Low-Chloride Diet Prevents the Development of Arterial Hypertension and Protects Kidney Function in Angiotensin II-Infused Mice.

INTRODUCTION: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl- while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. METHODS: C56BL/6J mice fed with standard Cl- diet or a low-Cl- diet (equimolar substitution of Cl- by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl- diet. RESULTS: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl- diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl- diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl- diet and infused with AngII presented a similar contractile response. CONCLUSION: We conclude that the reduction in dietary Cl- as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.

Lamellar Ionenes with Highly Dissociative, Anionic Channels Provide Lower Barriers for Cation Transport.

Solid polymer electrolytes have the potential to enable safer and more energy-dense batteries; however, a deeper understanding of their ion conduction mechanisms, and how they can be optimized by molecular design, is needed to realize this goal. Here, we investigate the impact of anion dissociation energy on ion conduction in solid polymer electrolytes via a novel class of ionenes prepared using acyclic diene metathesis (ADMET) polymerization of highly dissociative, liquid crystalline fluorinated aryl sulfonimide-tagged ("FAST") anion monomers. These ionenes with various cations (Li+, Na+, K+, and Cs+) form well-ordered lamellae that are thermally stable up to 180 °C and feature domain spacings that correlate with cation size, providing channels lined with dissociative FAST anions. Electrochemical impedance spectroscopy (EIS) and differential scanning calorimetry (DSC) experiments, along with nudged elastic band (NEB) calculations, suggest that cation motion in these materials operates via an ion-hopping mechanism. The activation energy for Li+ conduction is 59 kJ/mol, which is among the lowest for systems that are proposed to operate via an ion conduction mechanism that is decoupled from polymer segmental motion. Moreover, the addition of a cation-coordinating solvent to these materials led to a >1000-fold increase in ionic conductivity without detectable disruption of the lamellar structure, suggesting selective solvation of the lamellar ion channels. This work demonstrates that molecular design can facilitate controlled formation of dissociative anionic channels that translate to significant enhancements in ion conduction in solid polymer electrolytes.

High-CO2 Levels Rather than Acidification Restrict Emiliania huxleyi Growth and Performance.

The coccolithophore Emiliania huxleyi shows a variety of responses to ocean acidification (OA) and to high-CO2 concentrations, but there is still controversy on differentiating between these two factors when using different strains and culture methods. A heavily calcified type A strain isolated from the Norwegian Sea was selected and batch cultured in order to understand whether acclimation to OA was mediated mainly by CO2 or H+, and how it impacted cell growth performance, calcification, and physiological stress management. Emiliania huxleyi responded differently to each acidification method. CO2-enriched aeration (1200 µatm, pH 7.62) induced a negative effect on the cells when compared to acidification caused by decreasing pH alone (pH 7.60). The growth rates of the coccolithophore were more negatively affected by high pCO2 than by low pH without CO2 enrichment with respect to the control (400 µatm, pH 8.1). High CO2 also affected cell viability and promoted the accumulation of reactive oxygen species (ROS), which was not observed under low pH. This suggests a possible metabolic imbalance induced by high CO2 alone. In contrast, the affinity for carbon uptake was negatively affected by both low pH and high CO2. Photochemistry was only marginally affected by either acidification method when analysed by PAM fluorometry. The POC and PIC cellular quotas and the PIC:POC ratio shifted along the different phases of the cultures; consequently, calcification did not follow the same pattern observed in cell stress and growth performance. Specifically, acidification by HCl addition caused a higher proportion of severely deformed coccoliths, than CO2 enrichment. These results highlight the capacity of CO2 rather than acidification itself to generate metabolic stress, not reducing calcification.

Effects of elevated CO2 on growth, calcification, and spectral dependence of photoinhibition in the coccolithophore Emiliania huxleyi (Prymnesiophyceae)1.

We studied the effects of elevated CO2 concentrations on cell growth, calcification, and spectral variation in the sensitivity of photosynthesis to inhibition by solar radiation in the globally important coccolithophore Emiliania huxleyi. Growth rates and chlorophyll a content per cell showed no significant differences between elevated (800 ppmv) and ambient (400 ppmv) CO2 conditions. However, the production of organic carbon and the cell quotas for both carbon and nitrogen, increased under elevated CO2 conditions, whilst particulate inorganic carbon production rates decreased under the same conditions. Biometric analyses of cells showed that coccoliths only presented significant differences due to treatments in the central area width. Most importantly, the size of the coccosphere decreased under elevated CO2 conditions. The susceptibility of photosynthesis to inhibition by ultraviolet radiation (UVR) was estimated using biological weighting functions (BWFs) and a model that predicts photosynthesis under photosynthetically active radiation and UVR exposures. BWF results demonstrated that the sensitivity of photosynthesis to UVR was not significantly different between E. huxleyi cells grown under elevated and present CO2 concentrations. We propose that the acclimation to elevated CO2 conditions involves a physiological mechanism of regulation and allocation of energy and metabolites in the cell, which is also responsible for altering the sensitivity to UVR. In coccolithophores, this mechanism might be affected by the decrease in the calcification rates.

Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury.

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.

The mental health continuum-short form: The structure and application for cross-cultural studies-A 38 nation study.

OBJECTIVE: The Mental Health Continuum-Short Form (MHC-SF) is a brief scale measuring positive human functioning. The study aimed to examine the factor structure and to explore the cross-cultural utility of the MHC-SF using bifactor models and exploratory structural equation modelling. METHOD: Using multigroup confirmatory analysis (MGCFA) we examined the measurement invariance of the MHC-SF in 38 countries (university students, N = 8,066; 61.73% women, mean age 21.55 years). RESULTS: MGCFA supported the cross-cultural replicability of a bifactor structure and a metric level of invariance between student samples. The average proportion of variance explained by the general factor was high (ECV = .66), suggesting that the three aspects of mental health (emotional, social, and psychological well-being) can be treated as a single dimension of well-being. CONCLUSION: The metric level of invariance offers the possibility of comparing correlates and predictors of positive mental functioning across countries; however, the comparison of the levels of mental health across countries is not possible due to lack of scalar invariance. Our study has preliminary character and could serve as an initial assessment of the structure of the MHC-SF across different cultural settings. Further studies on general populations are required for extending our findings.

Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells.

Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8;21) that fuses RUNX1 and ETO genes. We report here that Wnt/ß-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that ß-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction. Notably, long-term treatment of cells with Wnt3a induces the generation a frequent RUNX1-ETO translocation event. Thus, Wnt/ß-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/development of leukemia.

Experience with the Nuss technique for the treatment of Pectus Excavatum in Spanish Thoracic Surgery Departments.

INTRODUCTION: Although the Nuss technique revolutionized the surgical treatment of pectus excavatum, its use has not become widespread in our country. The aim of this study was to analyze the current use of this technique in a sample of Thoracic Surgery Departments in Spain. METHODS: Observational rectrospective multicentric study analyzing the main epidemiological aspects and clinical results of ten years experience using the Nuss technique. RESULTS: Between 2001 and 2010 a total of 149 patients were operated on (mean age 21.2 years), 74% male. Initial aesthetic results were excellent or good in 93.2%, mild in 4.1% and bad in 2.7%. After initial surgery there were complications in 45 patients (30.6%). The most frequent were wound seroma, bar displacement, stabilizer break, pneumothorax, haemothorax, wound infection, pneumonia, pericarditis and cardiac tamponade that required urgent bar removal. Postoperative pain appeared in all patients. In 3 cases (2%) it was so intense that it required bar removal. After a mean follow-up of 39.2 months, bar removal had been performed in 72 patients (49%), being difficult in 5 cases (7%). After a 1.6 year follow-up period good results persisted in 145 patients (98.7%). CONCLUSION: Nuss technique in adults has had good results in Spanish Thoracic Surgery Departments, however its use has not been generalized. The risk of complications must be taken into account and its indication must be properly evaluated. The possibility of previous conservative treatment is being analyzed in several departments at present.

(E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists.

A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.

Alcohol use among children and adolescents with chronic pain. Scoping review.

AIM: To examine and map alcohol consumption in children and adolescents with chronic pain (CP). METHOD: A scoping review of international databases (CINAHL, WOS, PubMed, PsycINFO, Scopus, Embase, and MEDLINE) and grey literature was conducted between September 2022 and February 2023. Documents addressing the relationship between alcohol consumption and CP in children and adolescents, published in English and Spanish between 2012 and 2023, were included. Those papers with a population suffering from CP derived from neurodegenerative diseases, chronic infectious diseases or cognitive impairment were excluded. We assessed the level of evidence (LE) and the degree of recommendation (DR) of the studies included in accordance with the Scottish Intercollegiate Guidelines Network. Finally, 11 documents were considered out of the 479 reviewed. RESULTS: The relationship between substance consumption and CP in adolescents is a scarcely investigated topic. While there is a trend towards lower rates of alcohol consumption in youth with pain, there is evidence suggesting an association, particularly in cases of intense pain. The use of various substances, both legal and illegal, for pain management underscores the importance of comprehensively addressing this phenomenon in this population. CONCLUSIONS: Further research is needed to assess the relationship between alcohol consumption in children and adolescents with CP.

Nicaraguan surgical and anesthesia infrastructure: survey of Ministry of Health hospitals.

BACKGROUND: Developing countries have surgical and anesthesia needs that are unique and disparate compared to those of developed countries. However, the extent of these disparities and the specific country-based needs are, for the most part, unknown. The goal of this study was to assess the surgical capacity of Nicaragua's public hospitals as part of a multinational study. METHODS: A survey adapted from the World Health Organization Tool for Situational Analysis to Assess Emergency and Essential Surgical care was used to study 28 primary, departmental, regional, and national referral hospitals within the Ministry of Health system. Data were obtained at the national and hospital levels via interviews with administrators and surgical and anesthesia chiefs of services. RESULTS: There are 580 obstetrician/gynecologists (OB/GYN), 1,040 non-OB/GYN surgeons, and 250 anesthesiologists in Nicaragua. Primary, departmental, regional, and national referral hospitals perform an annual average of 374, 4,610, 7,270, and 7,776 surgeries, respectively. All but six primary hospitals were able to perform surgeries. Four hospitals reported routine water shortages. Routine medication shortages were reported in 11 hospitals. Eight primary hospitals lacked blood banks on site. Of 28 hospitals, 22 reported visits from short-term surgical brigades within the past 2 years. Measurement of surgical outcomes was inconsistent across hospitals. CONCLUSIONS: Surgical capacity varies by hospital type, with primary hospitals having the least surgical capacity and surgical volume. Departmental, regional, and national referral hospitals have adequate surgical capacity. Surgical subspecialty care appears to be insufficient, as evidenced by the large presence of NGOs and other surgical brigade teams filling this gap.

Reduced gravity effects on gait coordinative structures.

Humans have stepped on the Lunar surface for less than 80 h of Extravehicular Activity, providing a narrow understanding of Lunar gait patterns. NASA's Human-crewed Artemis missions are quickly approaching; understanding how fractional gravity affects gait patterns will be critical for the Moon's and Mars' long-term habitation. This study examined gait patterns under 1.0 g (Earth), simulated 0.38 g (Martian), and 0.17 g (Lunar). Participants walked and ran on a treadmill supported by ARGOS (Active Response Gravity Offload System), simulating fractional gravity. Vicon motion capture data and principal component analysis software were used to capture and quantify coordinated gait structures. There were found to be significant differences (p < 0.05) in the coordinative gait structures for ambulation between fractional gravity conditions. Additionally, there were significantly higher asymmetric gait components for Lunar conditions. Finally, a skipping coordinative structure was identified within Lunar and Martian running.

Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors.

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

Discovery and Evaluation of Novel Angular Fused Pyridoquinazolinonecarboxamides as RNA Polymerase I Inhibitors.

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.

Fundamental Science and Engineering Questions in Planetary Cave Exploration.

Nearly half a century ago, two papers postulated the likelihood of lunar lava tube caves using mathematical models. Today, armed with an array of orbiting and fly-by satellites and survey instrumentation, we have now acquired cave data across our solar system-including the identification of potential cave entrances on the Moon, Mars, and at least nine other planetary bodies. These discoveries gave rise to the study of planetary caves. To help advance this field, we leveraged the expertise of an interdisciplinary group to identify a strategy to explore caves beyond Earth. Focusing primarily on astrobiology, the cave environment, geology, robotics, instrumentation, and human exploration, our goal was to produce a framework to guide this subdiscipline through at least the next decade. To do this, we first assembled a list of 198 science and engineering questions. Then, through a series of social surveys, 114 scientists and engineers winnowed down the list to the top 53 highest priority questions. This exercise resulted in identifying emerging and crucial research areas that require robust development to ultimately support a robotic mission to a planetary cave-principally the Moon and/or Mars. With the necessary financial investment and institutional support, the research and technological development required to achieve these necessary advancements over the next decade are attainable. Subsequently, we will be positioned to robotically examine lunar caves and search for evidence of life within Martian caves; in turn, this will set the stage for human exploration and potential habitation of both the lunar and Martian subsurface.

An Animation- Versus Text-Based Computer-Tailored Game Intervention to Prevent Alcohol Consumption and Binge Drinking in Adolescents: Study Protocol.

The purpose of this paper is to describe the protocol for the design, implementation, and evaluation of an animation- versus text-based computer tailoring game intervention aimed at preventing alcohol consumption and binge drinking (BD) in adolescents. A cluster-randomized controlled trial (CRCT) is carried out in students aged 14-19 enrolled in 24 high schools from Andalusia (Spain), which are randomized either to experimental (EC-1, EC-2) or waiting-list control conditions (CC). EC-1 receives an online intervention (Alerta Alcohol) with personalized health advice, using textual feedback and several gamification techniques. EC-2 receives an improved version (Alerta Alcohol 2.0) using animated videos and new gamification strategies. Both programs consist of nine sessions (seven taking place at high school and two at home): session 1 or baseline, sessions 2 and 3 that provide tailored advice based on the I-Change Model; sessions 4, 5, 7, and 8 are booster sessions, and sessions 6 and 9 are follow-up questionnaires at six and twelve months. The CC completes the baseline and the evaluation questionnaires. The primary outcome is BD within 30 days before post-test evaluations, and as secondary outcomes we assess other patterns of alcohol use. The findings should help the development of future alcohol drinking prevention interventions in adolescents.

Early life trophodynamic influence on daily growth patterns of the Alboran Sea sardine (Sardina pilchardus) from two distinct nursery habitats (bays of málaga and almería) in the western Mediterranean Sea.

The Alborán Sea sardine (Sardina pilchardus) is the most abundant small pelagic fish in the Mediterranean Sea. Along the northern coast of the Alborán Sea, Málaga and Almería Bay are two important nursery grounds with contrasting oceanographic characteristics. Post-larval stages of S. pilchardus were collected during the late autumn and late winter along with the mesozooplankton community. We examined the influence of feeding behavior on larval growth using environmental variables, daily growth metrics, otolith biometry, stable isotope analysis and trophodynamics. Trophic positions were calculated using mesoozooplankton as potential prey for S. pilchardus. During both seasons, we observed faster growth in larger otoliths that also corresponded to higher trophic positions. Our results indicate that the isotopic signature of larvae is highly influenced by the mesozooplankton community structure. Moreover, the trophic variables showed a significant linear relationship with the estimated ages for all larvae indicating dietary changes throughout ontogenic development.

Occurrence of recently diagnosed atrial fibrillation in the immediate postoperative period of myocardial revascularization surgery. Although common, a devalued complication.

Atrial fibrillation (AF) is the most common arrhythmia in the postoperative period of cardiac surgery, with a prevalence between 15-40% after coronary artery bypass surgery (CABG). Several strategies have been tested for the prevention and management of AF postoperatively. Previous studies and analysis of records have shown higher rates of hospitalization and clinical outcomes associated with this entity, including increased mortality in the short- and long-term. This perspective reviews the topic, and offers recommendations for the management of this arrhythmia in the postoperative period of CABG, with a special focus on anticoagulation strategies.

Assessment of patients with acute respiratory symptoms during the COVID-19 pandemic by Telemedicine: clinical features and impact on referral.

OBJECTIVE: To characterize variables associated with referral to the emergency department following Telemedicine consultation during the COVID-19 pandemic. METHODS: Cross-sectional retrospective study conducted between March and May 2020, with a sample of 500 adult patients. The inclusion criterion was the manifestation of respiratory symptoms, regardless of type. RESULTS: The mean age of patients was 34.7±10.5 years, and 59% were women. Most patients (62.6%) perceived their own health status as malaise and some (41.4%) self-diagnosed COVID-19. Cough (74.4%), rhinorrhea (65.6%), sore throat (38.6%) and sneezing (20.6%) were the most common infection-related symptoms. Overall, 29.4% and 16% of patients reported dyspnea and chest pain, respectively. The Roth score was calculated for a sizeable number of patients (67.6%) and was normal, moderately altered or severely altered in 83.5%, 10.7% and 5.6% of patients, respectively. The percentage of suspected COVID-19 cases was 67.6%. Of these, 75% were managed remotely and only one quarter referred for emergency assessment. CONCLUSION: Telemedicine assessment is associated with reclassification of patient's subjective impression, better inspection of coronavirus disease 2019 and identification of risk patients. Referral is therefore optimized to avoid inappropriate in-person assessment, and low-risk patients can be properly guided. Telemedicine should be implemented in the health care system as a cost-effective strategy for initial assessment of acute patients.