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The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

OBJECTIVE: To determine physician practice and perception about the management of intensive care unit (ICU)-acquired bacteriuria and funguria. DESIGN: Cross-sectional, self-administered, Web-based survey. SETTING: All provinces within Canada. PARTICIPANTS: Staff ICU physicians who are members of either the Canadian Critical Care Trials Group or the Canadian Critical Care Society. INTERVENTIONS: Survey items were developed by four ICU clinicians, and survey sensibility was assessed by five independent intensivists. Nonrespondents received three follow-up reminders. Participants were asked questions about general perceptions and practices regarding the management of ICU-acquired bacteriuria and funguria. Clinical scenarios were used to elicit management strategies, including antimicrobial prescriptions. MEASUREMENTS AND MAIN RESULTS: Ninety of 198 physicians (45%) responded. Bacteriuria was perceived by 63% of the respondents to be a frequent but low-morbidity problem. Most intensivists (98%) did not use a protocol for management. Traditional symptoms were rarely used to interpret the significance of bacteriuria. Presence of systemic inflammatory response syndrome (93%), presence of hemodynamic changes (91%), and urinalysis (69%) were used often. Within clinical scenarios, source control via urinary catheter change was not universal, ranging from 44% to 67% in the various scenarios, even in patients presenting with septic shock. Prescription of antimicrobials was common across scenarios despite the low-morbidity perception. In an asymptomatic patient, 19% of respondents would prescribe antimicrobials. Changing the species from fungus to bacteria and the presence of systemic inflammatory response syndrome or shock increased the likelihood of antimicrobial use up to 70% to 80%. CONCLUSIONS: ICU physicians perceive bacteriuria to have low morbidity. However, management approaches vary considerably, and systemic antimicrobials are frequently prescribed. Increased clinical instability and bacterial vs. fungal organisms isolated in urine cultures increased the use of antimicrobials. The considerable variability in practice and discordance between likelihood of urinary tract infection and antimicrobial prescription, highlights the need for additional clinical trials. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Acute lung injury can result from distinct insults, such as sepsis, ischemia-reperfusion, and ventilator-induced lung injury. Physiologic and morphologic manifestations of disparate forms of injury are often indistinguishable. We sought to demonstrate that acute lung injury resulting from distinct insults may lead to different gene expression profiles. DESIGN: Microarray analysis was used to examine early molecular events in lungs from three rat models of acute lung injury: lipopolysaccharide, hemorrhage shock/resuscitation, and high-volume ventilation. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats (body weight, 300-350 g). INTERVENTIONS: Rats were subjected to hemorrhagic shock or lipopolysaccharide followed by resuscitation or were subjected to sham operation. First hit was followed by ventilation with either low (6 mL/kg) or high (12 mL/kg) tidal volume for 4 hrs. MEASUREMENTS AND MAIN RESULTS: Physiologic and morphologic variables were assessed. Total RNA was hybridized to Affymetrix chips. Bioconductor was used to identify significantly altered genes. Functional enrichment predictions were performed in Gene Ontology Tree Machine. Confirmation studies included real-time polymerase chain reaction, Western blots, and immunohistochemistry. Physiologic and morphologic variables were noncontributory in determining the cause of acute lung injury. In contrast, molecular analysis revealed unique gene expression patterns that characterized exposure to lipopolysaccharide and high-volume ventilation. We used hypergeometric probability to demonstrate that specific functional enrichment groups were regulated by biochemical vs. biophysical factors. Genes stimulated by lipopolysaccharide were involved in metabolism, defense response, immune cell proliferation, differentiation and migration, and cell death. In contrast, high-volume ventilation led to the regulation of genes involved primarily in organogenesis, morphogenesis, cell cycle, proliferation, and differentiation. CONCLUSIONS: These results demonstrate the application of functional genomics to the molecular 'fingerprinting' of acute lung injury and the potential for decoupling biophysical from biochemical injury. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the feasibility of surgery radioguided with intravenous (99m)Tc sestamibi associated with magnetic resonance imaging (MRI) of the breast to detect tumor extent and guide complete tumor resection. A descriptive experimental study was developed with 10 breast cancer patients (stage IIA-IIB) who underwent mastectomy. From 2 to 10 days before surgery, the patients underwent breast MRI with 0.1 mmol/kg of gadolinium and scintimammography with a 740 MBq of (99m)Tc sestamibi. A region of interest was drawn around the tumor image and an uptake curve as a function of time was plotted to calculate the optimal time to perform radioguided surgery. In the perioperative period, the same dose of (99m)Tc sestamibi was intravenously injected into the patients. Tumor resection was performed under the guidance of a gamma probe. MRI was used to evaluate the skin and deep fascia involvement and to detect occult tumor foci which were also excised. Subsequently a modified radical mastectomy was performed. Tumor and residual breast were histopathologically examined. In a series of 10 women, all demonstrated (99m)Tc sestamibi uptake in tumor cells. Eight patients showed no disease in the residual breast, one presented with one foci of invasive ductal carcinoma measuring 0.5 cm in diameter located 5 cm from the tumor bed, and one presented with one foci of ductal carcinoma in situ measuring 0.8 cm at the resection margin. The mean tumor size in the histopathologic assessment was 3.3 cm and in MRI was 5.0 cm. Radioguided surgery using (99m)Tc sestamibi associated with MRI is a feasible technique that can be employed in tumor resection. [ABSTRACT FROM AUTHOR]

Propolis is a natural resinous mixture produced by honeybees with numerous biological activities. Considering the recently reported potential of propolis as an adjuvant in COVID-19 treatment, a methodology for the fractionation of the hexane extract of Brazilian green propolis (HEGP) was developed for the obtention of prenylated biomarkers by countercurrent chromatography. The inhibition of the interaction between the receptor binding domain (RBD) of spike and ACE2 receptor was evaluated by the Lumitᵀᴹ immunoassay. Fractionation of HEGP was performed by both normal (CCC1 and CCC2, with extended elution) and reversed (CCC3) phase elution-extrusion modes with the solvent system hexane-ethanol-water 4:3:1. The normal elution mode of CCC1 (471 mg HEGP in a 80 mL column volume, 1.6 mm id) was scaled-up (CCC5, 1211 mg HEGP in a 112 mL column volume, 2.1 mm id), leading to the isolation of 89.9 mg of artepillin C, 1; 52.7 mg of baccharin, 2; and 26.6 mg of chromene, with purities of 93 %, 83 % and 88 %, respectively, by HPLC-PDA. Among the isolated compounds, artepillin C, 1, and baccharin, 2, presented the best results in the Lumitᵀᴹ immunoassay, showing 67% and 51% inhibition, respectively, at the concentration of 10 μM. This technique proved to be of low operational cost and excellent reproducibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypo- and hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CM Hyper ) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CM Hypo and MSC-CM Hyper significantly reduced IL-6 and tumor necrosis factor alpha (TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CM Hyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Microbiota exposed to pollution provide insights into host physiology and ecosystem disruption. This study evaluated Enterococcus spp. tolerant to arsenic (As), copper (Cu), and mercury (Hg) from red-billed tropicbirds (Phaethon aethereus) and brown boobies (Sula leucogaster), which previously showed these metals in their blood and feathers, and their potential use as bioindicators of metal contamination. Enterococcus casseliflavus (47.9 %), E. faecalis (34.1 %), E. hirae (11.7 %), and E. faecium (5.3 %) were identified. Both seabird species had a high incidence of As-tolerant bacteria (84.0 %), with 40.4 % of these strains containing As efflux system genes (arsA_I and arsA_II). Cu efflux pump gene (tcrB) was detected in 30.9 % of strains, while Hg reductase genes (mer) were not found. As- and Cu-tolerance in enterococci observed in this study underlines their potential as bioindicators in metal-polluted marine environments. Further research may elucidate the role of these metal-tolerant enterococci in seabird gut and their adaptability to polluted environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diabetes Mellitus (DM) is a disease characterized by high blood glucose levels, known as hyperglycemia. Diabetes represents a risk factor for the development of neurodegenerative diseases, such as Alzheimer's Disease (AD), one of the most prevalent neurodegenerative diseases worldwide, which leads to progressive mental, behavioral, and functional decline, affecting many brain structures, especially the hippocampus. Here, we aim to characterize the ultrastructural, nanomechanical, and vibrational changes in hyperglycemic hippocampal tissue using atomic force microscopy (AFM) and Raman spectroscopy. DM was induced in rats by streptozotocin injection (type 1) or dietary intervention (type 2). Cryosections of the hippocampus were prepared and analyzed on an MM8 AFM (Bruker) in Peak Force Quantitative Nanomechanics mode, performing 25 μm 2 scans in 9 regions of 3 samples from each group. Ultrastructural and nanomechanical data such as surface roughness, area, volume, Young's modulus, and adhesion were evaluated. The hippocampal samples were also analyzed on a T64000 Spectrometer (Horiba), using a laser λ = 632.8 nm, and for each sample, four spectra were obtained in different regions. AFM analyses show changes on the ultrastructural scale since diabetic animals had hippocampal tissue with greater roughness and volume. Meanwhile, diabetic tissues had decreased adhesion and Young's modulus compared to control tissues. These were corroboratedby Raman data that shows changes in the molecular composition of diabetic tissues. The individual spectra show that the most significant changes are in the amide, cholesterol, and lipid bands. Overall, the data presented here show that hyperglycemia induces biophysical alterations in the hippocampal tissue of diabetic rats, providing novel biophysical and vibrational cues on the relationship between hyperglycemia and dementia., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 μM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10 + oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.

Neutralizing antibodies (nAbs) produced from infection or vaccination play an important role in acquired immunity. Determining virus-specific nAb titers is a useful tool for measuring aquired immunity in an individual. The standard methods to do so rely on titrating serum samples against live virus and monitoring viral infection in cultured cells which requires high biosafety level containment. The surrogate virus neutralization test (sVNT) reduces the biohazards and it is suitable for designing rapid test device in a lateral flow assay (LFA) format. Here, we introduce the fabrication and development of a unique paper-based LFA device for determining the level of SARS-CoV-2 nAb in a sample with a semiquantitative direct colorimetric readout. A LFA-based gradient assay design was used to facilitate the sVNT, where the spike glycoprotein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) stand in as proxies for viruses and cells, respectively. The gradient assay employed multiple test dots of ACE2 spotted in increasing concentration along the sample flow path and gold nanoparticle-conjugated RBD for readout. In this way, the number of developed spots is inversely proportional to the concentration of nAbs present in the sample. The assay was tested with both standard solutions of nAb as well as human serum samples. We have demonstrated that the device can effectively provide semiquantitative test results of nAbs by direct instrument-free colorimetric detection.

In the context of hydroelectric plants, this article emphasizes the imperative of robust monitoring strategies. The utilization of fiber-optic sensors (FOSs) emerges as a promising approach due to their efficient optical transmission, minimal signal attenuation, and resistance to electromagnetic interference. These optical sensors have demonstrated success in diverse structures, including bridges and nuclear plants, especially in challenging environments. This article culminates with the depiction of the development of an array of sensors featuring Fiber Bragg Gratings (FBGs). This array is designed to measure deformation and temperature in protective grids surrounding the turbines at the Santo Antônio Hydroelectric Plant. Implemented in a real-world scenario, the device identifies deformation peaks, indicative of water flow obstructions, thereby contributing significantly to the safety and operational efficiency of the plant.

Background and Objective: Collection of biosamples for translational research studies is vital for understanding biological pathways, discovering disease-related biomarkers, and identifying novel therapeutic targets. However, a lack of infrastructure for sample procurement, processing, storage, and shipping may hinder the ability of clinical research units to effectively engage in translational research. The purpose of this study was to identify the barriers to biosampling-based translational research in the critical care setting in Canada., Methods: We administered an online survey to members of the Canadian Critical Care Trials Group (CCCTG), the Canadian Critical Care Translational Biology Group (CCCTBG), and the Canadian Critical Care Research Coordinators Group (CCCRCG). The survey focused on participants' personal experience of biosampling research, research infrastructure, motivating factors, and perceived barriers., Results: We received 59 responses from 31 sites, including 6 community intensive care unit (ICU) sites. The overall response rate was 11.3%. The majority of respondents were research coordinators (44%), followed by clinician-investigators (33.8%), graduate students (10.2%), and PhD-investigators (8.5%). Although most (63.8%) respondents reported an interest in participating in translational research, they also reported that their ICUs were currently contributing to a third of the number of translational studies compared to clinical studies. For respondents with experience in participating in translational research studies, the most common barriers were lack of funding, lack of time, and insufficient research staff. For respondents without previous experience, the perceived facilitators were more interest from their research group, improved training/mentorship, increased funding, and better access to laboratory equipment., Conclusions: Our survey found that the majority of participants were interested in and recognize the value of participating in biosampling-based translational research but lacked funding, time, and research personnel trained in biosampling protocols. Our survey also identified factors that might encourage participation at new sites. Addressing these barriers will be a key step towards increasing translational research capacity across Canada., Competing Interests: No authors have competing interests., (Copyright: © 2024 Cani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The COVID-19 pandemic caused a global shortage of nasopharyngeal (NP) swabs, required for RT-PCR testing. Canadian manufacturers were contacted to share NP swab innovations. The primary objective was to determine whether novel NP test swabs were comparable to commercially available swabs regarding user characteristics, ability to collect a specimen, and diagnostic performance using RT-PCR testing., Methods: Participants were randomized by swab (test/control) and nostril (left/right). A calculated positive percent agreement ≥90% was considered successful. Mean Ct values of viral genes and housekeeping gene (RNase P) were considered similar if a Ct difference ≤ 2 between control and test group was obtained. There also was a qualitative assessment of swabs usability., Results: 647 participants were enrolled from Huaycan Hospital in Lima, Peru, distributed over 8 NP swabs brands. Seven brands agreed to share their results. There were no statistically significant differences between the test swabs of these 7 brands and control swabs., Conclusion: All the seven brands are comparable to the commercially available flocked swabs used for SARS-CoV-2 regarding test results agreement, ability to collect a specimen, and user characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Palomino-Padilla, Caceres-Cardenas, Calderon, Ko, Garnett, Doan, Chong, Lino, Caceres, Veres, Dos Santos, Nielsen and Ugarte-Gil.)

Background Aims: Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical manifestations with the potential to progress to multiple organ dysfunction in severe cases. Extracellular vesicles (EVs) carry a range of biological cargoes, which may be used as biomarkers of disease state., Methods: An exploratory secondary analysis of the SARITA-2 and SARITA-1 datasets (randomized clinical trials on patients with mild and moderate/severe COVID-19) was performed. Serum-derived EVs were used for proteomic analysis to identify enriched biological processes and key proteins, thus providing insights into differences in disease severity. Serum-derived EVs were separated from patients with COVID-19 by size exclusion chromatography and nanoparticle tracking analysis was used to determine particle concentration and diameter. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to identify and quantify protein signatures. Bioinformatics and multivariate statistical analysis were applied to distinguish candidate proteins associated with disease severity (mild versus moderate/severe COVID-19)., Results: No differences were observed in terms of the concentration and diameter of enriched EVs between mild (n = 14) and moderate/severe (n = 30) COVID-19. A total of 414 proteins were found to be present in EVs, of which 360 were shared while 48 were uniquely present in severe/moderate compared to mild COVID-19. The main biological signatures in moderate/severe COVID-19 were associated with platelet degranulation, exocytosis, complement activation, immune effector activation, and humoral immune response. Von Willebrand factor, serum amyloid A-2 protein, histone H4 and H2A type 2-C, and fibrinogen β-chain were the most differentially expressed proteins between severity groups., Conclusion: Exploratory proteomic analysis of serum-derived EVs from patients with COVID-19 detected key proteins related to immune response and activation of coagulation and complement pathways, which are associated with disease severity. Our data suggest that EV proteins may be relevant biomarkers of disease state and prognosis., Competing Interests: Declaration of competing interest All authors declare no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence (bias) their work., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis., Objective: To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis., Methods: A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool., Results: Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains., Conclusions: These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock., (© The Author(s) 2024. Published by Oxford University Press.)

Aims: An elevated risk of adverse events persists for years in cardiogenic shock (CS) survivors with high mortality rate and physical/mental disability. This study aims to link clinical CS-survivor phenotypes with distinct late host-response patterns at intensive care unit (ICU) discharge and long-term outcomes using model-based clustering., Methods and Results: In the original prospective, observational, international French and European Outcome Registry in Intensive Care Units (FROG-ICU) study, ICU patients with CS on admission were identified (N = 228). Among them, 173 were discharged alive from the ICU and included in the current study. Latent class analysis was applied to identify distinct CS-survivor phenotypes at ICU discharge using 15 readily available clinical and laboratory variables. The primary endpoint was 1 year of mortality after ICU discharge. Secondary endpoints were readmission and physical/mental disability [short form-36 questionnaire (SF-36) score] within 1 year after ICU discharge. Two distinct phenotypes at ICU discharge were identified (A and B). Patients in Phenotype B (38%) were more anaemic and had higher circulating levels of lactate, sustained kidney injury, and persistent elevation in plasma markers of inflammation, myocardial fibrosis, and endothelial dysfunction compared with Phenotype A. They had also a higher rate of non-ischaemic origin of CS and right ventricular dysfunction on admission. CS survivors in Phenotype B had higher 1 year of mortality compared with Phenotype A (P = 0.045, Kaplan-Meier analysis). When adjusted for traditional risk factors (i.e. age, severity of illness, and duration of ICU stay), Phenotype B was independently associated with 1 year of mortality [adjusted hazard ratio = 2.83 (95% confidence interval 1.21-6.60); P = 0.016]. There was a significantly lower physical quality of life in Phenotype B patients at 3 months (i.e. SF-36 physical component score)., Conclusions: A phenotype with sustained inflammation, myocardial fibrosis, and endothelial dysfunction at ICU discharge was identified from readily available data and was independently associated with poor long-term outcomes in CS survivors., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)-induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation-induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2-induced myocardial inflammation, we established that administration of endothelial cell-derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor-nuclear factor κB signaling axis.

Aim: This study explores chia oil, rich in ω-3 fatty acids and nutraceutical components, as a potential remedy for diseases, especially those linked to inflammation and cancer. Methods/materials: A chia oil-based nanoemulsion, developed through single emulsification, underwent comprehensive analysis using various techniques. In vitro and in vivo assays, including macrophage polarization, nitrite and cytokine production, cellular uptake and biodistribution, were conducted to assess the anti-inflammatory efficacy. Results & conclusion: Results reveal that the chia nanoemulsion significantly inhibits inflammation, outperforming pure oil with twice the efficacy. Enhanced uptake by macrophage-like cells and substantial accumulation in key organs indicate its potential as an economical and effective anti-inflammatory nanodrug, addressing global economic and health impacts of inflammation-related diseases.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions.

MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the β-amyloid peptide (Aβ, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that β-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-β, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aβ, as well as inflammatory cytokines IL1-β, IL-6, and NOS2. In cells stimulated with Aβ, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD.

Objectives: DNA methylation can be used to determine an individual's biological age, as opposed to chronological age, an indicator of underlying health status. This study aimed to assess epigenetic age in critically ill patients with and without sepsis to determine if higher epigenetic age is associated with admission diagnosis or mortality., Design: Secondary analysis of whole blood DNA methylation data generated from a nested case-control study of critically ill septic and nonseptic patients., Setting: Four tertiary care hospitals in Canada., Interventions: None., Patients: Critically ill patients with and without sepsis., Measurements and Main Results: Epigenetic age was derived from DNA methylation data using the Hannum and PhenoAge algorithms and deviation from the patient's chronological age in years was determined. Of the 66 patients with sepsis, 34 were male (51.5%), the mean age was 65.03 years and 25 patients (37.8%) died before discharge. Of the 68 nonseptic patients, 47 were male (69.1%), the mean age was 64.92 years and 25 (36.7%) died before discharge. Epigenetic age calculated using the PhenoAge algorithm showed a significant age acceleration of 4.97 years in septic patients ( p = 0.045), but no significant acceleration in nonseptic patients. Epigenetic age calculated using the Hannum algorithm showed no significant acceleration in the septic or nonseptic patients. Similarly, in the combined septic and nonseptic cohorts, nonsurvivors showed an epigenetic age acceleration of 7.62 years ( p = 0.004) using the PhenoAge algorithm while survivors showed no significant age acceleration. Survivor status was not associated with age acceleration using the Hannum algorithm., Conclusions: In critically ill patients, epigenetic age acceleration, as calculated by the PhenoAge algorithm, was associated with sepsis diagnosis and mortality., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Croton heliotropiifolius Kunth, popularly known as "velame," is a shrub that resides in northeastern Brazil. The essential oil of C. heliotropiifolius contains high concentrations of volatile compounds in the leaves and is widely used in folk medicine for many purposes as an antiseptic, analgesic, sedative, and anti-inflammatory agent. Due to the apparent limited amount of information, the aim of this study was to determine the cytotoxic potential of essential oil extracted from leaves of C. heliotropiifolius , utilizing different human cancer cell lines (HL-60, leukemia; HCT-116, colon; MDA-MB435, melanoma; SF295, glioblastoma) and comparison to murine fibroblast L929 cell line. The chemical characterization of the essential oil revealed the presence of large amounts of monoterpenes and sesquiterpenes, the majority of which were aristolene (22.43%), germacrene D (11.38%), ɣ-terpinene (10.85%), and limonene (10.21%). The essential oil exerted significant cytotoxicity on all cancer cells, with low activity on murine L929 fibroblasts, independent of disruption of cell membranes evidenced by absence of hemolytic activity. The cytotoxicity identified was associated with oxidative stress, which culminated in mitochondrial respiration dysfunction and direct or indirect DNA damage (strand breaks and oxidative damage), triggering cell death via apoptosis. Our findings suggest that extracts of essential oil of C. Heliotropiifolius may be considered as agents to be used therapeutically in treatment of certain cancers.

Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) have emerged as innovative therapeutic agents for the treatment of sepsis and acute respiratory distress syndrome (ARDS). Although their potential remains undisputed in pre-clinical models, this has yet to be translated to the clinic. In this review, we focused on the role of microRNAs contained in MSC-derived EVs, the EV microRNAome, and their potential contribution to therapeutic mechanisms of action. The evidence that miRNA transfer in MSC-derived EVs has a role in the overall therapeutic effects is compelling. However, several questions remain regarding how to reconcile the stochiometric issue of the low copy numbers of the miRNAs present in the EV particles, how different miRNAs delivered simultaneously interact with their targets within recipient cells, and the best miRNA or combination of miRNAs to use as therapy, potency markers, and biomarkers of efficacy in the clinic. Here, we offer a molecular genetics and systems biology perspective on the function of EV microRNAs, their contribution to mechanisms of action, and their therapeutic potential.

Aim: Evaluate the anticandidal effect of Croton heliotropiifolius Kunth essential oil and its interaction with azoles and N-acetylcysteine (NAC) against planktonic cells and biofilms. Materials & methods: Broth microdilution and checkerboard methods were used to evaluate the individual and combined activity with fluconazole and itraconazole (ITRA). The antibiofilm effect of the oil was assessed in 96-well plates alone and combined with ITRA and NAC, and cytotoxicity determined by MTT. Results: The oil inhibited all Candida species growth. The activity was enhanced when associated with ITRA and NAC for planktonic cells and biofilms in formation. The effective concentrations were lower than the toxic ones to V79 cells. Conclusion: C. heliotropiifolius Kunth essential oil is an anticandidal alternative, and can be associated with ITRA and NAC.

Herpes simplex virus type 2 (HSV-2) is the most common agent of sexually transmitted infections around the world. Currently, no vaccine is available, and acyclovir is the reference compound in treatment HSV-2 infections. However, the emergence of resistant strains has reduced the efficacy in treatment. Several studies have shown marine seaweed biological activities, but there are no studies yet about the activity anti-HSV-2 of two its secundary metabolites, atomaric acid (1) and marine dolastane (2), isolated from Stypopodium zonale and Canistrocarpus cervicornis respectively. Therefore, we evaluated the anti-HSV-2 activity of compounds 1 and 2. Both compounds showed anti-HSV-2 activity with low cytotoxicity and compound 1 inactivated 90% of the viral particles at 50 µM. Both compounds inhibited the penetration and results in silico indicated the compound 1 as possible therapy alternative anti -HSV-2.

MnO x -based nanomaterials are promising large-scale electrochemical energy storage devices due to their high specific capacity, low toxicity, and low cost. However, their slow diffusion kinetics is still challenging, restricting practical applications. Here, a one-pot and straightforward method was reported to produce Zn-doped MnO x nanowires with abundant defects and tunable small cross-sections, exhibiting an outstanding specific capacitance. More specifically, based on a facile hydrothermal strategy, zinc sites could be uniformly dispersed in the α-MnO x nanowires structure as a function of composition (0.3, 2.1, 4.3, and 7.6 wt.% Zn). Such a process avoided the formation of different crystalline phases during the synthesis. The reproducible method afforded uniform nanowires, in which the size of cross-sections decreased with the increase of Zn composition. Surprisingly, we found a volcano-type relationship between the storage performance and the Zn loading. In this case, we demonstrated that the highest performance material could be achieved by incorporating 2.1 wt.% Zn, exhibiting a remarkable specific capacitance of 1082.2 F.g -1 at a charge/discharge current density of 1.0 A g -1 in a 2.0 mol L -1 KOH electrolyte. The optimized material also afforded improved results for hybrid supercapacitors. Thus, the results presented herein shed new insights into preparing defective and controlled nanomaterials by a simple one-step method for energy storage applications., (© 2023. The Author(s).)

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT 7 mice but not in CATT 5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT 7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT 6/7/8 )., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease has remained one of the leading causes of mortality in the world. The basic pathophysiology of coronary artery disease (CAD) is a reduction of the blood flow in coronary vessels, leading to restricted blood flow to the heart muscle. Both modifiable and non-modifiable risk factors contribute to its multifactorial etiology. The clinical presentation ranges from asymptomatic to typical symptoms like chest pain, shortness of breath, and left arm or jaw pain. The purpose of this review is to investigate and analyze the variation of CAD depending on the biological sex, age, race, or ethnicity and how it might differ in the studied population while comparing the symptoms and prognosis of CAD. For this research, PubMed's database was used. A total of 926 articles were selected using pre-determined inclusion and exclusion criteria, with 74 articles eligible to be included in the narrative review. Studies were selected from the general population of patients with CAD, regardless of their severity, stage of diagnosis, and treatment plan. The scale for the assessment of non-systematic review articles (SANRA) was used to assess the quality of the study. As humans age, the incidence of CAD increases, and people over 75 are more likely to have multiple-vessel CAD. It has been observed that South Asians have the highest rate of CAD at 24%, while the White population has the lowest at 8%. The prevalence of CAD also depends on race, with the White population having the lowest rate at 3.2%, followed by Hispanics at 5%, Black women at 5.2%, and Black men at 5.7%. Younger Black women tend to have more chest pain. Men with CAD commonly experience chest pain, and women are more likely to present with atypical symptoms. Modifiable risk factors such as smoking and alcoholism are more commonly observed in young men than in young women. Coronary artery disease in the elderly, female, minority, and Black patients is associated with a higher mortality rate. Acknowledging the prevalence of certain risk factors, signs, results, and responses to treatment in certain socio-demographic groups, as well as the provision and accessibility of diagnosis and treatment, would lead to a better outcome for all individuals. The impact of this shift can range from an earlier diagnosis of CAD to a faster and more customized treatment plan tailored to each patient's individual requirements., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Lima Dos Santos et al.)

Thematic collections (TCs), which are composed of genotypes with superior agronomic traits and reduced size, offer valuable opportunities for parental selection in plant breeding programs. Three TCs were created to focus on crucial attributes: root yield (CC_Yield), pest and disease resistance (CC_Disease), and root quality traits (CC_Root_quality). The genotypes were ranked using the best linear unbiased predictors (BLUP) method, and a truncated selection was implemented for each collection based on specific traits. The TCs exhibited minimal overlap, with each collection comprising 72 genotypes (CC_Disease), 63 genotypes (CC_Root_quality), and 64 genotypes (CC_Yield), representing 4%, 3.5%, and 3.5% of the total individuals in the entire collection, respectively. The Shannon-Weaver Diversity Index values generally varied but remained below 10% when compared to the entire collection. Most TCs exhibited observed heterozygosity, genetic diversity, and the inbreeding coefficient that closely resembled those of the entire collection, effectively retaining 90.76%, 88.10%, and 88.99% of the alleles present in the entire collection (CC_Disease, CC_Root_quality, and CC_Disease, respectively). A PCA of molecular and agro-morphological data revealed well-distributed and dispersed genotypes, while a discriminant analysis of principal components (DAPC) displayed a high discrimination capacity among the accessions within each collection. The strategies employed in this study hold significant potential for advancing crop improvement efforts.

Introduction: Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features, suggesting that severe COVID-19 is a form of viral sepsis. Our objective was to identify shared gene expression trajectories strongly associated with eventual mortality between severe COVID-19 patients and contemporaneous non-COVID-19 sepsis patients in the intensive care unit (ICU) for potential therapeutic implications., Methods: Whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Using systems biology methods, drug candidates targeting key genes in the pathophysiology of COVID-19 and sepsis were identified., Results: When compared to survivors, non-survivors (irrespective of COVID-19 status) had 3.6-fold more "persistent" genes (genes that stayed up/downregulated at both timepoints) (4,289 vs. 1,186 genes); these included persistently downregulated genes in T-cell signaling and persistently upregulated genes in select innate immune and metabolic pathways, indicating unresolved immune dysfunction in non-survivors, while resolution of these processes occurred in survivors. These findings of persistence were further confirmed using two publicly available datasets of COVID-19 and sepsis patients. Systems biology methods identified multiple immunomodulatory drug candidates that could target this persistent immune dysfunction, which could be repurposed for possible therapeutic use in both COVID-19 and sepsis., Discussion: Transcriptional evidence of persistent immune dysfunction was associated with 28-day mortality in both COVID-19 and non-COVID-19 septic patients. These findings highlight the opportunity for mitigating common mechanisms of immune dysfunction with immunomodulatory therapies for both diseases., Competing Interests: RH has a significant ownership position in Sepset Biotherapeutics Inc and RH and AJB have filed patents for sepsis diagnostic gene expression assays an indirect relationship to this work. CS is on the Data and Safety Monitoring Board of SEMPATICO NCT04615871. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 An, Baghela, Zhang, Falsafi, Lee, Trahtemberg, Baker, Santos and Hancock.)

Cassava ( Manihot esculenta Crantz) holds significant importance as one of the world's key starchy crop species. This study aimed to develop core collections by utilizing both phenotypic data (15 quantitative and 33 qualitative descriptors) and genotypic data (20,023 single-nucleotide polymorphisms) obtained from 1,486 cassava accessions. Six core collections were derived through two optimization strategies based on genetic distances: Average accession-to-nearest-entry and Average entry-to-nearest-entry, along with combinations of phenotypic and genotypic data. The quality of the core collections was evaluated by assessing genetic parameters such as genetic diversity Shannon-Weaver Index, inbreeding ( Fis ), observed ( Ho ), and expected ( Hs ) heterozygosity. While the selection of accessions varied among the six core collections, a seventh collection (consolidated collection) was developed, comprising accessions selected by at least two core collections. Most collections exhibited genetic parameters similar to the complete collection, except for those developed by the Average accession-to-nearest-entry algorithm. However, the variations in the maximum and minimum values of Ho , Hs , and Fis parameters closely resembled the complete collection. The consolidated collection and the collection constructed using genotypic data and the Average entry-to-nearest-entry algorithm (GenEN) retained the highest number of alleles (>97%). Although the differences were not statistically significant (above 5%), the consolidated collection demonstrated a distribution profile and mean trait values most similar to the complete collection, with a few exceptions. The Shannon-Weaver Index of qualitative traits exhibited variations exceeding ±10% when compared to the complete collection. Principal component analysis revealed that the consolidated collection selected cassava accessions with a more uniform dispersion in all four quadrants compared to the other core collections. These findings highlight the development of optimized and valuable core collections for efficient breeding programs and genomic association studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santos, Andrade, Carmo and Oliveira.)

Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite the considerable morbidity and mortality of yellow fever virus (YFV) infections in Brazil, our understanding of disease outbreaks is hampered by limited viral genomic data. Here, through a combination of phylogenetic and epidemiological models, we reconstructed the recent transmission history of YFV within different epidemic seasons in Brazil. A suitability index based on the highly domesticated Aedes aegypti was able to capture the seasonality of reported human infections. Spatial modeling revealed spatial hotspots with both past reporting and low vaccination coverage, which coincided with many of the largest urban centers in the Southeast. Phylodynamic analysis unraveled the circulation of three distinct lineages and provided proof of the directionality of a known spatial corridor that connects the endemic North with the extra-Amazonian basin. This study illustrates that genomics linked with eco-epidemiology can provide new insights into the landscape of YFV transmission, augmenting traditional approaches to infectious disease surveillance and control.

The COVID-19 pandemic has created an urgency to study the host gene response that leads to variable clinical presentations of the disease, particularly the critical illness response. miRNAs have been implicated in the mechanism of host immune dysregulation and thus hold potential as biomarkers and/or therapeutic agents with clinical application. Hence, further analyses of their altered expression in COVID-19 is warranted. An important basis for this is identifying appropriate reference genes for high quality expression analysis studies. In the current report, NanoString technology was used to study the expression of 798 miRNAs in the peripheral blood of 24 critically ill patients, 12 had COVID-19 and 12 were COVID-19 negative. A list of potentially stable candidate reference genes was generated that included ten miRNAs. The top six were analyzed using reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a total of 41 patients so as to apply standard computational algorithms for validating reference genes, namely geNorm, NormFinder, BestKeeper and RefFinder. There was general agreement among all four algorithms in the ranking of four stable miRNAs: miR-186-5p, miR-148b-3p, miR-194-5p and miR-448. A detailed analysis of their output rankings led to the conclusion that miR-186-5p and miR-148b-3p are appropriate reference genes for miRNA expression studies using PaxGene tubes in the peripheral blood of patients critically ill with COVID-19 disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Formosa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Spinel ferrites are versatile, low-cost, and abundant metal oxides with remarkable electronic and magnetic properties, which find several applications. Among them, they have been considered part of the next generation of electrochemical energy storage materials due to their variable oxidation states, low environmental toxicity, and possible synthesis through simple green chemical processing. However, most traditional procedures lead to the formation of poorly controlled materials (in terms of size, shape, composition, and/or crystalline structure). Thus, we report herein a cellulose nanofibers-mediated green procedure to prepare controlled highly porous nanocorals comprised of spinel Zn-ferrites. Then, they presented remarkable applications as electrodes in supercapacitors, which were thoroughly and critically discussed. The spinel Zn-ferrites nanocorals supercapacitor showed a much higher maximum specific capacitance (2031.81 F g -1 at a current density of 1 A g -1 ) than Fe 2 O 3 and ZnO counterparts prepared by a similar approach (189.74 and 24.39 F g -1 at a current density of 1 A g -1 ). Its cyclic stability was also scrutinized via galvanostatic charging/discharging and electrochemical impedance spectroscopy, indicating excellent long-term stability. In addition, we manufactured an asymmetric supercapacitor device, which offered a high energy density value of 18.1 Wh kg -1 at a power density of 2609.2 W kg -1 (at 1 A g -1 in 2.0 mol L -1 KOH electrolyte). Based on our findings, we believe that higher performances observed for spinel Zn-ferrites nanocorals could be explained by their unique crystal structure and electronic configuration based on crystal field stabilization energy, which provides an electrostatic repulsion between the d electrons and the p orbitals of the surrounding oxygen anions, creating a level of energy that determines their final supercapacitance then evidenced, which is a very interesting property that could be explored for the production of clean energy storage devices.

Agathisflavone, purified from Cenostigma pyramidale (Tul.) has been shown to be neuroprotective in in vitro models of glutamate-induced excitotoxicity and inflammatory damage. However, the potential role of microglial regulation by agathisflavone in these neuroprotective effects is unclear. Here we investigated the effects of agathisflavone in microglia submitted to inflammatory stimulus in view of elucidating mechanisms of neuroprotection. Microglia isolated from cortices of newborn Wistar rats were exposed to Escherichia coli lipopolysaccharide (LPS, 1 µg/mL) and treated or not with agathisflavone (1 µM). Neuronal PC12 cells were exposed to a conditioned medium from microglia (MCM) treated or not with agathisflavone. We observed that LPS induced microglia to assume an activated inflammatory state (increased CD68, more rounded/amoeboid phenotype). However, most microglia exposed to LPS and agathisflavone, presented an anti-inflammatory profile (increased CD206 and branched-phenotype), associated with the reduction in NO, GSH mRNA for NRLP3 inflammasome, IL1-β, IL-6, IL-18, TNF, CCL5, and CCL2. Molecular docking also showed that agathisflavone bound at the NLRP3 NACTH inhibitory domain. Moreover, in PC12 cell cultures exposed to the MCM previously treated with the flavonoid most cells preserved neurites and increased expression of β-tubulin III. Thus, these data reinforce the anti-inflammatory activity and the neuroprotective effect of agathisflavone, effects associated with the control of NLRP3 inflammasome, standing out it as a promising molecule for the treatment or prevention of neurodegenerative diseases.

The effects of the administration of mesenchymal stromal cells (MSC) may vary according to the source. We hypothesized that MSC-derived extracellular vesicles (EVs) obtained from bone marrow (BM), adipose (AD), or lung (L) tissues may also lead to different effects in sepsis. We profiled the proteome from EVs as a first step toward understanding their mechanisms of action. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (SEPSIS) and SHAM (control) animals only underwent laparotomy. Twenty-four hours after surgery, animals in the SEPSIS group were randomized to receive saline or 3 × 10 6 MSC-derived EVs from BM, AD, or L. The diffuse alveolar damage was decreased with EVs from all three sources. In kidneys, BM-, AD-, and L-EVs reduced edema and expression of interleukin-18. Kidney injury molecule-1 expression decreased only in BM- and L-EVs groups. In the liver, only BM-EVs reduced congestion and cell infiltration. The size and number of EVs from different sources were not different, but the proteome of the EVs differed. BM-EVs were enriched for anti-inflammatory proteins compared with AD-EVs and L-EVs. In conclusion, BM-EVs were associated with less organ damage compared with the other sources of EVs, which may be related to differences detected in their proteome.

Objectives: Evatuate if Bacillus Calmette-Guérin (BCG) vaccine could be used as a tool against SARS-CoV-2 based on the concept of trained immunity., Methods: A multicenter, double-blinded, randomized clinical trial recruited health care workers (HCWs) in Brazil. The incidence rates of COVID-19, clinical manifestations, absenteeism, and adverse events among HCWs receiving BCG vaccine (Moreau or Moscow strains) or placebo were compared. BCG vaccine-mediated immune response before and after implementing specific vaccines for COVID-19 (CoronaVac or COVISHIELD) was analyzed. Cox proportional hazard and linear mixed effect modeling were used., Results: A total of 264 volunteers were included for analysis (BCG = 134 and placebo = 130). The placebo group presented a COVID-19 cumulative incidence of 0.75% vs 0.52% of BCG. The Moreau strain also presented a higher incidence rate (1.60% × 0.22%). BCG did not show a protective hazard ratio against COVID-19. In addition, the log (immunoglobulin G) level against SARS-CoV-2 presented a higher increase in the BCG group, whether or not participants had COVID-19, but also without statistical significance., Conclusion: Our results suggest that BCG has a tendency of protection against SARS-CoV-2 and higher immunoglobulin G levels than placebo. The clinical trial was registered at https://clinicaltrials.gov/ (NCT04659941)., Competing Interests: Declaration Of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The mineral wealth of the Amazon region is prone to intense exploration with consequent metals mobilization in ecosystems. Besides that, a number of other anthropogenic activities contribute to the imbalance of this important environment. The Pará River is an important water body in the Amazon basin and is under multiple anthropogenic influences, including disorderly urbanization, port activities and processing of minerals such as bauxite and kaolin. In this study, metals concentrations (Al, Cr, Pb, Ba, Ni, and Mn) in water, sediment and organisms (the fish Cheirocerus goeldii and the shrimp Macrobrachium amazonicum) and biochemical biomarkers (total antioxidant capacity, ACAP and lipid peroxidation, LPO) were analyzed along five points in the Para River with different distances to a center of anthropogenic activity, in three seasonal periods (rainy, transition and dry). Metals concentrations were similar among sites in each seasonal period but Aluminium (Al) presented the highest concentrations among all analyzed metals both in sediment and water considering all sampling points and all seasonal periods. In the dissolved fraction, Al had values above those established by the local environmental agency, especially during the rainy season. In the biotic compartment, both fish and shrimps showed higher concentrations of metals (Al and Ba) in the rainy season compared to the other seasons. Shrimp was more responsive to metal accumulation than fish, showing an adaptive response of biomarkers. Fish showed an increase of LPO in gills for individuals from the point of greater anthropogenic interference during the rainy season, but no differences in metal accumulation. We conclude that there is a seasonal pattern of metals concentration in different environmental compartments. Metal concentration in organisms and biomarkers responses, showed the effect of anthropogenic influences, which was not evident in results from chemical analyses alone, due to the intensive hydrodynamics in the region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Proteomic analysis of human plasma by LC-ESI-MS/MS has discovered a limited number of new cellular protein biomarkers that may be confirmed by independent biochemical methods. Analysis of COVID-19 plasma has indicated the re-purposing of known biomarkers that might be used as prognostic markers of COVID-19 infection. However, multiple molecular approaches have previously indicated that the SARS-COV2 infection cycle is linked to the biology of mitochondria and that the response to infections may involve the action of heme containing oxidative enzymes., Methods: Human plasma from COVID-19 and ICU-ARDS was analyzed by classical analytical biochemistry techniques and classical frequency-based statistical approaches to look for prognostic markers of severe COVID-19 lung damage. Plasma proteins from COVID-19 and ICU-ARDS were identified and enumerated versus the controls of normal human plasma (NHP) by LC-ESI-MS/MS. The observation frequency of proteins detected in COVID-19 and ICU-ARDS patients were compared to normal human plasma, alongside random and noise MS/MS spectra controls, using the Chi Square (χ 2 ) distribution., Results: PCR showed the presence of MT-ND1 DNA in the plasma of COVID-19, ICU-ARDS, as well as normal human plasma. Mitochondrial proteins such as MRPL, L2HGDH, ATP, CYB, CYTB, CYP, NDUF and others, were increased in COVID-19 and ICU-ARDS plasma. The apparent activity of the cytochrome components were tested alongside NHP by dot blotting on PVDF against a purified cytochrome c standard preparation for H 2 O 2 dependent reaction with luminol as measured by enhanced chemiluminescence (ECL) that showed increased activity in COVID-19 and ICU-ARDS patients., Discussion: The results from PCR, LC-ESI-MS/MS of tryptic peptides, and cytochrome ECL assays confirmed that mitochondrial components were present in the plasma, in agreement with the established central role of the mitochondria in SARS-COV-2 biology. The cytochrome activity assay showed that there was the equivalent of at least nanogram amounts of cytochrome(s) in the plasma sample that should be clearly detectable by LC-ESI-MS/MS. The release of the luminol oxidase activity from cells into plasma forms the basis of a simple and rapid test for the severity of cell damage and lung injury in COVID-19 infection and ICU-ARDS., (© 2023. The Author(s).)

Introduction: Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features. To what extent they share mechanistically-based gene expression trajectories throughout hospitalization was unknown. Our objective was to compare gene expression trajectories between severe COVID-19 patients and contemporaneous non-COVID-19 severe sepsis patients in the intensive care unit (ICU)., Methods: In this prospective single-center observational cohort study, whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways., Results: At ICU admission, despite COVID-19 patients being almost clinically indistinguishable from non-COVID-19 sepsis patients, COVID-19 patients had 1,215 differentially expressed genes compared to non-COVID-19 sepsis patients. After one week in the ICU, the number of differentially expressed genes dropped to just 9 genes. This drop coincided with decreased expression of antiviral genes and relatively increased expression of heme metabolism genes over time in COVID-19 patients, eventually reaching expression levels seen in non-COVID-19 sepsis patients. Both groups also had similar underlying immune dysfunction, with upregulation of immune processes such as "Interleukin-1 signaling" and "Interleukin-6/JAK/STAT3 signaling" throughout disease compared to healthy controls., Discussion: Early on, COVID-19 patients had elevated antiviral responses and suppressed heme metabolism processes compared to non-COVID-19 severe sepsis patients, although both had similar underlying immune dysfunction. However, after one week in the ICU, these diseases became indistinguishable on a gene expression level. These findings highlight the importance of early antiviral treatment for COVID-19, the potential for heme-related therapeutics, and consideration of immunomodulatory therapies for both diseases to treat shared immune dysfunction., Competing Interests: RH has a significant ownership position in Sepset Biotherapeutics Inc and has filed patents for sepsis diagnostic assays an indirect relationship to this work. CS is on the Data and Safety Monitoring Board of SEMPATICO NCT04615871. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 An, Baghela, Zhang, Falsafi, Lee, Trahtemberg, Baker, dos Santos and Hancock.)