONCERNS: A 60-years-old female with a history of allo-HCT developed de novo cGVHD 11 months after allo-HCT with isolated liver involvement. The patient presented with jaundice, cytolysis, cholestasis and concomitant acute digital ischemia. Liver biopsy and autoimmunity tests were performed and were found to be compatible with immune-mediated liver damage. Nailfold capillaroscopy revealed microangiopathy, characterized by avascular areas and some enlarged capillaries resembled an early systemic sclerosis pattern. DIAGNOSIS: Biliary cholangitis-like and digital ischemia related to cGVHD. INTERVENTIONS: The patient was treated with high-dose prednisone and ursodeoxycholic acid, and extracorporeal photopheresis. The patient required hospital admission for administration of intravenous prostacyclin due to refractory Raynaud syndrome. OUTCOMES: After 6 to 8 weeks, the patient achieved a good response, with evident clinical improvement and progressive normalization of liver function. LESSONS: cGVHD is a multiorgan pathological condition, and this case emphasizes that a multidisciplinary team, including rheumatologists, should be involved in the follow-up of allo-transplant patients to ensure that the clinical complications are adequately addressed. Early intervention is critical for improving patient' prognosis.In addition, we performed a systemic literature review based on published case articles on hepatic cGVHD and digital ischemia published up to August 2022. To the best of our knowledge, this is the first reported case of such an association.

Nursing students' perceptions of spiritual needs at the end of life. A qualitative study.

Spirituality is defined as the meaning of life, being the very essence of life made up of all of the aspects inherent to it. During end-of-life processes, this need is shown to be particularly altered in patients and yet it is an aspect that the health professionals accompanying patients in this situation report being least equipped to address, alongside therapies that could help to meet these needs, such as art therapy. An exploratory qualitative study was conducted, adheres to the guidelines of COREQ (41). The study population were final year students undertaking a nursing degree at the University of Huelva, Spain. The sample was selected via intentional sampling using snowball recruitment from the study population. Stratification according to gender was performed due to the feminised nature of the population. Sample size was determined progressively during the research, with recruitment ceasing at 13 informants once information saturation was achieved. Inclusion criteria required that participants were to be final year students enrolled on a nursing degree who had provided consent to participate voluntarily in the research. The analysis Realized was interpretive phenomenological (IPA) as described by Smith (43-45). The present study revealed that students perceive their training on spiritual care to be deficient. Despite them reporting that they possess the skills and tools to provide end-of-life care, this is not enough to provide effective accompaniment, given that this moment brings them into touch with their own insecurities. Students verbalized the need to learn strategies to address this shortcoming regarding final accompaniment, for instance, through art, with creativity being one of the skills with the potential to uncover the meaning of life.

Cell-based therapies for lung disease.

INTRODUCTION OR BACKGROUND: The adult lung is a complex organ whose large surface area interfaces extensively with both the environment and circulatory system. Yet, in spite of the high potential for exposure to environmental or systemic harm, epithelial cell turnover in adult lung is comparatively slow. Moreover, loss of lung function with advancing age is becoming an increasingly costly healthcare problem. Cell-based therapies stimulating endogenous stem/progenitor cells or supplying exogenous ones have therefore become a prime translational goal. Alternatively when lung repair becomes impossible, replacement with tissue-engineered lung is an attractive emerging alternative using a decellularized matrix or bioengineered scaffold. SOURCES OF DATA: Endogenous and exogenous stem cells for lung therapy are being characterized by defining developmental lineages, surface marker expression, functions within the lung and responses to injury and disease. Seeding decellularized lung tissue or bioengineered matrices with various stem and progenitor cells is an approach that has already been used to replace bronchus and trachea in human patients and awaits further development for whole lung tissue. AREAS OF AGREEMENT: Cellular therapies have clear potential for respiratory disease. However, given the surface size and complexity of lung structure, the probability of a single cellular population sufficing to regenerate the entire organ, as in the bone marrow, remains low. Hence, lung regenerative medicine is currently focused around three aims: (i) to identify and stimulate resident cell populations that respond to injury or disease, (ii) to transplant exogenous cells which can ameliorate disease and (iii) to repopulate decellularized or bioengineered lung matrix creating a new implantable organ. AREAS OF CONTROVERSY: Lack of consensus on specific lineage markers for lung stem and progenitor cells in development and disease constrains transferability of research between laboratories and sources of cellular therapy. Furthermore, effectiveness of individual cellular therapies to correct gas exchange and provide other critical lung functions remains unproven. Finally, feasibility of autologous whole organ replacement has not been confirmed as a durable therapy. Growing points Cellular therapies for lung regeneration would be enhanced by better lineage tracing within the lung, the ability to direct differentiation of exogenous stem or progenitor cells, and the development of functional assays for cellular viability and regenerative properties. Whether endogenous or exogeneous cells will ultimately play a greater therapeutic role remains to be seen. Reducing the need for lung replacement via endogenous cell-mediated repair is a key goal. Thereafter, improving the potential of donor lungs in transplant recipients is a further area where cell-based therapies may be beneficial. Ultimately, lung replacement with autologous tissue-engineered lungs is another goal for cell-based therapy. Areas timely for developing research Defining 'lung stem or progenitor cell' populations in both animal models and human tissue may help. Additionally, standardizing assays for assessing the potential of endogenous or exogenous cells within the lung is important. Understanding cell-matrix interactions in real time and with biomechanical insight will be central for lung engineering. Cautionary note Communicating the real potential for cell-based lung therapy needs to remain realistic, given the keen expectations of patients with end-stage lung disease.

A focused educational program after religious services to improve organ donation in Hispanic Americans.

Religion is an important determinant in Hispanic Americans (HA) becoming organ donors as HA often believe religion forbids donation. We investigated the effect of an educational program targeting HA organ donation in places of worship. A prospective observational study was conducted at four Catholic churches with a high percentage of HA. A 45-min "culturally sensitive" educational program, conducted in Spanish, was implemented. Organ donation awareness, knowledge, perception, and beliefs, as well as the intent to become an organ donor, were measured before and after the intervention. Differences between before and after the intervention were analyzed. A total of 182 surveys were conducted before and 159 surveys were conducted after the educational program. A significant increase was observed in organ donation knowledge (54% vs. 70%, p<0.0001), perception (43% vs. 58%, p<0.0001), and beliefs (50% vs. 60%, p=0.0001). However, no significant difference was found in the willingness to discuss donation with family, intent-to-donate, or registering to donate after the intervention. This study demonstrates that a focused educational program in places of worship can significantly improve HA knowledge, perceptions, and beliefs regarding organ donation. Further work is needed to understand why intent-to-donate does not increase despite the increase in organ donation awareness.

Influence of the COVID-19 Pandemic on Medication Reconciliation in Frail Elderly People at Hospital Discharge: Perception of Healthcare Professionals.

The current demographic panorama in Spain corresponds to an aging population; this situation is characterized by the need to care for an elderly population, which contains polymedicated and pluripathological individuals. Polymedication is a criterion of frailty in the elderly and a risk factor for mortality and morbidity due to the increased risk of drug interactions and medication errors. There are numerous studies that measure reconciliation at hospital discharge and at admission, and even the methodology of reconciliation, but we have not found many studies that measure reconciliation in the context of the COVID-19 pandemic from the point of view of health professionals regarding difficulties and the strategies carried out, which is essential to begin to glimpse solutions. METHODS: This was a qualitative study based on 21 in-depth interviews and two discussion groups, conducted between January and April 2021 (13 nurses and 8 doctors, in rural and urban areas). The discourse was analyzed according to the Taylor-Bodgan model and processed using Atlas.ti software. RESULTS: The areas altered by the health crisis were access to patients, their reconciliation of medication, and changes in the care modality, including the greater use of telephone communication, changes in work organization, and time dedicated to patient care and family work. Difficulties encountered during COVID-19: change in medication format, the specific characteristics of the patient and their pathologies, and difficulties arising from communication with the patient and their family. The strategies applied: the collaboration of home assistants and caregivers, emphasis on patient-health professional communication, and the use of Information and Communication Technologies (ICT). CONCLUSION: The discharge was interrupted by the health crisis caused by COVID-19, in terms of both the traditional access of patients and by the remote care modalities generated by telemedicine.

Esrrb Regulates Specific Feed-Forward Loops to Transit From Pluripotency Into Early Stages of Differentiation.

Characterization of pluripotent states, in which cells can both self-renew or differentiate, with the irreversible loss of pluripotency, are important research areas in developmental biology. Although microRNAs (miRNAs) have been shown to play a relevant role in cellular differentiation, the role of miRNAs integrated into gene regulatory networks and its dynamic changes during these early stages of embryonic stem cell (ESC) differentiation remain elusive. Here we describe the dynamic transcriptional regulatory circuitry of stem cells that incorporate protein-coding and miRNA genes based on miRNA array expression and quantitative sequencing of short transcripts upon the downregulation of the Estrogen Related Receptor Beta (Esrrb). The data reveals how Esrrb, a key stem cell transcription factor, regulates a specific stem cell miRNA expression program and integrates dynamic changes of feed-forward loops contributing to the early stages of cell differentiation upon its downregulation. Together these findings provide new insights on the architecture of the combined transcriptional post-transcriptional regulatory network in embryonic stem cells.