The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.

Perturbed development of calb2b expressing dI6 interneurons and motor neurons underlies locomotor defects observed in calretinin knock-down zebrafish larvae.

Calcium binding proteins are essential for neural development and cellular activity. Calretinin, encoded by calb2a and calb2b, plays a role during early zebrafish development and has been proposed as a marker for distinct neuronal populations within the locomotor network. We generated a calb2b:hs:eGFP transgenic reporter line to characterize calretinin expressing cells in the developing spinal cord and describe morphological and behavioral defects in calretinin knock-down larvae. eGFP was detected in primary and secondary motor neurons, as well as in dI6 and V0v interneurons. Knock-down of calretinin lead to disturbed development of motor neurons and dI6 interneurons, revealing a crucial role during early development of the locomotor network. Primary motor neurons showed delayed axon outgrowth and the distinct inhibitory CoLo neurons, originating from the dI6 lineage, were absent. These observations explain the locomotor defects we observed in calretinin knock-down animals where the velocity, acceleration and coordination were affected during escapes. Altogether, our analysis suggests an essential role for calretinin during the development of the circuits regulating escape responses and fast movements within the locomotor network.

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

Antibiotic biocompatibility assay and anti-biofilm strategies for Pseudomonas aeruginosa infection in bioengineered artificial skin substitutes.

OBJECTIVES: Bioengineered artificial skin substitutes (BASS) are an advanced therapy for treating extensively burned patients. Pseudomonas aeruginosa (P. aeruginosa) infections represent a major challenge in these patients as formation of biofilms impede wound healing and perpetuate a chronic inflammatory state. Here we assessed antibiotics (alone or in combination) with respect to cytotoxicity, as well as antimicrobial efficacy in P. aeruginosa biofilm formed on infection of BASS. METHODS: Cell viability, structure and functionality were evaluated using microscopy and trans-epidermal water loss analyses, respectively. BASS were established and infected for 24 h to allow P. aeruginosa biofilm formation, after which two antimicrobial approaches, treatment and prevention, were tested. In the latter, antibiotics were added to BASS before infection. The antimicrobial effect was determined using real-time calorimetry. RESULTS: In dose-response experiments, 1.25 mg/mL amikacin, 0.02 mg/mL ciprofloxacin, 0.051 mg/mL colistin, 1 mg/mL meropenem and colistin in combination with either amikacin, ciprofloxacin and meropenem did not affect BASS' viability, structure and functionality. All antibiotics, except colistin, showed effective antimicrobial activity at these non-cytotoxic concentrations. For concentrations below the highest non-cytotoxic ones, successive treatments resulted in higher bacterial metabolic rates. Only the combinations managed to eradicate the infection with repeated treatments. With respect to prevention of infection, all antibiotics at the highest non-cytotoxic concentrations and the combinations were effective. This preventive capacity was maintained for at least 5 days. CONCLUSION: The findings highlight the potential for developing BASS with antimicrobial properties that can prevent infections during wound healing in burn patients.

Prevalence of orthostatic intolerance in long covid clinic patients and healthy volunteers: A multicenter study.

Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with OI symptoms and comorbidities. Participants with a diagnosis of long covid were recruited from eight UK long covid clinics, and healthy volunteers from general population. All undertook standardized National Aeronautics and Space Administration Lean Test (NLT). Participants' history of typical OI symptoms (e.g., dizziness, palpitations) before and during the NLT were recorded. Two hundred seventy-seven long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or symptoms during NLT or PoTS, 10% had asymptomatic OH. One hundred thirty (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. Forty-one (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS, and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive abnormal readings to one abnormal reading during the NLT, resulted in 11% of long covid participants (an additional 4%) meeting criteria for PoTS, but not in healthy volunteers. More than half of long covid patients experienced OI symptoms during NLT and more than one in 10 patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We therefore recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.

Improving Assessment and Learning Environments for Graduate Medical Trainees to Advance Healthcare Language Equity.

Language-appropriate care is critical for equitable, high-quality health care, but educational standards to assure graduate medical trainees are prepared to give such care are lacking. Detailed guidance for graduate medical education is provided by the Accreditation Council for Graduate Medical Education through the following: (1) an assessment framework for competencies, subcompetencies, and milestones for trainees and (2) the Clinical Learning Environment Review (CLER) Pathways for assessment of trainees' learning environments. These tools do not include a robust framework to evaluate trainees' abilities to offer language-appropriate care. They also do not address the learning environment's potential to support such care. A multidisciplinary group of linguistic, medical, and educational experts drafted a new subcompetency with milestones and an expanded CLER Pathway to highlight the importance of equitable care for patients who prefer languages other than English. These resources offer residency and fellowship programs tools to guide assessment, curriculum development, and learning-environment improvements related to language-appropriate care. Recognizing that programs have unique needs and resources, we propose a range of initial actions to address language equity. A focus on language diversity in the learning environment can have a broad and lasting impact on care quality, patient safety, and health equity.

Effectiveness of Mepolizumab in Patients with Severe Eosinophilic Asthma with/without Nasal Polyposis: A Real-Life Study.

INTRODUCTION: Asthma is one of the most common chronic diseases and affects around 334 million people worldwide. The estimated prevalence of severe asthma is 3-10% of the asthmatic population. Mepolizumab has demonstrated efficacy in reducing exacerbations, oral corticosteroid use, and improving quality of life, asthma control, and lung function in patients with severe eosinophilic asthma (SEA). Our study aimed to check the response to mepolizumab in a series of severe asthma patients regarding exacerbations, oral corticosteroid use, asthma control, quality of life, and lung function and to compare the response between patients with and without nasal polyps. METHOD: This is a retrospective, multicenter study of RE-ASGRAMUR (Register of Severe Asthma of the Region of Murcia) performed in eight hospitals of the Region of Murcia (Spain) under routine clinical practice conditions. We included patients diagnosed with SEA who completed at least 1 year of treatment with mepolizumab. We analyzed clinical characteristics, drug tolerance, and effectiveness: exacerbations, ACT, miniAQLQ, forced expiratory volume in 1 s (FEV1), and use of oral corticosteroids. We also compared the results between patients with and without nasal polyps. RESULTS: The median of exacerbations before treatment was 3 and decreased to 0 after treatment (mean decrease of 77.4%). The median diary oral prednisone intake was 15 mg before treatment and 5 mg after treatment (mean 56% reduction). We have obtained a significant improvement in other variables: ED visits and hospitalizations, asthma control (ACT), quality of life (miniAQLQ), and lung function (FEV1). Thirty-four out of 70 patients (48.57%) fulfilled the criteria of super-responder, and 17 out of 70 (24.29%) had a complete response. More patients in the group with nasal polyps fulfilled the criteria of super-responder and complete response to mepolizumab. CONCLUSIONS: Mepolizumab is a safe and effective treatment for SEA patients, improving exacerbations, oral corticosteroid intake, asthma control, quality of life, and lung function. In patients with associated nasal polyposis, there is a statistically significant higher proportion of super-responders and complete responders.

Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart.

Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and additional, less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound down-regulation of mitochondrial components. We also describe the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced inflammatory responses. In vitro, glycolysis inhibition reduces the production of tumor necrosis factor (TNF) by memory macrophages, whereas in vivo, it produces the reversion of the memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.

Springing forward: Migrating songbirds catch up with the start of spring in North America.

In temperate regions, the annual pattern of spring onset can be envisioned as a 'green wave' of emerging vegetation that moves across continents from low to high latitudes, signifying increasing food availability for consumers. Many herbivorous migrants 'surf' such resource waves, timing their movements to exploit peak vegetation resources in early spring. Although less well studied at the individual level, secondary consumers such as insectivorous songbirds can track vegetation phenology during migration as well. We hypothesized that four species of ground-foraging songbirds in eastern North America-two warblers and two thrushes-time their spring migrations to coincide with later phases of vegetation phenology, corresponding to increased arthropod prey, and predicted they would match their migration rate to the green wave but trail behind it rather than surfing its leading edge. We further hypothesized that the rate at which spring onset progresses across the continent influences bird migration rates, such that individuals adjust migration timing within North America to phenological conditions they experience en route. To test our hypotheses, we used a continent-wide automated radio telemetry network to track individual songbirds on spring migration between the U.S. Gulf Coast region and northern locations closer to their breeding grounds. We measured vegetation phenology using two metrics of spring onset, the spring index first leaf date and the normalized difference vegetation index (NDVI), then calculated the rate and timing of spring onset relative to bird detections. All individuals arrived in the southeastern United States well after local spring onset. Counter to our expectations, we found that songbirds exhibited a 'catching up' pattern: Individuals migrated faster than the green wave of spring onset, effectively closing in on the start of spring as they approached breeding areas. While surfing of resource waves is a well-documented migration strategy for herbivorous waterfowl and ungulates, individual songbirds in our study migrated faster than the green wave and increasingly caught up to its leading edge en route. Consequently, songbirds experience a range of vegetation phenophases while migrating through North America, suggesting flexibility in their capacity to exploit variable resources in spring.

En las regiones templadas, el patrón anual de inicio de la primavera puede concebirse como una "ola verde" de vegetación emergente que se desplaza por los continentes desde las latitudes bajas a las altas, lo que significa una mayor disponibilidad de alimento para los consumidores. Muchos herbívoros migratorios "surfean" estas olas de recursos, programando sus movimientos para aprovechar los picos de vegetación a principios de primavera. Aunque menos estudiados a nivel de individuo, los consumidores secundarios, como las aves terrestres insectívoras, también pueden seguir la fenología de la vegetación durante la migración. Hipotetizamos es que cuatro especies de aves terrestres que se alimentan en el suelo en el este de Norteamérica - dos reinitas y dos zorzales - programan sus migraciones primaverales para que coincidan con las fases más tardías de la fenología de la vegetación, que se corresponden con un aumento de artrópodos, y predijimos que sincronizarian su ritmo de migración con la ola verde, pero que irían detrás de ella en lugar de surfear su borde delantero. También hipotetizamos que el ritmo al que avanza la primavera en el continente influye en las tasas de migración de las aves, de modo que los individuos ajustan la fecha de migración dentro de Norteamérica a las condiciones fenológicas que experimentan en ruta. Para comprobar nuestras hipótesis, utilizamos una red automatizada de radiotelemetría a escala continental para seguir individuos en su migración primaveral entre la región de la costa del Golfo de EEUU y las localidades septentrionales más cercanas a sus zonas de cría. Medimos la fenología de la vegetación utilizando dos métricas del inicio de la primavera, el índice de la fecha de la primera hoja primaveral y el índice de vegetación de diferencia normalizada (NDVI), luego calculamos la tasa y el tiempo de la aparaciòn de la primavera relativo a las detecciones de aves. Todos los individuos llegaron al sureste de EEUU bastante después del inicio de la primavera local. Contrario a nuestras expectativas, descubrimos que las aves terrestres mostraron un patrón de Carrera para "ponerse al día": los individuos migraron frente a la ola verde del inicio de la primavera, acercándose efectivamente al inicio de la primavera a medida que llegaban a las zonas de cría. Mientras que el surfing de las olas de recursos es una estrategia migratoria bien documentada para las aves acuáticas herbívoras y los ungulados, los individuos de aves terrestres de nuestro estudio migraron más rápido que la ola verde y alcanzaron cada vez más el borde delantero en ruta. En consecuencia, las aves terrestres experimentan una serie de fases fenológicas de la vegetación mientras migran a través de Norteamérica, lo que sugiere flexibilidad en su capacidad para explotar recursos variables en primavera.

Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation.

PURPOSE: MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (1H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare 1H-MRS of MELAS patients with controls, the 1H-MRS after glutamine supplementation in the MELAS group, and investigate the association between 1H-MRS and CSF lactate, glutamate, and glutamine levels. METHODS: We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software. RESULTS: Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003). CONCLUSION: No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and 1H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

Challenges in Psoriasis Research: A Systematic Review of Preclinical Models.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease with variable clinical presentation, multifactorial etiology and an immunogenetic basis. Several studies demonstrate that it results from a dysregulated interaction between skin keratinocytes, immune cells, and the environment that leads to a persistent inflammatory process modulated by cytokines and T cells. The development of new treatment options requires increased understanding of pathogenesis. However, the successful implementation of effective drugs requires well-characterized and highly available preclinical models that allow researchers to quickly and reproducibly determine their safety and efficacy. METHODS: A systematic search on PubMed and Scopus databases was performed and assessed to find appropriate articles about psoriasis models applying the key words previously defined. The PRISMA guidelines were employed. RESULTS: A total of 45 original articles were selected that met the selection criteria. Among these, there are articles on in vivo, in vitro, and ex vivo models, with the in vitro model being the majority due to its ease of use. Within animal models, the most widely used in recent years are chemically induced models using a compound known as imiquimod. However, the rest of the animal models used throughout the disease's research were also discussed. On the other hand, in vitro models were divided into two and three dimensions. The latter were the most used due to their similarity to human skin. Lastly, the ex vivo models were discussed, although they were the least used due to their difficulty in obtaining them. CONCLUSIONS: Therefore, this review summarizes the current preclinical models (in vivo, in vitro, and ex vivo), discussing how to develop them, their advantages, limitations, and applications. There are many challenges to improve the development of the different models. However, research in these in vitro model studies could reduce the use of animals. This is favored with the use of future technologies such as 3D bioprinting or organ-on-a-chip technologies.

What can we learn from general practitioners who left Spain? A mixed methods international study.

BACKGROUND: International mobility of health workforce affects the performance of health systems and has major relevance in human resources for health policy and planning. To date, there has been little research exploring the reasons why general practitioners (GPs) migrate. This mixed methods study aimed to investigate the reasons why Spain-trained GPs migrate and develop GP retention and recruitment health policy recommendations relevant to Spanish primary care. METHODS: The study followed an explanatory sequential mixed methods study design combining surveys with semi-structured interviews and focus groups with GPs who qualified in Spain and were living overseas at the time of the study. The survey data examined the reasons why GPs left Spain and their intention to return and were analysed using quantitative methods. The transcripts from interviews and focus groups centred on GPs' insights to enhance retention and recruitment in Spain and were analysed thematically. RESULTS: The survey had 158 respondents with an estimated 25.4% response rate. Insufficient salary (75.3%), job insecurity and temporality (67.7%), excessive workload (67.7%), poor primary care governance (55.7%), lack of flexibility in the workplace (43.7%) and personal circumstances (43.7%) were the main reasons for leaving Spain. Almost half of the respondents (48.7%) would consider returning to Spanish general practice if their working conditions improved. Interviews and focus groups with respondents (n = 24) pointed towards the need to improve the quality of employment contracts, working conditions, opportunities for professional development, and governance in primary care for effective retention and recruitment. CONCLUSION: Efforts to improve GP retention and recruitment in Spain should focus on salary, job security, flexibility, protected workload, professional development, and governance. We draw ten GP retention and recruitment recommendations expected to inform urgent policy action to tackle existing and predicted GP shortages in Spanish primary care.

Radiological insights into rheumatoid meningitis - a rare central nervous system manifestation of rheumatoid arthritis: a retrospective review of six cases.

BACKGROUND: The objective is to analyze and review the clinical, laboratory, and neuroimaging characteristics of rheumatoid meningitis (RM) in six patients with known rheumatoid arthritis (RA). METHODS: We performed a retrospective review of patients diagnosed with RM from August 2012 to June 2023. To identify the cases, we used medical term search engines and the hospital´s radiology case database. Clinical information and laboratory findings were gathered from the medical records. A neuroradiologist with five years of experience reviewed and analyzed the RM to determine the characteristics findings of RM. RESULTS: Six patients with RM are included. Seizures along with headaches were among the clinical signs that were documented. All the patients had high levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptides (ACPA) in the peripheral blood. Biopsy in two cases confirmed typical rheumatoid nodules. Leptomeningeal enhancement was found bilaterally in all cases and was predominantly found in the frontoparietal region. "Mismatch DWI/FLAIR" was found in five patients. Bilateral subdural collections could be found in two patients. Brain PET scan revealed increased metabolism in two cases. CONCLUSION: Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA) with challenging clinical diagnosis due to non-specific symptoms. This study highlights the importance of MR in detecting characteristic neuroimaging patterns, including "mismatch DWI/FLAIR", to aid in early diagnosis. Increased awareness of this condition may facilitate timely intervention and improve prognosis. These results still need to be verified by large studies.

How pollen and ovule development underlay dioecy in Chloroluma gonocarpa (Sapotaceae).

Previous studies have determined that Chloroluma gonocarpa (Sapotaceae), is a species that has cryptic dioecy. This type of sexual system is characterized by flowers that are morphologically perfect (both sexual whorls are present) but functionally pistillate or staminate (in each type of flower one of the sexual whorls is non-functional). In C. gonocarpa the pistillate flowers present well-developed stigma, functional ovules, and staminodes, while the staminate flowers present a poorly developed stigma, collapsed ovules, and pollen-producing anthers. In angiosperms, the abortion of sexual organs can occur at different stages of development (from pre-meiosis to post-meiosis), that is why we conducted an anatomical analysis of both flower types at various developmental stages. Using light microscopy, we described the processes of sporogenesis and gametogenesis to establish when the staminate flowers lose their pistillate function. To achieve this, we collected, fixed, and processed the flowers following conventional anatomical techniques for observation under a light microscope. Our findings reveal that pollen development occurs only in staminate flowers, while ovule development begins in both types of flowers but ceases in staminate flowers due to post-meiosis abortion. In contrast, normal development continues in pistillate flowers. These results suggest that dioecy in C. gonocarpa may have arisen from a gynodioecious pathway.

Inequality in mortality between Black and White Americans by age, place, and cause and in comparison to Europe, 1990 to 2018.

Although there is a large gap between Black and White American life expectancies, the gap fell 48.9% between 1990 and 2018, mainly due to mortality declines among Black Americans. We examine age-specific mortality trends and racial gaps in life expectancy in high- and low-income US areas and with reference to six European countries. Inequalities in life expectancy are starker in the United States than in Europe. In 1990, White Americans and Europeans in high-income areas had similar overall life expectancy, while life expectancy for White Americans in low-income areas was lower. However, since then, even high-income White Americans have lost ground relative to Europeans. Meanwhile, the gap in life expectancy between Black Americans and Europeans decreased by 8.3%. Black American life expectancy increased more than White American life expectancy in all US areas, but improvements in lower-income areas had the greatest impact on the racial life expectancy gap. The causes that contributed the most to Black Americans' mortality reductions included cancer, homicide, HIV, and causes originating in the fetal or infant period. Life expectancy for both Black and White Americans plateaued or slightly declined after 2012, but this stalling was most evident among Black Americans even prior to the COVID-19 pandemic. If improvements had continued at the 1990 to 2012 rate, the racial gap in life expectancy would have closed by 2036. European life expectancy also stalled after 2014. Still, the comparison with Europe suggests that mortality rates of both Black and White Americans could fall much further across all ages and in both high-income and low-income areas.

New insights about the toxicity of 2,4-D: Gene expression analysis reveals modulation on several subcellular responses in Chironomus riparius.

Herbicides are the main class of pesticides applied in crops and are capable of polluting the surrounding freshwater system; thus, understanding their impact on non-target species, whose mechanism of action is not described, helps to elucidate the real risks of these pollutants to the environment. 2,4-dichlorophenoxyacetic acid (2,4-D) is frequently detected in water and, due to its persistence, poses a risk to wildlife. In this way, the present work aimed to describe the implication of exposure to concentrations of 2,4-D already reported in aquatic environments in several physiological mechanisms of C. riparius at molecular and biochemical levels. To achieve this, bioassays were conducted with fourth instar larvae exposed to three concentrations of 2,4-D (0.1, 1.0, and 7.5 µg L-1). Larvae were collected after 24 and 96 h of exposure, and the expression of 42 genes, related to six subcellular mechanisms, was assessed by Real-Time PCR (RT-PCR). Besides, the activity of the enzymes catalase (CAT), glutathione S-transferase (GST), and acetylcholinesterase (AChE) was determined. The main metabolic route altered after exposure to 2,4-D was the endocrine system (mainly related to 20-hydroxyecdysone and juvenile hormone), confirming its endocrine disruptor potential. Four of the eleven stress response genes studied were down-regulated, and later exposure modulated DNA-repair genes suggesting genotoxic capacity. Moreover, only one gene from each detoxification phase was modulated at short exposure to 1.0 µg L-1. The molecular responses were not dose-dependent, and some early responses were not preserved after 96 h, indicating a transient response to the herbicide. Exposure to 2,4-D did not alter the activity of CAT, GST, and AChE enzymes. The responses described in this study reveal new mechanistic pathways of toxicity for 2,4-D in non-target organisms and highlight potential ecological consequences for chironomids in aquatic systems at the edges of agricultural fields.

Exploring value creation in a virtual community of practice: a framework analysis for knowledge and skills development among primary care professionals.

BACKGROUND: Healthcare professionals traditional education reflects constraints to face the complex needs of people with chronic diseases in primary care settings. Since more innovative and practical solutions are required, Virtual Community of Practices (vCoP) seem to better respond to learning updates, improving professional and organizational knowledge. However, little is known about the value created in vCoPs as social learning environments. The objective of this project was to explore the value creation process of a gamified vCoP ("e-mpodera vCoP") aimed at improving the knowledge and attitudes of primary healthcare professionals (PCPs) (nurses and general practitioners) to the empowerment of people with chronic conditions. METHODS: A framework analysis assessed the value creation process using a mixed methods approach. The framework provided awareness about knowledge and usefulness in a learning community through five cycles: (1) immediate value, (2) potential value, (3) applied value, (4) realized value, and (5) reframing value. Quantitative data included vCoP analytics such as logins, contributions, points, badges, and performance metrics. Qualitative data consisted of PCPs' forum contributions from Madrid, Catalonia, and Canary Islands over 14 months. RESULTS: A total of 185 PCPs had access to the e-mpodera vCoPs. The vCoP showed the dynamic participation of 146 PCPs, along 63 content activities posted, including a total of 3,571 contributions (including text, images, links to webpages, and other files). Regarding the value creation process, the e-mpodera vCoP seems to encompass a broad spectrum of value cycles, with indicators mostly related to cycle 1 (immediate value - activities and interactions) and cycle 2 (potential value - knowledge capital); and to a lesser extent for cycle 3 (applied value - changes in practice) and for cycle 4 (realized value - performance improvement). The presence of indicators related to cycle 5 (reframing value), was minimal, due to few individual redefinitions of success. CONCLUSION: To reach a wider range of value possibilities, a combination of learning objectives, competence framework, challenged-based gamified platform, and pathway model of skill development seems crucial. However, additional research is required to gain clearer insights into organizational values, professionals' lifelong educational needs in healthcare, and the long-term sustainability of performance improvement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02757781. Registered on 02/05/2016.

Medical deserts in Spain-Insights from an international project.

INTRODUCTION: Medical deserts are a growing phenomenon across many European countries. They are usually defined as (i) rural areas, (ii) underserved areas or (iii) by applying a measure of distance/time to a facility or a combination of the three characteristics. The objective was to define medical deserts in Spain as well as map their driving factors and approaches to mitigate them. METHODS: A mixed methods approach was applied following the project "A Roadmap out of medical deserts into supportive health workforce initiatives and policies" work plan. It included the following elements: (i) a scoping literature review; (ii) a questionnaire survey; (iii) national stakeholders' workshop; (iv) a descriptive case study on medical deserts in Spain. RESULTS: Medical deserts in Spain exist in the form of mostly rural areas with limited access to health care. The main challenge in their identification and monitoring is local data availability. Diversity of both factors contributing to medical deserts and solutions applied to eliminate or mitigate them can be identified in Spain. They can be related to demand for or supply of health care services. More national data, analyses and/or initiatives seem to be focused on the health care supply dimension. CONCLUSIONS: Addressing medical deserts in Spain requires a comprehensive and multidimensional approach. Effective policies are needed to address both the medical staff education and planning system, working conditions, as well as more intersectoral approach to the population health management.

Post-transcriptional control of executioner caspases by RNA-binding proteins.

Caspases are key components of apoptotic pathways. Regulation of caspases occurs at several levels, including transcription, proteolytic processing, inhibition of enzymatic function, and protein degradation. In contrast, little is known about the extent of post-transcriptional control of caspases. Here, we describe four conserved RNA-binding proteins (RBPs)-PUF-8, MEX-3, GLD-1, and CGH-1-that sequentially repress the CED-3 caspase in distinct regions of the Caenorhabditis elegans germline. We demonstrate that GLD-1 represses ced-3 mRNA translation via two binding sites in its 3' untranslated region (UTR), thereby ensuring a dual control of unwanted cell death: at the level of p53/CEP-1 and at the executioner caspase level. Moreover, we identified seven RBPs that regulate human caspase-3 expression and/or activation, including human PUF-8, GLD-1, and CGH-1 homologs PUM1, QKI, and DDX6. Given the presence of unusually long executioner caspase 3' UTRs in many metazoans, translational control of executioner caspases by RBPs might be a strategy used widely across the animal kingdom to control apoptosis.

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.