Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis.

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from healthy controls and SSc patients stimulated by soluble factors that drive inflammation and fibrosis in SSc deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

Cumulative epinephrine dose during cardiac arrest and neurologic outcome after extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Epinephrine is recommended without an apparent ceiling dosage during cardiac arrest. However, excessive alpha- and beta-adrenergic stimulation may contribute to unnecessarily high aortic afterload, promote post-arrest myocardial dysfunction, and result in cerebral microvascular insufficiency in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: This was a retrospective cohort study of adults (≥ 18 years) who received ECPR at large academic ECMO center from 2018 to 2022. Patients were grouped based on the amount of epinephrine given during cardiac arrest into low (≤ 3 mg) and high (> 3 mg) groups. The primary endpoint was neurologic outcome at hospital discharge, defined by cerebral performance category (CPC). Multivariable logistic regression was used to assess the relationship between cumulative epinephrine dosage during arrest and neurologic outcome. RESULTS: Among 51 included ECPR cases, the median age of patients was 60 years, and 55% were male. The mean cumulative epinephrine dose administered during arrest was 6.2 mg but ranged from 0 to 24 mg. There were 18 patients in the low-dose (≤ 3 mg) and 25 patients in the high-dose (> 3 mg) epinephrine groups. Favorable neurologic outcome at discharge was significantly greater in the low-dose (55%) compared to the high-dose (24%) group (p = 0.025). After adjusting for age, those who received higher doses of epinephrine during the arrest were more likely to have unfavorable neurologic outcomes at hospital discharge (odds ratio 4.6, 95% CI 1.3, 18.0, p = 0.017). CONCLUSION: After adjusting for age, cumulative epinephrine doses above 3 mg during cardiac arrest may be associated with unfavorable neurologic outcomes after ECPR and require further investigation.

An update of murine models and their methodologies in immune-mediated joint damage and pain research.

Murine models have played an indispensable role in the understanding of rheumatic and musculoskeletal disorders (RMD), elucidating the genetic, endocrine and biomechanical pathways involved in joint pathology and associated pain. To date, the available models in RMD can be classified as induced or spontaneous, both incorporating transgenic alternatives that improve specific insights. It is worth noting that the selection of the most appropriate model together with the evaluation of their specific characteristics and technical capabilities are crucial when designing the experiments. Furthermore, it is also imperative to consistently adhere to the ethical standards concerning animal experimentation. Recognizing the inherent limitation that any model can entirely encapsulates the complexity of the pathophysiology of these conditions, the aim of this review is to provide an updated overview on the methodology of current murine models in major arthropathies and their immune-mediated pathways, addressing to basic, translational and pharmacological research in joint damage and pain.

A Modular Implementation to Handle and Benchmark Drift Correction for High-Density Extracellular Recordings.

High-density neural devices are now offering the possibility to record from neuronal populations in vivo at unprecedented scale. However, the mechanical drifts often observed in these recordings are currently a major issue for "spike sorting," an essential analysis step to identify the activity of single neurons from extracellular signals. Although several strategies have been proposed to compensate for such drifts, the lack of proper benchmarks makes it hard to assess the quality and effectiveness of motion correction. In this paper, we present a benchmark study to precisely and quantitatively evaluate the performance of several state-of-the-art motion correction algorithms introduced in the literature. Using simulated recordings with induced drifts, we dissect the origins of the errors performed while applying a motion correction algorithm as a preprocessing step in the spike sorting pipeline. We show how important it is to properly estimate the positions of the neurons from extracellular traces in order to correctly estimate the probe motion, compare several interpolation procedures, and highlight what are the current limits for motion correction approaches.

Sustainable proteins from wine industrial by-product: Ultrasound-assisted extraction, fractionation, and characterization.

Plant proteins are increasingly being used in the food industry due to their sustainability. They can be isolated from food industry waste and converted into value-added ingredients, promoting a more circular economy. In this study, ultrasound-assisted alkaline extraction (UAAE) was optimized to maximize the extraction yield and purity of protein ingredients from grapeseeds. Grapeseed protein was extracted using UAAE under different pH (9-11), temperature (20-50 °C), sonication time (15-45 min), and solid/solvent ratio (10-20 mL/g) conditions. The structural and functional attributes of grapeseed protein and its major fractions (albumins and glutelins) were investigated and compared. The albumin fractions had higher solubilities, emulsifying properties, and in vitro digestibilities but lower fluid binding capacities and thermal stability than the UAAE and glutelin fraction. These findings have the potential to boost our understanding of the structural and functional characteristics of grapeseed proteins, thereby increasing their potential applications in the food and other industries.

Clove Essential Oil: Chemical Profile, Biological Activities, Encapsulation Strategies, and Food Applications.

Plants have proven to be important sources for discovering new compounds that are useful in the treatment of various diseases due to their phytoconstituents. Clove (Syzygium aromaticum L.), an aromatic plant widely cultivated around the world, has been traditionally used for food preservation and medicinal purposes. In particular, clove essential oil (CEO) has attracted attention for containing various bioactive compounds, such as phenolics (eugenol and eugenol acetate), terpenes (ß-caryophyllene and α-humulene), and hydrocarbons. These constituents have found applications in cosmetics, food, and medicine industries due to their bioactivity. Pharmacologically, CEO has been tested against a variety of parasites and pathogenic microorganisms, demonstrating antibacterial and antifungal properties. Additionally, many studies have also demonstrated the analgesic, antioxidant, anticancer, antiseptic, and anti-inflammatory effects of this essential oil. However, CEO could degrade for different reasons, impacting its quality and bioactivity. To address this challenge, encapsulation is viewed as a promising strategy that could prolong the shelf life of CEO, improving its physicochemical stability and application in various areas. This review examines the phytochemical composition and biological activities of CEO and its constituents, as well as extraction methods to obtain it. Moreover, encapsulation strategies for CEO and numerous applications in different food fields are also highlighted.

Temporal regularities shape perceptual decisions and striatal dopamine signals.

Perceptual decisions should depend on sensory evidence. However, such decisions are also influenced by past choices and outcomes. These choice history biases may reflect advantageous strategies to exploit temporal regularities of natural environments. However, it is unclear whether and how observers can adapt their choice history biases to different temporal regularities, to exploit the multitude of temporal correlations that exist in nature. Here, we show that male mice adapt their perceptual choice history biases to different temporal regularities of visual stimuli. This adaptation was slow, evolving over hundreds of trials across several days. It occurred alongside a fast non-adaptive choice history bias, limited to a few trials. Both fast and slow trial history effects are well captured by a normative reinforcement learning algorithm with multi-trial belief states, comprising both current trial sensory and previous trial memory states. We demonstrate that dorsal striatal dopamine tracks predictions of the model and behavior, suggesting that striatal dopamine reports reward predictions associated with adaptive choice history biases. Our results reveal the adaptive nature of perceptual choice history biases and shed light on their underlying computational principles and neural correlates.

State-dependent alteration of respiration in a rat model of Parkinson's disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. Besides major deficits in motor coordination, patients may also display sensory and cognitive impairments, which are often overlooked despite being inherently part of the PD symptomatology. Amongst those symptoms, respiration, a key mechanism involved in the regulation of multiple physiological and neuronal processes, appears to be altered. Importantly, breathing patterns are highly correlated with the animal's behavioral states. This raises the question of the potential impact of behavioral state on respiration deficits in PD. To answer this question, we first characterized the respiratory parameters in a neurotoxin-induced rat model of PD (6-OHDA) across three different vigilance states: sleep, quiet waking and exploration. We noted a significantly higher respiratory frequency in 6-OHDA rats during quiet waking compared to Sham rats. A higher respiratory amplitude was also observed in 6-OHDA rats during both quiet waking and exploration. No effect of the treatment was noted during sleep. Given the relation between respiration and olfaction and the presence of olfactory deficits in PD patients, we then investigated the odor-evoked sniffing response in PD rats, using an odor habituation/cross-habituation paradigm. No substantial differences were observed in olfactory abilities between the two groups, as assessed through sniffing frequency. These results corroborate the hypothesis that respiratory impairments in 6-OHDA rats are vigilance-dependent. Our results also shed light on the importance of considering the behavioral state as an impacting factor when analyzing respiration.

Understanding Team Dynamics and Culture of Safety Using Video Reflexive Ethnography during Real-Time Emergent Intubation.

Rationale: Endotracheal intubation is the third most common bedside procedure in U.S. hospitals. In over 40% of intubations, preventable complications attributable to human factors occur. A better understanding of team dynamics during intubation may improve patient safety. Objectives: To explore team dynamics and safety-related actions during emergent endotracheal intubations in the emergency department and intensive care unit and to engage members of the care team in reflection for process improvement through a novel video-based team debriefing technique. Methods: Video-reflexive ethnography involves in situ video recording and reflexive discussions with practitioners to scrutinize behaviors and to identify opportunities for improvement. In this study, real-time intubations were recorded in the emergency department and intensive care unit at Mayo Clinic Rochester, and facilitated video-reflexive sessions were conducted with the multidisciplinary procedural teams. Themes about team dynamics and safety-related action were identified inductively from transcriptions of recorded sessions. Results: Between December 2022 and January 2023, eight video-reflexive sessions were conducted with a total of 78 participants. Multidisciplinary members included nurses (n = 23), respiratory therapists (n = 16), pharmacists (n = 7), advanced practitioners (n = 5), and physicians (n = 26). In video-reflexive discussions, major safety gaps were identified and several solutions were proposed related to the use of a multidisciplinary intubation checklist, standardized communication and team positioning, developing a culture of safety, and routinely debriefing after the procedure. Conclusions: The findings of this study may inform the development of a team supervision model for emergent endotracheal intubations. This approach could integrate key components such as a multidisciplinary intubation checklist, standardized communication and team positioning, a culture of safety, and debriefing as part of the procedure itself.

Experience with tafamidis in peritoneal dialysis for a patient diagnosed with transthyretin cardiac amyloidosis.

Cardiac amyloidosis is a cardiomyopathy resulting from the extracellular deposition of proteins such as transthyretin (TTR). We present the case of a 72-year-old male with hereditary cardiac amyloidosis. After confirming the diagnosis, tafamidis, a TTR stabilizer, was administered. Remarkably, tafamidis, when coupled with peritoneal dialysis for chronic kidney disease, maintained stability in both cardiac and renal functions. Previous studies have demonstrated the efficacy of tafamidis in reducing all-cause mortality and cardiovascular hospitalizations, although its use in severe renal failure lacks specific evaluation. This case suggests a potential application of tafamidis in moderate-severe kidney disease, emphasizing the need for further research in this population.

Development of a non-separative screening strategy based on mass spectrometry for the semi-quantification of urinary polycyclic aromatic hydrocarbon metabolites.

A fast and non-separative screening strategy is presented for the analysis of five urinary metabolites of polycyclic aromatic hydrocarbons (PAHs), namely 2-naphthol, 1-acenaphthenol, 2-hydroxyfluorene, 9-phenanthrol and 1-hydroxypyrene. These hydroxylated derivatives (OH-PAHs) were subjected to enzymatic hydrolysis and were extracted from urine using a liquid-liquid extraction (LLE). The profile signals were obtained by direct injection of the sample into a programmed temperature vaporizer coupled to a quadrupole mass spectrometer via a deactivated fused silica tubing (PTV-qMS). Semi-quantitative determination was carried out by means of partial least squares regression (PLS1) using urine samples free of the analytes and spiked at several uncorrelated concentration levels. The multivariate calibration models worked satisfactorily, with errors ranging between 30 and 33 % for all the analytes except for 1-acenaphthenol that provided an error of 39 % when external validation set was considered. The repeatability and reproducibility, expressed as relative standard deviation (RSD), were ranged between 8-16 % and 11-18 %, respectively. The proposed method could be a useful tool for semi-quantification purposes of five OH-PAHs in urine samples, identifying positive samples for subsequent further chromatographic separation (confirmation), thus saving time and costs.

Spyglass: a framework for reproducible and shareable neuroscience research.

Scientific progress depends on reliable and reproducible results. Progress can also be accelerated when data are shared and re-analyzed to address new questions. Current approaches to storing and analyzing neural data typically involve bespoke formats and software that make replication, as well as the subsequent reuse of data, difficult if not impossible. To address these challenges, we created Spyglass, an open-source software framework that enables reproducible analyses and sharing of data and both intermediate and final results within and across labs. Spyglass uses the Neurodata Without Borders (NWB) standard and includes pipelines for several core analyses in neuroscience, including spectral filtering, spike sorting, pose tracking, and neural decoding. It can be easily extended to apply both existing and newly developed pipelines to datasets from multiple sources. We demonstrate these features in the context of a cross-laboratory replication by applying advanced state space decoding algorithms to publicly available data. New users can try out Spyglass on a Jupyter Hub hosted by HHMI and 2i2c: https://spyglass.hhmi.2i2c.cloud/.

Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults.

Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD, PRODH, DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS (p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.

Determinants of Intravenous Infusion Longevity and Infusion Failure via a Nonlinear Model Analysis of Smart Pump Event Logs: Retrospective Study.

BACKGROUND: Infusion failure may have severe consequences for patients receiving critical, short-half-life infusions. Continued interruptions to infusions can lead to subtherapeutic therapy. OBJECTIVE: This study aims to identify and rank determinants of the longevity of continuous infusions administered through syringe drivers, using nonlinear predictive models. Additionally, this study aims to evaluate key factors influencing infusion longevity and develop and test a model for predicting the likelihood of achieving successful infusion longevity. METHODS: Data were extracted from the event logs of smart pumps containing information on care profiles, medication types and concentrations, occlusion alarm settings, and the final infusion cessation cause. These data were then used to fit 5 nonlinear models and evaluate the best explanatory model. RESULTS: Random forest was the best-fit predictor, with an F1-score of 80.42, compared to 5 other models (mean F1-score 75.06; range 67.48-79.63). When applied to infusion data in an individual syringe driver data set, the predictor model found that the final medication concentration and medication type were of less significance to infusion longevity compared to the rate and care unit. For low-rate infusions, rates ranging from 2 to 2.8 mL/hr performed best for achieving a balance between infusion longevity and fluid load per infusion, with an occlusion versus no-occlusion ratio of 0.553. Rates between 0.8 and 1.2 mL/hr exhibited the poorest performance with a ratio of 1.604. Higher rates, up to 4 mL/hr, performed better in terms of occlusion versus no-occlusion ratios. CONCLUSIONS: This study provides clinicians with insights into the specific types of infusion that warrant more intense observation or proactive management of intravenous access; additionally, it can offer valuable information regarding the average duration of uninterrupted infusions that can be expected in these care areas. Optimizing rate settings to improve infusion longevity for continuous infusions, achieved through compounding to create customized concentrations for individual patients, may be possible in light of the study's outcomes. The study also highlights the potential of machine learning nonlinear models in predicting outcomes and life spans of specific therapies delivered via medical devices.

Type I Interferons induce endothelial destabilization in Systemic Lupus Erythematosus in a Tie2-dependent manner.

Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-ß (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.

Semaphorin3B promotes an anti-inflammatory and pro-resolving phenotype in macrophages from rheumatoid arthritis patients in a MerTK-dependent manner.

Previous works from our group show that Semaphorin3B (Sema3B) is reduced in RA and plays a protective role in a mouse arthritis model. In turn, MerTK plays a protective function in murine arthritis models, is expressed by synovial tissue macrophages and is linked to remission in patients with RA. In this study, we examined the role of Sema3B in the phenotypic characteristics of RA macrophages and the implication of MerTK. Peripheral blood monocytes from RA patients were differentiated into IFN-γ (RA MØIFN-γ) or M-CSF (RA MØM-CSF) macrophages and stimulated with LPS, Sema3B or their combination. Alternatively, RA fibroblast like synoviocytes (FLS) were stimulated with RA MØIFN-γ and RA MØM-CSF supernatants. Gene expression was determined by qPCR and protein expression and activation by flow cytometry, ELISA and western blot. Sema3B down-regulated the expression of pro-inflammatory mediators, in both RA MØIFN-γ and RA MØM-CSF. We observed a similar reduction in RA FLS stimulated with the supernatant of Sema3B-treated RA MØIFN-γ and RA MØM-CSF. Sema3B also modulated cell surface markers in macrophages towards an anti-inflammatory phenotype. Besides, MerTK expression and activation was up-regulated by Sema3B, just as GAS6 expression, Resolvin D1 secretion and the phagocytic activity of macrophages. Importantly, the inhibition of MerTK and neuropilins 1 and 2 abrogated the anti-inflammatory effect of Sema3B. Our data demonstrate that Sema3B modulates the macrophage characteristics in RA, inducing a skewing towards an anti-inflammatory/pro-resolving phenotype in a MerTK-dependant manner. Therefore, here we identify a new mechanism supporting the protective role of Sema3B in RA pathogenesis.

Afección cardiaca por COVID-19, ¿importa la ecocardiografía? Respuesta / Cardiac involvement in COVID-19: does echocardiography matter? Response

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