Functional Significance Research Articles

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19

BackgroundRenal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes.MethodsThis retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression.ResultsThe prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03–1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36–2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64–4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08–3.23, P = 0.025) only.ConclusionsClinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

#2931 Advancing personalized extracorporeal therapies for albumin bound toxins through serum albumin binding function

Abstract Background and Aims Liver failure poses a significant clinical challenge with compromised functionality of the liver and accumulation of toxic metabolites. The lack of bedside-compatible methods to evaluate treatment response during therapy underscores the urgent need for refined diagnostic tools. Albumin, the principal transport protein, reflecting the elevated toxin and metabolite levels in liver failure, assumes a critical role in assessing the severity of hepatic dysfunction. This research introduces a novel method centered on a dansylsarcosine-based kinetic modeling of serum albumin binding, aiming to improve therapeutic decision-making in hepatic failure. This biomarker is designed to offer critical insights into albumin's dynamic interactions, essential for assessing liver function and effectiveness of therapeutic interventions. The study aims to supplement existing diagnostic methods, providing a more comprehensive evaluation of irreversible damages of albumin in liver failure and guiding more effective treatment strategies. Method In this study, we employed a novel method for measuring binding affinity at varying levels of dansylsarcosine, aiming to describe the kinetic properties of the Sudlow II binding site. The binding behavior of albumin under various concentrations of dansylsarcosine was characterized using a modified Michaelis-Menten kinetic model. To enhance accuracy, a formula correction was employed for both intrinsic absorbance and the influence of dansylsarcosine. The method facilitates kinetic modeling, exploring the behavior of the binding site under diverse ligand concentrations. Emerging from this are two key players: Bmax and Kd. Bmax quantifies the maximum capacity of binding sites available for occupation by dansylsarcosine. Kd signifies the concentration of dansylsarcosine at which half of the Sudlow II binding sites are saturated. The method was applied to a patient database of patients with hepatic failure treated with OPAL or MARS liver support systems (albumin dialysis with albumin regeneration). The applied analysis focused on the correlation with existing clinical scores and the description of therapeutic effects. Results The new method correlates with established markers, scores and therapeutic effects. For Patient samples from the OPALESCE database, Bmax and Kd exhibited correlations with established albumin biomarkers. Subgroup analysis revealed associations with clinical scores such as GCS, SOFA, MELD, ACLF, CLIF-OF and ABiC emphasizing the clinical relevance of Bmax and Kd values. Therapeutic effects were assessed using the OPALESCE database, demonstrating the capability of Bmax and Kd to describe therapy outcomes. Significant differences between the start and end of the first treatment were detected for MARS with Bmax and OPAL with Kd. Bmax and Kd values proved to be valuable indicators for therapeutic effects, aligning with established parameters such as ABiC and the CLIF-OF Score. These findings underscore the potential clinical utility of Bmax and Kd as robust markers for assessing therapy outcomes in liver support interventions. Conclusion The results help to provide a comprehensive understanding of albumin binding dynamics in patients with hepatic failure, offering a valuable tool for therapeutic decisions. The impact of therapy can be described using Bmax and Kd, both of which correlate with established clinical scores within the patient population. Bmax unveils irreversible damages to the albumin molecule, showcasing its potential to identify scenarios where applied therapies fail to enhance albumin binding functions. This insight prompts the consideration of alternative therapeutic pathways, including the consideration of therapeutic plasma exchange when extracorporeal methods are insufficient, showcasing the biomarker's utility in guiding precision therapeutic decisions for improved outcomes in hepatic failure management. The significance of albumin function for uraemic toxins needs to be further investigated. Optimization of dialysis for patients with renal insufficiency appears possible.

A Chemical Structure and Machine Learning Approach to Assess the Potential Bioactivity of Endogenous Metabolites and Their Association with Early Childhood Systemic Inflammation.

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother-child cohort. The annotated part of the metabolome consists of 517 chemical compounds curated using automated procedures. We created a filtering method for the quantified metabolites using predicted quantitative structure-bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines. The metabolites measured in the children's serums are predicted to affect specific targeted models, known for their significance in inflammation, immune function, and health outcomes. The targets from Tox21 have been used as targets with quantitative structure-activity relationships (QSARs). They were trained for ~7000 structures, saved as models, and then applied to the annotated metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation.

Multi-omics characterization of macrophage polarization-related features in osteoarthritis based on a machine learning computational framework

BackgroundOA imposes a heavy burden on patients and society in that its mechanism is still unclear, and there is a lack of effective targeted therapy other than surgery. MethodsThe osteoarthritis dataset GSE55235 was downloaded from the GEO database and analyzed for differential genes by limma package, followed by analysis of immune-related modules by xcell immune infiltration combined with the WGCNA method, and macrophage polarization-related genes were downloaded according to the Genecard database, and VennDiagram was used to determine their intersection. These genes were also subjected to gene ontology (GO), disease ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Using machine learning, the key osteoarthritis genes were finally screened. Using single gene GSEA and GSVA, we examined the significance of these key gene functions in immune cell and macrophage pathways. Next, we confirmed the correctness of the hub gene expression profile using the GSE55457 dataset and the ROC curve. Finally, we projected TF, miRNA, and possible therapeutic drugs using the miRNet, TargetScanHuman, ENCOR, and NetworkAnalyst databases, as well as Enrichr. ResultsVennDiagram obtained 71 crossover genes for DEGs, WGCNA-immune modules, and Genecards; functional enrichment demonstrated NF-κB, IL-17 signaling pathway play an important role in osteoarthritis-macrophage polarization genes; machine learning finally identified CSF1R, CX3CR1, CEBPB, and TLR7 as hub genes; GSVA analysis showed that CSF1R, CEBPB play essential roles in immune infiltration and macrophage pathway; validation dataset GSE55457 analyzed hub genes were statistically different between osteoarthritis and healthy controls, and the AUC values of ROC for CSF1R, CX3CR1, CEBPB and TLR7 were more outstanding than 0.65. ConclusionsCSF1R, CEBPB, CX3CR1, and TLR7 are potential diagnostic biomarkers for osteoarthritis, and CSF1R and CEBPB play an important role in regulating macrophage polarization in osteoarthritis progression and are expected to be new drug targets.

Advancing arboriculture through human and tree ecology

This paper explores the significance of ecosystem functions in maintaining the health and balance of ecological systems, particularly in the context of planning, managing, and maintaining trees in landscape settings. It emphasises the multifaceted relationship between humans and trees, encompassing cultural, ecological, economic, and emotional connections, and underscores the value of traditional ecological knowledge alongside empirical science. By combining these two ways of knowing, along with social science insights into human health and well-being, future landscapes can be crafted to be sustainable, diverse, and functional. As urbanisation continues to shape landscapes globally, urban planners face the challenge of managing rapidly changing environments. Urban forestry and arboriculture have emerged to address these challenges, aiming to enhance environmental quality and human well-being. The concept of Nature-based Solutions (NbS) has gained traction, recognising the importance of integrating natural systems into urban planning to address environmental challenges while preserving functional ecosystems. This paper advocates for an enhanced understanding of tree and human ecology to navigate the complex relations between trees, people, and their environments. It calls for interdisciplinary collaboration, research, and education to inform policy, assess environmental impacts, and widen approaches to ecosystem management. By monitoring ecosystem health and collaborating across disciplines, arboriculturists and urban foresters can shape resilient practices for tree conservation and sustainable urban development. In conclusion, integrating tree ecology into urban planning and management practices is essential for ensuring the health, resilience, and sustainability of tree populations and the ecosystems they inhabit. By embracing a holistic understanding of trees and their environments, professionals can contribute to shaping future landscapes that support both human well-being and biodiversity.

Research on Alternative Relationship between Chinese Renewable Energy and Imported Coal for China

The issue of energy security in the new development paradigm featuring dual circulation has been paid attention to by all sectors, but at present, there are few results from relevant quantitative analyses. With a focus on China’s actual energy trade, this research examines the core elements of energy security in international and Chinese cycles. In this context, the “gravity model” and “Allen substitution elasticity” are optimized and expanded. An integrated assessment methodology is developed as a result of this effort. This methodology consists of an international-cycle trade gravity model and a Chinese-cycle price elasticity model. Additionally, it empirically analyzes the effects of China’s renewable energy substitution from the perspective of the “dual cycles” of energy security, and illustrates the current state of China’s energy security through the analysis of energy substitution relationship data. The results show that Chinese renewable energy does have a buffer effect on imported coal in terms of trade efficiency, scale, and behavior, as well as performance, and the energy trade price has a direct guiding significance for this buffer function, but the enhancement function of economy-driven efficiency is indirect. Furthermore, as far as the absolute price elasticity and net price elasticity are concerned, although Chinese wind power generation is a substitute for imported coal, its price elasticity also confirms that Chinese wind power generation is not a “normal commodity”. Moreover, at present, Chinese photovoltaic power generation shows the attribute of a “normal commodity”, but it has a certain degree of complementarity with imported coal, although this complementarity will weaken in the near future with the trend of changing to substitution.

Humanin’s impact on pain markers and neuronal viability in diabetic neuropathy model

Objective This study investigates the impact of chronic humanin (HN) treatment on pain-related markers (NMDA, substance P, TRPV1, and IL-1β) in diabetic mice’s dorsal root ganglia (DRG). Additionally, we assess the effects of HN on cellular viability in DRG neurons. Methods In vivo experiments involved 15 days of HN administration (4 mg/kg) to diabetic mice (n = 10). Protein levels of NMDA, IL-1β, TRPV1, and substance P were measured in diabetic DRG. In vitro experiments explored HN’s impact on apoptosis and cellular viability, focusing on the JAK2/STAT3 pathway. Results Humanin significantly reduced the elevated expression of NMDA, IL-1β, TRPV1, and substance P induced by diabetes (p < .05). Furthermore, HN treatment increased cellular viability in DRG neurons through JAK2/STAT3 pathway activation (p < .05). Conclusion These findings highlight the significance of understanding mitochondrial function and pain markers, as well as apoptosis in diabetes. The study provides insights for managing the condition and its complications.

Comparative study of robust optimization model of multimaterial emergency logistics in an uncertain environment

AbstractGiven the significance of objective functions in alleviating human suffering within the humanitarian relief supply chain, it is imperative to consider both logistics costs and the cost of deprivation as ideal targets. This study investigates a multimaterial single‐cycle stochastic mixed integer model, integrating uncertainties about post‐disaster demand, supply survival, and road networks. An innovative heuristic approach is used to solve the stochastic facility location problem, which minimizes unfulfilled requests and response times in lexicographic order. This research also compares the cost‐minimization model of the pre‐positioning problem to an alternative model that maximizes demand satisfaction under resource constraints. Empirical validation through numerous case studies and solutions confirms the effectiveness and feasibility of the alternative model. The results of our experiments consistently demonstrate that the best solution provided by the alternative model not only satisfies the minimum cost model but also surpasses the conventional problem, without compromising performance. Consequently, it is crucial to avoid the cost‐minimization approach at the expense of human suffering.

Unraveling the significance of PPP1R1A gene in pancreatic β-cell function: A study in INS-1 cells and human pancreatic islets

Background and aimsThe protein phosphatase 1 regulatory inhibitor subunit 1A (PPP1R1A) has been linked with insulin secretion and diabetes mellitus. Yet, its full significance in pancreatic β-cell function remains unclear. This study aims to elucidate the role of the PPP1R1A gene in β-cell biology using human pancreatic islets and rat INS-1 (832/13) cells. ResultsDisruption of Ppp1r1a in INS-1 cells was associated with reduced insulin secretion and impaired glucose uptake; however, cell viability, ROS, apoptosis or proliferation were intact. A significant downregulation of crucial β-cell function genes such as Ins1, Ins2, Pcsk1, Cpe, Pdx1, Mafa, Isl1, Glut2, Snap25, Vamp2, Syt5, Cacna1a, Cacna1d and Cacnb3, was observed upon Ppp1r1a disruption. Furthermore, silencing Pdx1 in INS-1 cells altered PPP1R1A expression, indicating that PPP1R1A is a target gene for PDX1. Treatment with rosiglitazone increased Ppp1r1a expression, while metformin and insulin showed no effect. RNA-seq analysis of human islets revealed high PPP1R1A expression, with α-cells showing the highest levels compared to other endocrine cells. Muscle tissues exhibited greater PPP1R1A expression than pancreatic islets, liver, or adipose tissues. Co-expression analysis revealed significant correlations between PPP1R1A and genes associated with insulin biosynthesis, exocytosis machinery, and intracellular calcium transport. Overexpression of PPP1R1A in human islets augmented insulin secretion and upregulated protein expression of Insulin, MAFA, PDX1, and GLUT1, while silencing of PPP1R1A reduced Insulin, MAFA, and GLUT1 protein levels. ConclusionThis study provides valuable insights into the role of PPP1R1A in regulating β-cell function and glucose homeostasis. PPP1R1A presents a promising opportunity for future therapeutic interventions.

Mathematics discourse in instruction during functions lessons in grade 10 rural classrooms

Despite the global significance of functions in mathematics education, there has been limited research on how South African rural teachers address specific mathematical concepts related to functions. This qualitative multiple case study, conducted within a post-structural paradigm, delved into the discourses of Grade 10 teachers during functions lessons in rural classrooms. The study focused on the teaching of mathematical concepts related to functions and involved five mathematics teachers from rural school sites in Acornhoek, Mpumalanga Province, South Africa. These teachers were selected based on their experience in teaching mathematics. The research employed semi-structured interviews, unstructured classroom observations, and Video-Stimulated Recall Interviews with all five teachers. By narrowing the focus to one teacher's lesson, this paper analyses the presentation of functions concepts using the Mathematical Discourse in Instruction (MDI) framework. The study revealed that clear teaching materials and learner-engaging instructional methods enable meaningful engagement and concept internalisation. Through the visible use of the components of the MDI framework, the teacher successfully engaged learners, clarified misconceptions, and encouraged learners' participation, ultimately enhancing the coherence and understanding of mathematical concepts related to functions in the Grade 10 classroom.

Job function as determinant of clinker exposure at workplaces during cement production.

In the cement production industry, exposure to airborne particulate matter is associated with a decline in lung function and increased airway symptoms. Exposure to clinker-the major constituent of cement and supposedly the cause of the observed adverse health effects-was determined recently in 15 cement production plants located in 8 different countries (Estonia, Greece, Italy, Norway, Sweden, Switzerland, Spain, Turkey). It was shown that the median clinker abundance in the thoracic fraction varied between approximately 20% and 70% for individual plants. The present study complements the previous work by investigating the significance of job function as a determinant of clinker exposure. The elemental composition (water and acid-soluble fractions separately) of 1,227 personal thoracic workplace samples was analyzed by positive matrix factorization (PMF) to determine the contribution of different sources to the composition of airborne particulate matter and to quantify the clinker content. Median thoracic mass air concentrations varied for individual job functions between 0.094 and 12mg/m3 (estimated separately for different plants). The PMF 5-factor solution yielded median relative clinker abundances in the personal thoracic samples between 7.6% and 81% for individual job functions. Thoracic clinker air concentrations are highest for cleaning, production, and maintenance work, and lowest for administration and other work. Foremen and laboratory personnel show intermediate exposure levels. The plant was found to have a much higher contribution to the total variance of the thoracic clinker air concentrations than the job function. Thoracic clinker air concentrations (medians between 0.01 and 5.5mg/m3) are strongly correlated with the thoracic mass air concentrations and to a lesser extent with the relative clinker abundance in an aerosol sample. Job function is an important predictor of exposure to clinker in the cement production industry. As clinker is suspected to be the causal agent for the observed adverse health effects among cement production workers, the clinker air concentration may be a better exposure metric than thoracic air mass concentration despite the strong correlation between the two. Reduction strategies should focus on the most exposed job categories cleaning, production, and maintenance work.

Abstract 3930: The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma

Abstract Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, differences in classification methods have made it difficult to use these findings in clinical applications. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes. Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). A cluster of clusters approach (COCA) was used to find consensus subtypes of gastric tumors. We constructed the GAC predictor of the integrated consensus subtype with 120 genes (GPICS120) and applied it to the validation data set in order to validate the clinical significance of the new subtypes. By analyzing genomic and proteomic data we evaluated each subtype's potential response rate to standard and experimental treatments such radiation therapy, targeted therapy, and immunotherapy and further validated their functional significance in cell line models. Results: We identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) by integrating 8 previously established genomic subtypes. CGS1 is characterized by worst prognosis, remarkably high stem cell characteristics, high IGF1 expression, and low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. CGS5 has highest mutation burden and moderately elevated immune activity that is characteristics of MSI-high tumors. The majority of CGS6 tumors have extremely high methylation, high immune activity, and are EBV-positive. The most intriguing finding is that CGS1 is the most responsive to immunotherapy whereas CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level of ferroptosis. Furthermore, we showed that ferroptosis inducer statin sensitized radiation-resistant GAC cells to ionizing radiation, suggesting that statin can be used to enhance the efficacy of chemoradiation in GAC and it would warrant further investigation in preclinical models. Conclusion: Consensus subtype is robust classification system and can serve as the basis for future clinical trials as well as pre-clinical research into targeted subtype-based therapies. Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3930.

Abstract 7072: MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival

Abstract The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and functions of specific acetylated lysine (K) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and non-malignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type- dependent manner. Lysine-to-arginine substitutions indicate that although none of the acetylated K (AcK) residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism, and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC-transformed cells in vivo. These AcK residues may also preferentially activate transcription via facilitating MYC binding to several cancer-associated target gene promoters and via enhancing RNAP II recruitment. With the knowledge that MYC lysine residues can be acetylated by HATs GCN5 and P300, some HATs and HAT associated cofactors (i.e. YEATS2 and PIN1) are important for MYC recruitment to DNA binding. By identifying MYC acetylation-dependent coregulators and their oncogenic function, we proposed to understand whether and how MYC acetylation residues cooperate with its cofactors and influence malignant transformation in breast cancer cells.Overall, this study will uncover the functions and mechanisms of MYC acetylation in regulation of malignant transformation and the impact on breast cancer initiation and progression. By analyzing deregulated target genes and MYC-relevant coactivators, the MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities. Citation Format: Jeffrey J. Pino, Matthew Hurd, Yifan Zhao, Kay Jang, Michael Allevato, Marina Vorontchikhina, Wataru Ichikawa, Ryan Gates, Emily Villalpando, Michael Hamilton, Francesco Failo, Songqin Pan, Yue Qi, Yu-wen Hung, Thomas Girke, David Ann, Victoria Seewaldt, Ernest Martinez. MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7072.

The impact of ovarian stimulation on the human endometrial microenvironment.

How does ovarian stimulation (OS), which is used to mature multiple oocytes for ART procedures, impact the principal cellular compartments and transcriptome of the human endometrium in the periovulatory and mid-secretory phases? During the mid-secretory window of implantation, OS alters the abundance of endometrial immune cells, whereas during the periovulatory period, OS substantially changes the endometrial transcriptome and impacts both endometrial glandular and immune cells. Pregnancies conceived in an OS cycle are at risk of complications reflective of abnormal placentation and placental function. OS can alter endometrial gene expression and immune cell populations. How OS impacts the glandular, stromal, immune, and vascular compartments of the endometrium, in the periovulatory period as compared to the window of implantation, is unknown. This prospective cohort study carried out between 2020 and 2022 included 25 subjects undergoing OS and 25 subjects in natural menstrual cycles. Endometrial biopsies were performed in the proliferative, periovulatory, and mid-secretory phases. Blood samples were processed to determine serum estradiol and progesterone levels. Both the endometrial transcriptome and the principal cellular compartments of the endometrium, including glands, stroma, immune, and vasculature, were evaluated by examining endometrial dating, differential gene expression, protein expression, cell populations, and the three-dimensional structure in endometrial tissue. Mann-Whitney U tests, unpaired t-tests or one-way ANOVA and pairwise multiple comparison tests were used to statistically evaluate differences. In the periovulatory period, OS induced high levels of differential gene expression, glandular-stromal dyssynchrony, and an increase in both glandular epithelial volume and the frequency of endometrial monocytes/macrophages. In the window of implantation during the mid-secretory phase, OS induced changes in endometrial immune cells, with a greater frequency of B cells and a lower frequency of CD4 effector T cells. The data underlying this article have been uploaded to the Genome Expression Omnibus/National Center for Biotechnology Information with accession number GSE220044. A limited number of subjects were included in this study, although the subjects within each group, natural cycle or OS, were homogenous in their clinical characteristics. The number of subjects utilized was sufficient to identify significant differences; however, with a larger number of subjects and additional power, we may detect additional differences. Another limitation of the study is that proliferative phase biopsies were collected in natural cycles, but not in OS cycles. Given that the OS cycle subjects did not have known endometrial factor infertility, and the comparisons involved subjects who had a similar and robust response to stimulation, the findings are generalizable to women with a normal response to OS. OS substantially altered the periovulatory phase endometrium, with fewer transcriptomic and cell type-specific changes in the mid-secretory phase. Our findings show that after OS, the endometrial microenvironment in the window of implantation possesses many more similarities to that of a natural cycle than does the periovulatory endometrium. Further investigation of the immune compartment and the functional significance of this cellular compartment under OS conditions is warranted. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (R01AI148695 to A.M.B. and N.C.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD109152 to R.A.), and the March of Dimes (5-FY20-209 to R.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or March of Dimes. All authors declare no conflict of interest.

Spatial ecology of Haemophilus and Aggregatibacter in the human oral cavity.

Understanding the microbial ecology of the mouth is essential for comprehending human physiology. This study employs metapangenomics to reveal that various Haemophilus and Aggregatibacter species exhibit distinct ecological preferences within the oral cavity of healthy individuals, thereby supporting the site-specialist hypothesis. Additionally, it was observed that the gene pool of different Haemophilus species correlates with their ecological niches. These findings shed light on the significance of key metabolic functions in shaping microbial distribution patterns and interspecies interactions in the oral ecosystem.

Type-I-interferon-responsive microglia shape cortical development and behavior

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

Extracellular acidification attenuates bronchial contraction via an autocrine activation of EP2 receptor: Its diminishment in murine experimental asthma

PurposeExtracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological significance in bronchial function is not fully understood. Currently, the functional role of extracellular acidification on bronchial contraction was explored. MethodsLeft main bronchi were isolated from male BALB/c mice. Epithelium-removed tissues were exposed to acidic pH under submaximal contraction induced by 10−5 M acetylcholine in the presence or absence of a COX inhibitor indomethacin (10−6 M). Effects of AH6809 (10−6 M, an EP2 receptor antagonist), BW A868C (10−7 M, a DP receptor antagonist) and CAY10441 (3×10−6 M, an IP receptor antagonist) on the acidification-induced change in tension were determined. The release of prostaglandin E2 (PGE2) from epithelium-denuded tissues in response to acidic pH was assessed using an ELISA. ResultsIn the bronchi stimulated with acetylcholine, change in the extracellular pH from 7.4 to 6.8 caused a transient augmentation of contraction followed by a sustained relaxing response. The latter inhibitory response was abolished by indomethacin and AH6809 but not by BW A868C or CAY10441. Both indomethacin and AH6809 significantly increased potency and efficacy of acetylcholine at pH 6.8. Stimulation with low pH caused an increase in PGE2 release from epithelium-denuded bronchi. Interestingly, the acidic pH-induced bronchial relaxation was significantly reduced in a murine asthma model that had a bronchial hyperresponsiveness to acetylcholine. ConclusionTaken together, extracellular acidification could inhibit the bronchial contraction via autocrine activation of EP2 receptors. The diminished acidic pH-mediated inhibition of bronchial tone may contribute to excessive bronchoconstriction in inflamed airways such as asthma.

Features of the course and treatment of bronchial asthma combined with arterial hypertension: a review

Bronchial asthma (BA) is a serious medical and social problem. Many patients with asthma have various concomitant chronic diseases, among which the pathology of the cardiovascular system occupies an important place. Most often, asthma occurs with arterial hypertension (AH). This concurrence can lead to mutual aggravation and progression of these diseases and may negatively affect the prognosis. Usually, difficulties appear when choosing the most effective therapy for BA along with hypertension. This review aimed to analyse the available publications on the problem of the combination of BA and hypertension. A review of the literature presents the summary, examines data on prevalence and indicates risk factors for the development of hypertension among patients with asthma. The coexistence of these diseases is more typical in older people. The review includes questions regarding the pathophysiology of this comorbidity. The role of impaired gas exchange and hypoxia, endothelial dysfunction, participation of the nitric oxide system and obesity in the development of hypertension in combination with asthma are highlighted. The significance of impaired nonrespiratory lung function is shown, and the inflammation features in this comorbid pathology are indicated, as well as the contribution of numerous genes to the development of asthma along with hypertension. In the literature, 330 common genes have been identified that may be involved in the molecular mechanisms of asthma and hypertension. This study shows the effect of concomitant hypertension on the course, asthma control and quality of life of the patients. In addition, the article shows modern approaches to effective therapy with the main groups of drugs used to treat these diseases. To date, studies have demonstrated the prevalence of the combination of asthma and hypertension in the structure of comorbidity, mutual influence and aggravation of these pathologies. Coexistence of BA and hypertension increases the severity of clinical symptoms. This article shows the important aspects of the treatment of a combination of diseases. The need for a thorough assessment of the safety of pharmacological therapy for BA along with hypertension has been demonstrated.

Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans

Most eukaryotic genes undergo alternative splicing (AS), but the overall functional significance of this process remains a controversial issue. It has been noticed that the complexity of organisms (assayed by the number of distinct cell types) correlates positively with their genome-wide AS rate. This has been interpreted as evidence that AS plays an important role in adaptive evolution by increasing the functional repertoires of genomes. However, this observation also fits with a totally opposite interpretation: given that ‘complex’ organisms tend to have small effective population sizes (Ne), they are expected to be more affected by genetic drift, and hence more prone to accumulate deleterious mutations that decrease splicing accuracy. Thus, according to this ‘drift barrier’ theory, the elevated AS rate in complex organisms might simply result from a higher splicing error rate. To test this hypothesis, we analyzed 3496 transcriptome sequencing samples to quantify AS in 53 metazoan species spanning a wide range of Ne values. Our results show a negative correlation between Ne proxies and the genome-wide AS rates among species, consistent with the drift barrier hypothesis. This pattern is dominated by low abundance isoforms, which represent the vast majority of the splice variant repertoire. We show that these low abundance isoforms are depleted in functional AS events, and most likely correspond to errors. Conversely, the AS rate of abundant isoforms, which are relatively enriched in functional AS events, tends to be lower in more complex species. All these observations are consistent with the hypothesis that variation in AS rates across metazoans reflects the limits set by drift on the capacity of selection to prevent gene expression errors.

Soil metabolomics - current challenges and future perspectives

Soil is an extremely complex and dynamic matrix, in part, due to the wide diversity of organisms living within it. Soil organic matter (SOM) is the fundamental substrate on which the delivery of ecosystem services depends, providing the metabolic fuel to drive soil function. As such, studying the soil metabolome (the diversity and concentration of low molecular weight metabolites), as a subset of SOM, holds the potential to greatly expand our understanding of the behaviour, fate, interaction and functional significance of small organic molecules in soil. Encompassing a wide range of chemical classes (including amino acids, peptides, lipids and carbohydrates) and a large number of individual molecules (ca. n = 105 to 106), the metabolome is a resultant (indirect) output of several layers of a biological hierarchy, namely the metagenome, metatranscriptome and metaproteome. As such, it may also provide support and validation for these “multi-omics” datasets. We present a case for the increased use of untargeted metabolomics in soil biochemistry, particularly for furthering our fundamental understanding of the functions driving SOM composition and biogeochemical cycling. Further, we discuss the scale of the challenge in terms of metabolite extraction, analysis and interpretation in complex plant-soil-microbial systems. Lastly, we highlight key knowledge gaps which currently limit our use of metabolomic approaches to better understand soil processes, including: (i) interpretation of large untargeted metabolomic datasets; (ii) the source, emission and fate of soil-derived volatile organic compounds (VOCs), (iii) assessing temporal fluxes of metabolites, and (iv) monitoring ecological interactions in the rhizosphere. While the application of metabolomics in ecosystem science is still in its relative infancy, its importance in understanding the biochemical system in relation to regulation, management and underpinning the delivery of ecosystem services is key to further elucidating the complex links between organisms, as well as the fundamental ability of the biological community to process and cycle key nutrients.