bluuebunny/crossref_metadata_2025 huggingface dataset:
The NR2F2-HAND2 signaling axis regulates progesterone actions in the uterus at early pregnancy
Authors: Oh Yeongseok , Quiroz Elvis , Wang Tianyuan , Medina-Laver Yassmin , Redecke Skylar Montague , Dominguez Francisco , Lydon John P. , DeMayo Francesco J. , Wu San-Pin
Published: August 2023

Endometrial function is dependent on a tight crosstalk between the epithelial and stromal cells of the endometrium. This communication is critical to ensure a fertile uterus and relies on progesterone and estrogen signaling to prepare a receptive uterus for embryo implantation in early pregnancy. One of the key mediators of this crosstalk is the orphan nuclear receptor NR2F2, which regulates uterine epithelial receptivity and stromal cell differentiation. In order to determine the molecular mechanism regulated by NR2F2, RNAseq analysis was conducted on the uterus of PgrCre;Nr2f2f/f mice at Day 3.5 of pregnancy. This transcriptomic analysis demonstrated Nr2f2 ablation in Pgr-expressing cells leads to a reduction of Hand2 expression, increased levels of Hand2 downstream effectors Fgf1 and Fgf18, and a transcriptome manifesting suppressed progesterone signaling with an altered immune baseline. ChIPseq analysis conducted on the Day 3.5 pregnant mouse uterus for NR2F2 demonstrated the majority of NR2F2 occupies genomic regions that have H3K27ac and H3K4me1 histone modifications, including the loci of major uterine transcription regulators Hand2, Egr1, and Zbtb16. Furthermore, functional analysis of an NR2F2 occupying site that is conserved between human and mouse was capable to enhance endogenous HAND2 mRNA expression with the CRISPR activator in human endometrial stroma cells. These data establish the NR2F2 dependent regulation of Hand2 in the stroma and identify a cis-acting element for this action. In summary, our findings reveal a role of the NR2F2-HAND2 regulatory axis that determines the uterine transcriptomic pattern in preparation for the endometrial receptivity.
Pharmaceutical compounds in urban drinking waters of Ecuador
Authors: Jara-Negrete Eliza , Cipriani-Avila Isabel , Molinero Jon , Pinos-Vélez Verónica , Acosta-López Sofía , Cabrera Marcela , Medina-Villamizar Evencio Joel , Leiva-Andrade David , Pozo Andrea , Martínez Omar , Mogollón Noroska G.S.
Published: August 2023

Introduction: Emerging contaminants (ECs) are substances with widely diverse chemical structures that may pose a risk to the environment and human beings. The limited scope of water treatment facilities, particularly in low and middle-income countries, allows ECs to be continuously introduced to the environment and become part of the cycle again for potabilization. In this work, we study for the first time the presence of these compounds in the drinking water of five Ecuadorian cities.

Methods: The compounds of interest were mainly pharmaceutical substances commonly present in prescription and over-the-counter medicines, along with caffeine, a known coadjuvant in some of these preparations. Samples were collected from Quito, Guayaquil, Cuenca, Ibarra, and Esmeraldas, considering each city’s distribution systems, and, after solid-phase extraction, analyzed by LC-MS/MS ESI+.

Results and discussion: Results showed a high occurrence of caffeine, the only analyte present in all cities, with concentrations ranging from <6.35 to 201 ngL-1 and an occurrence from 11% in Quito to 77% in Cuenca. The highest median was found in Cuenca, followed by Esmeraldas. Our observations regarding concentrations are comparable to other studies around the globe. Although in other cities, some pharmaceuticals appeared at levels below our detection limits. These findings highlight the ubiquitous nature of emerging contaminants while pointing out the need for regulatory frameworks that facilitate the implementation of treatment technologies at the source and wastewater level. These actions will safeguard public and environmental health in the long term.
Habitat associations of woody plant species in evergreen–deciduous broadleaf karst forests in southwest China
Authors: Su Liang , Du Hu , Zeng Fuping , Wang Hua , Lu Menzhen , Luo Liujuan , Peng Wanxia , Song Tongqing
Published: August 2023

The effects of habitat filtering on community assembly have been extensively researched, and topography has been identified as a critical factor influencing the spatial distribution of trees. In this study, a 25-ha plot was established in karst evergreen–deciduous broadleaf forests in southwestern China. Eight topographical factors were used to divide plots into four habitat types, i.e., hilltop, steep slope, gentle slope, and depression, using a multivariate regression tree. A total of 85 evergreen and deciduous tree species were recorded in these four habitats and classified into three life stages, the differentiation of which was assessed using torus-translation tests. A total of 65 species significantly positively associated with at least one habitat and 79 species significantly negatively associated with at least one habitat were identified. Most species, whether evergreen or deciduous, exhibited a positive correlation with steep slopes, whereas relatively few species were adapted to depressions. Moreover, the percentage of evergreen species positively associated with hilltops and steep slopes was higher than that of deciduous species. Both evergreen and deciduous species showed an increasing percentage of positive correlation with hilltops from the sapling stage to the mature stage. However, more evergreen species grew on steep slopes in the sapling stage, whereas deciduous species grew in the mature stage. Canonical correspondence was used to analyze the relationship between species and the eight topographical factors. Regardless of life form or life stage, results showed that species distribution was significantly affected by topography. Furthermore, the distribution of evergreen species on sapling-stage trees was found to be more influenced by topography, whereas deciduous species were more influenced by topography in the mature stage. Finally, elevation was identified as the most crucial topographical factor affecting species distribution.
Microbial management as a driver of parental care and family aggregations in carrion feeding insects
Authors: Körner Maximilian , Steiger Sandra , Shukla Shantanu P.
Published: August 2023

Social behaviors and lifestyles have evolved as successful strategies to cope with adverse and challenging living conditions, often by manipulating the immediate environment. These manipulations can extend to the surrounding microbiome, both in terms of combating harmful agents such as pathogens but also by facilitating the growth of beneficial microbes. In contrast to the largely antagonistic role traditionally assigned to microbes in social systems, these host–microbe interactions are receiving increasing attention as potential facilitators of social evolution. Here, we explore this perspective using Nicrophorus burying beetles, a group of insect carrion breeders which offer insights into the evolutionary interactions between sociality and microbial mutualists in a relatively simple family model. Recent studies have demonstrated the constant microbial challenges faced by Nicrophorus nurseries and the costly consequences they entail. Here, we provide an overview of these challenges and then explore the role of microbial mutualists in this social endeavor, focusing on the advantages they confer in terms of development and immunity. Additionally, we discuss how these mutualistic associations may select for committed parental care and more obligate forms of social life by promoting prolonged social associations through vertical transmission. Our review highlights the hypothesis that microbial mutualists not only provide immediate benefits but may also encourage social interactions in their hosts. However, the occurrence, degree, and underlying mechanisms of this phenomenon remain largely theoretical, as do the evolutionary feedbacks on microbes. Empirical evidence in this area is currently limited, emphasizing the need for further research. Nicrophorus burying beetles represent an ideal system to investigate the interplay between microbial mutualists and social evolution, offering a promising avenue for future studies. Overall, this review underscores the importance of understanding the complex interactions between microbial mutualists and social behaviors in challenging environments, and beyond.
Accelerated matrix-vector multiplications for matrices involving genotype covariates with applications in genomic prediction
Authors: Freudenberg Alexander , Vandenplas Jeremie , Schlather Martin , Pook Torsten , Evans Ross , Ten Napel Jan
Published: August 2023

In the last decade, a number of methods have been suggested to deal with large amounts of genetic data in genomic predictions. Yet, steadily growing population sizes and the suboptimal use of computational resources are pushing the practical application of these approaches to their limits. As an extension to the C/CUDA library miraculix, we have developed tailored solutions for the computation of genotype matrix multiplications which is a critical bottleneck in the empirical evaluation of many statistical models. We demonstrate the benefits of our solutions at the example of single-step models which make repeated use of this kind of multiplication. Targeting modern Nvidia® GPUs as well as a broad range of CPU architectures, our implementation significantly reduces the time required for the estimation of breeding values in large population sizes. miraculix is released under the Apache 2.0 license and is freely available at https://github.com/alexfreudenberg/miraculix.
Integrated transcriptomics, proteomics and metabolomics-based analysis uncover TAM2-associated glycolysis and pyruvate metabolic remodeling in pancreatic cancer
Authors: Li Xin , Du Yan , Jiang Wenkai , Dong Shi , Li Wancheng , Tang Huan , Yi Jianfeng , Zhou Wence , Zhang Hui
Published: August 2023

Introduction

Tumor-associated macrophage 2 (TAM2) abundantly infiltrates pancreatic ductal adenocarcinoma (PAAD), and its interaction with malignant cells is involved in the regulation of tumor metabolism. In this study, we explored the metabolic heterogeneity involved in TAM2 by constructing TAM2-associated metabolic subtypes in PAAD.

Materials and methods

PAAD samples were classified into molecular subtypes with different metabolic characteristics based on a multi-omics analysis strategy. 20 PAAD tissues and 10 normal pancreatic tissues were collected for proteomic and metabolomic analyses. RNA sequencing data from the TCGA-PAAD cohort were used for transcriptomic analyses. Immunohistochemistry was used to assess TAM2 infiltration in PAAD tissues.

Results

The results of transcriptomics and immunohistochemistry showed that TAM2 infiltration levels were upregulated in PAAD and were associated with poor patient prognosis. The results of proteomics and metabolomics indicated that multiple metabolic processes were aberrantly regulated in PAAD and that this dysregulation was linked to the level of TAM2 infiltration. WGCNA confirmed pyruvate and glycolysis/gluconeogenesis as co-expressed metabolic pathways of TAM2 in PAAD. Based on transcriptomic data, we classified the PAAD samples into four TAM2-associated metabolic subtypes (quiescent, pyruvate, glycolysis/gluconeogenesis and mixed). Metabolic subtypes were each characterized in terms of clinical prognosis, tumor microenvironment, immune cell infiltration, chemotherapeutic drug sensitivity, and functional mechanisms.

Conclusion

Our study confirmed that the metabolic remodeling of pyruvate and glycolysis/gluconeogenesis in PAAD was closely related to TAM2. Molecular subtypes based on TAM2-associated metabolic pathways provided new insights into prognosis prediction and therapy for PAAD patients.
CD44+ and CD31+ extracellular vesicles (EVs) are significantly reduced in polytraumatized patients with hemorrhagic shock – evaluation of their diagnostic and prognostic potential
Authors: Weber Birte , Sturm Ramona , Henrich Dirk , Marzi Ingo , Leppik Liudmila
Published: August 2023

Background

Hemorrhagic shock (HS) is responsible for approximately 2 million deaths per year worldwide and is caused in 80% by polytrauma. These patients need a precise and quick diagnostic, which should be based on a combination of laboratory markers and radiological data. Extracellular vesicles (EVs) were described as potential new markers and mediators in trauma. The aim of the present study was to analyze, whether the surface epitopes of plasma-EVs reflect HS in polytraumatized patients and whether cell-specific EV subpopulations are useful diagnostic tools.

Material and methods

Plasma samples from polytraumatized patients (ISS ≥16) with HS (n=10) and without (n=15), were collected at emergency room (ER) and 24h after trauma. Plasma-EVs were isolated via size exclusion chromatography and EV-concentrations were detected by Coomassie Plus (Bradford) Assay. The EVs subpopulations were investigated by a bead-based multiplex flow cytometry measurement of surface epitopes and were compared with healthy controls (n=10). To investigate the diagnostic and prognostic potential of EVs subpopulations, results were correlated with clinical outcome parameters documented in the electronical patients’ record.

Results

We observed a significant reduction of the total amount of plasma EVs in polytrauma patients with HS, as compared to polytrauma patients without HS and healthy controls. We found significant reduction of CD42a+ and CD41b+ (platelet-derived) EVs in all polytrauma patients, as well as a reduction of CD29+ EVs compared to healthy volunteers (*p<0.05). CD44+ and CD31+ EVs were specifically altered in patients with HS (*p<0.05). Both EV populations showed a moderate correlation (r² = 0.42) with the transfusion of erythrocyte concentrate, were associated with non-survival and the need for catecholamines (*p<0.05).

Conclusion

Our data reveal that polytrauma patients with a hemorrhagic shock are characterized by a reduction of CD44+ and CD31+ plasma-EVs. Both EV populations showed a moderate correlation with the need of erythrocyte transfusion, were associated with non-survival and the need for catecholamines.
Identification of immunogenic cell death-related signature on prognosis and immunotherapy in kidney renal clear cell carcinoma
Authors: Jiang Silin , Dong Yuxiang , Wang Jun , Zhang Xi , Liu Wei , Wei Yong , Zhou Hai , Shen Luming , Yang Jian , Zhu Qingyi
Published: August 2023

Background

Immunogenic cell death (ICD) is considered a particular cell death modality of regulated cell death (RCD) and plays a significant role in various cancers. The connection between kidney renal clear cell carcinoma (KIRC) and ICD remains to be thoroughly explored.

Methods

We conducted a variety of bioinformatics analyses using R software, including cluster analysis, prognostic analysis, enrichment analysis and immune infiltration analysis. In addition, we performed Quantitative Real-time PCR to evaluate RNA levels of specific ICD genes. The proliferation was measured through Cell Counting Kit-8 (CCK-8) assay and colony-formation assay in RCC cell lines.

Results

We determined two ICD subtypes through consensus clustering analysis. The two subtypes showed significantly different clinical outcomes, genomic alterations and tumor immune microenvironment. Moreover, we constructed the ICD prognostic signature based on TF, FOXP3, LY96, SLC7A11, HSP90AA1, UCN, IFNB1 and TLR3 and calculated the risk score for each patient. Kaplan-Meier survival analysis and ROC curve demonstrated that patients in the high-risk group had significantly poorer prognosis compared with the low-risk group. We then validated the signature through external cohort and further evaluated the relation between the signature and clinical features, tumor immune microenvironment and immunotherapy response. Given its critical role in ICD, we conducted further analysis on LY96. Our results indicated that downregulation of LY96 inhibited the proliferation ability of RCC cells.

Conclusions

Our research revealed the underlying function of ICD in KIRC and screened out a potential biomarker, which provided a novel insight into individualized immunotherapy in KIRC.
Identification of molecular subtypes based on PANoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma
Authors: Zhu Jinfeng , Huang Qian , Peng Xingyu , Luo Chen , Liu Zitao , Liu Dongdong , Yuan Huazhao , Yuan Rongfa , Cheng Xuexin
Published: August 2023

Background

Previous studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC).

Methods

Based on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments.

Results

This study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration.

Conclusion

PANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment.
Research on the biological mechanism and potential application of CEMIP
Authors: Liu Yang , Hu Gang , Li Yuetong , Kong Xinyi , Yang Kaming , Li Zhenlin , Lao Wanwen , Li Jiaxin , Zhong Jianhua , Zhang Shitong , Leng Yuxin , Bi Changlong , Zhai Aixia
Published: August 2023

Cell migration–inducing protein (CEMIP), also known as KIAA1199 and hyaluronan-binding protein involved in hyaluronan depolymerization, is a new member of the hyaluronidase family that degrades hyaluronic acid (HA) and remodels the extracellular matrix. In recent years, some studies have reported that CEMIP can promote the proliferation, invasion, and adhesion of various tumor cells and can play an important role in bacterial infection and arthritis. This review focuses on the pathological mechanism of CEMIP in a variety of diseases and expounds the function of CEMIP from the aspects of inhibiting cell apoptosis, promoting HA degradation, inducing inflammatory responses and related phosphorylation, adjusting cellular microenvironment, and regulating tissue fibrosis. The diagnosis and treatment strategies targeting CEMIP are also summarized. The various functions of CEMIP show its great potential application value.
Small molecular inhibitors for KRAS-mutant cancers
Authors: Wu Xuan , Song Wenping , Cheng Cheng , Liu Ziyang , Li Xiang , Cui Yu , Gao Yao , Li Ding
Published: August 2023

Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered “undruggable”, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.
Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications
Authors: Salek-Ardakani Shahram , Zajonc Dirk M. , Croft Michael
Published: August 2023

Costimulatory receptors on immune cells represent attractive targets for immunotherapy given that these molecules can increase the frequency of individual protective immune cell populations and their longevity, as well as enhance various effector functions. 4-1BB, a member of the TNF receptor superfamily, also known as CD137 and TNFRSF9, is one such molecule that is inducible on several cell types, including T cells and NK cells. Preclinical studies in animal models have validated the notion that stimulating 4-1BB with agonist reagents or its natural ligand could be useful to augment conventional T cell and NK cell immunity to protect against tumor growth and against viral infection. Additionally, stimulating 4-1BB can enhance regulatory T cell function and might be useful in the right context for suppressing autoimmunity. Two human agonist antibodies to 4-1BB have been produced and tested in clinical trials for cancer, with variable results, leading to the production of a wealth of second-generation antibody constructs, including bi- and multi-specifics, with the hope of optimizing activity and selectivity. Here, we review the progress to date in agonism of 4-1BB, discuss the complications in targeting the immune system appropriately to elicit the desired activity, together with challenges in engineering agonists, and highlight the untapped potential of manipulating this molecule in infectious disease and autoimmunity.
Bat behavioral immune responses in social contexts: current knowledge and future directions
Authors: Stockmaier Sebastian
Published: August 2023

Animals often mount complex immune responses to infections. Aside from cellular and molecular defense mechanisms, animals can alter their behavior in response to infection by avoiding, resisting, or tolerating negative effects of pathogens. These behaviors are often connected to cellular and molecular immune responses. For instance, sickness behaviors are a set of behavioral changes triggered by the host inflammatory response (e.g., cytokines) and could aid in resisting or tolerating infection, as well as affect transmission dynamics if sick animals socially withdraw or are being avoided by others. To fully understand the group and population level transmission dynamics and consequences of pathogen infections in bats, it is not only important to consider cellular and molecular defense mechanisms, but also behavioral mechanisms, and how both interact. Although there has been increasing interest in bat immune responses due to their ability to successfully cope with viral infections, few studies have explored behavioral anti-pathogen defense mechanisms. My main objective is to explore the interaction of cellular and molecular defense mechanisms, and behavioral alterations that results from infection in bats, and to outline current knowledge and future research avenues in this field.
DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase
Authors: Komorowicz Erzsébet , Farkas Veronika J. , Szabó László , Cherrington Sophie , Thelwell Craig , Kolev Krasimir
Published: August 2023

Background

Staphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure.

Objectives

To characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability.

Methods

Recombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry.

Results

Histones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present.

Conclusions

In the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization.
Immune cells as messengers from the CNS to the periphery: the role of the meningeal lymphatic system in immune cell migration from the CNS
Authors: Laaker Collin , Baenen Cameron , Kovács Kristóf G. , Sandor Matyas , Fabry Zsuzsanna
Published: August 2023

In recent decades there has been a large focus on understanding the mechanisms of peripheral immune cell infiltration into the central nervous system (CNS) in neuroinflammatory diseases. This intense research led to several immunomodulatory therapies to attempt to regulate immune cell infiltration at the blood brain barrier (BBB), the choroid plexus (ChP) epithelium, and the glial barrier. The fate of these infiltrating immune cells depends on both the neuroinflammatory environment and their type-specific interactions with innate cells of the CNS. Although the fate of the majority of tissue infiltrating immune cells is death, a percentage of these cells could become tissue resident immune cells. Additionally, key populations of immune cells can possess the ability to “drain” out of the CNS and act as messengers reporting signals from the CNS toward peripheral lymphatics. Recent data supports that the meningeal lymphatic system is involved not just in fluid homeostatic functions in the CNS but also in facilitating immune cell migration, most notably dendritic cell migration from the CNS to the meningeal borders and to the draining cervical lymph nodes. Similar to the peripheral sites, draining immune cells from the CNS during neuroinflammation have the potential to coordinate immunity in the lymph nodes and thus influence disease. Here in this review, we will evaluate evidence of immune cell drainage from the brain via the meningeal lymphatics and establish the importance of this in animal models and humans. We will discuss how targeting immune cells at sites like the meningeal lymphatics could provide a new mechanism to better provide treatment for a variety of neurological conditions.
Gut microbiota and sepsis: bidirectional Mendelian study and mediation analysis
Authors: Zhang Zhi , Cheng Lin , Ning Dong
Published: August 2023

Background

There is a growing body of evidence that suggests a connection between the composition of gut microbiota and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between gut microbiota, C-reactive protein (CRP), and sepsis, we conducted several Mendelian randomization (MR) analyses.

Methods

In this study, publicly available genome-wide association study (GWAS) summary statistics were examined to determine the correlation between gut microbiota and sepsis, including various sepsis subgroups (such as under 75, 28-day death, Critical Care Units (ICU), 28-day death in ICU). Initially, two-sample and reverse Mendelian randomization (MR) analyses were conducted to identify causality between gut microbiota and sepsis. Subsequently, multivariable and two-step MR analyses revealed that the relationship between microbiota and sepsis was mediated by CRP. The robustness of the findings was confirmed through several sensitivity analyses.

Findings

In our study, we revealed positive correlations between 24 taxa and different sepsis outcomes, while 30 taxa demonstrated negative correlations with sepsis outcomes. Following the correction for multiple testing, we found that the Phylum Lentisphaerae (OR: 0.932, p = 2.64E-03), class Lentisphaeria, and order Victivallales (OR: 0.927, p = 1.42E-03) displayed a negative relationship with sepsis risk. In contrast, Phylum Tenericutes and class Mollicutes (OR: 1.274, p = 2.89E-03) were positively related to sepsis risk and death within 28 days. It is notable that Phylum Tenericutes and class Mollicutes (OR: 1.108, p = 1.72E-03) also indicated a positive relationship with sepsis risk in individuals under 75. From our analysis, it was shown that C-reactive protein (CRP) mediated 32.16% of the causal pathway from Phylum Tenericutes and class Mollicutes to sepsis for individuals under 75. Additionally, CRP was found to mediate 31.53% of the effect of the genus Gordonibacter on sepsis. Despite these findings, our reverse analysis did not indicate any influence of sepsis on the gut microbiota and CRP levels.

Conclusion

The study showcased the connection between gut microbiota, CRP, and sepsis, which sheds new light on the potential role of CRP as a mediator in facilitating the impact of gut microbiota on sepsis.
Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells
Authors: Vellozo Natália S. , Matos-Silva Thayane C. , Lopes Marcela F.
Published: August 2023

During Trypanosoma cruzi infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease. Here, we highlight a key role of macrophage activation in early immune responses to T. cruzi that prevent escalating parasitemia, heart parasitism, and mortality during acute infection. We will discuss the mechanisms of macrophage activation and deactivation, such as T cell cytokines and efferocytosis, and how to improve macrophage-mediated immunity to prevent parasite persistence, inflammation, and the development of chagasic cardiomyopathy. Potential vaccines or therapy must enhance early T cell-macrophage crosstalk and parasite control to restrain the pathogenic outcomes of parasite-induced inflammation in the heart.
Immune responses to Neisseria gonorrhoeae and implications for vaccine development
Authors: Belcher Thomas , Rollier Christine S. , Dold Christina , Ross Jonathan D. C. , MacLennan Calman A.
Published: August 2023

Neisseria gonorrheoae is the causative agent of gonorrhea, a sexually transmitted infection responsible for a major burden of disease with a high global prevalence. Protective immunity to infection is often not observed in humans, possible due to high variability of key antigens, induction of blocking antibodies, or a large number of infections being relatively superficial and not inducing a strong immune response. N. gonorrhoeae is a strictly human pathogen, however, studies using mouse models provide useful insights into the immune response to gonorrhea. In mice, N. gonorrhoea appears to avoid a protective Th1 response by inducing a less protective Th17 response. In mouse models, candidate vaccines which provoke a Th1 response can accelerate the clearance of gonococcus from the mouse female genital tract. Human studies indicate that natural infection often induces a limited immune response, with modest antibody responses, which may correlate with the clinical severity of gonococcal disease. Studies of cytokine responses to gonococcal infection in humans provide conflicting evidence as to whether infection induces an IL-17 response. However, there is evidence for limited induction of protective immunity from a study of female sex workers in Kenya. A controlled human infection model (CHIM) has been used to examine the immune response to gonococcal infection in male volunteers, but has not to date demonstrated protection against re-infection. Correlates of protection for gonorrhea are lacking, which has hampered the progress towards developing a successful vaccine. However, the finding that the Neisseria meningitidis serogroup B vaccines, elicit cross-protection against gonorrhea has invigorated the gonococcal vaccine field. More studies of infection in humans, either natural infection or CHIM studies, are needed to understand better gonococcal protective immunity.
Moving beyond agriculture and aquaculture to integrated sustainable food systems as part of a circular bioeconomy
Authors: Olesen Ingrid , Bonaldo Alessio , Farina Roberta , Gonera Antje , Hughes Adam D. , Navrud Ståle , Orsini Francesco , Parma Luca , Zornoza Raul
Published: August 2023

The objective of this perspective paper is to present and discuss how systemic innovations can deliver a step change in the way food is produced in Europe. The production of healthy, safe and affordable food can contribute toward a just transition to net zero carbon (C) for Europe. A systemic and cross sectorial approach can contribute to climate mitigation by transfer of atmospheric CO2 to the terrestrial biosphere using low trophic species (LTS), including plants, seaweed and mussels (i.e. C sequestration) and increasing organic C stocks in soils and vegetation biomass (i.e. C storage). Innovative combinations of technologies applied to LTS, processed animal protein, new crops, and diversified and integrated production systems can link the high primary productivity rates of the marine environment to the C storage capability of the terrestrial food sector. Furthermore, the important roles of both private and public sector actors and better use of systemic approaches to further elucidate the multi-dimensional and multi-level interplays in complex food systems needs consideration. This can pave the way for linking and scaling up C-neutral marine and terrestrial food production systems into a future sustainable and circular bioeconomy. This systems-based approach can address some of the challenges associated with the current farming systems, as interdisciplinary research on aquaculture innovation can support the development of a resilient and sustainable food system. Examples of technologies provided include: a custom configured and digital user-oriented co-creation approach for Responsible Research and Innovation (RRI), a WebGIS tool on soil C storage, innovative composting methods, advanced breeding methods, new machinery for low greenhouse gas diversified orchard farming, AI model systems to improve decision support systems in management of soil, vertical farming, and animal feeding.
Diversity and assembly of planktonic protist communities in the Jeju Strait, Korea
Authors: Min Juhee , Kim Kwang Young
Published: August 2023

This study examined planktonic protists—microbial eukaryotes with cell sizes between 2 and 200 µm—to understand their diversity, assembly processes, and co-existence patterns in surface waters of the Jeju Strait (JS), Korea. Using small organelle-enriched metagenomics, the study identified 252 operational taxonomic units (OTUs) across three distinct oceanographic regions of the JS during multiple seasons. Interestingly, there were no significant variations in the diversity or phylogenetic structures of these planktonic protist communities (PPCs), indicating a uniform distribution of PPCs across the strait. However, a higher clustering of their phylogenetic structure was observed in November, implying that seasonal environmental factors influenced their assembly. The study also discovered that seasonal shifts had a major impact on the composition of these communities. For example, Myzozoa was more prevalent in March, while Ochrophyta dominated in November. Protist size also varied seasonally, with larger protists increasing from June to November and then decreasing by March. Neutral community model analysis provided insights into the role of stochastic processes in shaping community assembly. The majority of OTUs fell into the neutral category, while a smaller proportion displayed non-neutral patterns. For instance, certain species like Pseudo-nitzschia and Chaetoceros were frequently found but had lower abundance, while other species like Alexandrium and Protoceratium were less frequent but more abundant. The feeding patterns, or trophic modes, of these protists also showed variations. Additionally, the study unveiled a complex network of species interactions within the strait, including positive mutualistic relationships and negative competitive interactions. The intricate interaction network consisted of 61 distinct modules, suggesting the presence of specialized subgroups within the PPCs that fulfill unique ecological roles. These subgroups contribute significantly to the overall stability and resilience of the ecosystem.
Enhanced production of highly methylated brGDGTs linked to anaerobic bacteria from sediments of the Mariana Trench
Authors: Zeng Zhiyu , Xiao Wenjie , Zheng Fengfeng , Chen Yufei , Zhu Yuanqing , Tian Jiwei , Zhang Chuanlun
Published: August 2023

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are bacterial membrane lipids that are widely used in terrestrial paleoclimatic reconstructions. Recent studies have reported that brGDGTs can also be produced by marine bacteria. However, the environmental factors influencing marine-derived brGDGTs and their source organisms remain largely unknown. Here, we investigated the distribution and composition of brGDGTs and a suite of their putative derivatives called overly branched GDGTs (obGDGTs) in the Mariana Trench core sediments (water depth 8300 m, core length 320 cm), as well as the composition of bacterial communities. The ratio of the branched over isoprenoid tetraethers (BIT) was 0.03-0.21 (average 0.07; SD = 0.04; n = 21) and the ratio ΣIIIa/ΣIIa of brGDGTs was 0.93-7.47 (average 3.39; SD = 1.73; n = 21), which support the in situ production of brGDGTs. Co-occurrence network analysis revealed that a total of 33 types of bacteria at the order level (e.g., Armatimonadota DG-56, Proteobacteria Rhodospirillales, Chloroflexi SAR202_clade) were closely related to the distribution of brGDGTs and obGDGTs, which could be potential sources for these compounds. The abrupt increase in brGDGT and obGDGT concentrations in deeper oxygen-depleted sediments and their good correlations with anaerobic bacterial abundances suggest that these brGDGTs and obGDGTs may be produced by anaerobic bacteria residing in the anoxic sediments. Considerable variation in the degrees of methylation and cyclization of brGDGTs (obGDGTs) under different redox conditions indicate that sediment oxygen levels may have a profound impact on the presence and abundance of brGDGTs and obGDGTs, which should be considered when applying them for paleo-temperature or pH reconstructions. This study shows that brGDGTs and obGDGTs obtained from the Mariana Trench were probably produced by a variety of bacterial phyla indigenous in the hadal ocean, which are different from Acidobacteria commonly considered to be major terrestrial sources of brGDGTs.
CT-based radiomic phenotypes of lung adenocarcinoma: a preliminary comparative analysis with targeted next-generation sequencing
Authors: Liu Xiaowen , Xu Ting , Wang Shuxing , Chen Yaxi , Jiang Changsi , Xu Wuyan , Gong Jingshan
Published: August 2023

Objectives

This study aimed to explore the relationship between computed tomography (CT)-based radiomic phenotypes and genomic profiles, including expression of programmed cell death-ligand 1 (PD-L1) and the 10 major genes, such as epidermal growth factor receptor (EGFR), tumor protein 53 (TP53), and Kirsten rat sarcoma viral oncogene (KRAS), in patients with lung adenocarcinoma (LUAD).

Methods

In total, 288 consecutive patients with pathologically confirmed LUAD were enrolled in this retrospective study. Radiomic features were extracted from preoperative CT images, and targeted genomic data were profiled through next-generation sequencing. PD-L1 expression was assessed by immunohistochemistry staining (chi-square test or Fisher's exact test for categorical data and the Kruskal–Wallis test for continuous data). A total of 1,013 radiomic features were obtained from each patient's CT images. Consensus clustering was used to cluster patients on the basis of radiomic features.

Results

The 288 patients were classified according to consensus clustering into four radiomic phenotypes: Cluster 1 (n = 11) involving mainly large solid masses with a maximum diameter of 5.1 ± 2.0 cm; Clusters 2 and 3 involving mainly part-solid and solid masses with maximum diameters of 2.1 ± 1.4 cm and 2.1 ± 0.9 cm, respectively; and Cluster 4 involving mostly small ground-glass opacity lesions with a maximum diameter of 1.0 ± 0.9 cm. Differences in maximum diameter, PD-L1 expression, and TP53, EGFR, BRAF, ROS1, and ERBB2 mutations among the four clusters were statistically significant. Regarding targeted therapy and immunotherapy, EGFR mutations were highest in Cluster 2 (73.1%); PD-L1 expression was highest in Cluster 1 (45.5%).

Conclusion

Our findings provide evidence that CT-based radiomic phenotypes could non-invasively identify LUADs with different molecular characteristics, showing the potential to provide personalized treatment decision-making support for LUAD patients.
The analgesic efficacy of erector spinae plane block versus paravertebral block in thoracic surgeries: a meta-analysis
Authors: Fenta Efrem , Kibret Simegnew , Hunie Metages , Tamire Tadese , Mekete Getachew , Tiruneh Abebe , Fentie Yewlsew , Dessalegn Kaletsidik , Teshome Diriba
Published: August 2023

Background

Acute postoperative pain after thoracic surgery might lead to chronic postsurgical pain (PSP), which lowers quality of life. The literature suggests thoracic paravertebral block (PVB) as a pain management approach. The ESPB (erector spinae plane block) is regarded to be an effective PVB alternative. The analgesic efficacy of the two analgesic therapies is controversial. The purpose of this study is to compare the analgesic efficacy of ESPB and PVB in preventing acute PSP.

Methods

We searched relevant articles in PubMed, Cochrane Library, Embase, Web of Science, and Google Scholar databases. The primary outcome was postoperative pain score, with secondary outcomes including analgesic consumption, the frequency of rescue analgesia, and postoperative nausea and vomiting.

Results

This meta-analysis included ten RCTs with a total of 670 patients. PVB significantly lowered the pain scores at movement at 12 h following surgery as compared to the ESPB. The PVB group used much less opioids within 24 h after surgery compared to the ESPB group. However, there were no significant differences between the groups in terms of postoperative rescue analgesia or in the incidence of postoperative nausea and vomiting (p > 0.05).

Conclusion

PVB produced superior analgesia than ESPB in patients who underwent thoracic surgeries. In addition, PVB demonstrated greater opioid sparing effect by consuming much less opioids.

Systematic review registration

This trial is registered on PROSPERO, number CRD42023412159.
Development and validation of a novel necroptosis-related gene signature for predicting prognosis and therapeutic response in Ewing sarcoma
Authors: Zhao Runhan , Jiang Yu , Zhang Jun , Huang Yanran , Xiong Chuang , Zhao Zenghui , Huang Tianji , Liu Wei , Zhou Nian , Li Zefang , Luo Xiaoji , Tang Yongli
Published: August 2023

Ewing sarcoma (ES) is the second most common malignant bone tumor in children and has a poor prognosis due to early metastasis and easy recurrence. Necroptosis is a newly discovered cell death method, and its critical role in tumor immunity and therapy has attracted widespread attention. Thus, the emergence of necroptosis may provide bright prospects for the treatment of ES and deserves our further study. Here, based on the random forest algorithm, we identified 6 key necroptosis-related genes (NRGs) and used them to construct an NRG signature with excellent predictive performance. Subsequent analysis showed that NRGs were closely associated with ES tumor immunity, and the signature was also good at predicting immunotherapy and chemotherapy response. Next, a comprehensive analysis of key genes showed that RIPK1, JAK1, and CHMP7 were potential therapeutic targets. The Cancer Dependency Map (DepMap) results showed that CHMP7 is associated with ES cell growth, and the Gene Set Cancer Analysis (GSCALite) results revealed that the JAK1 mutation frequency was the highest. The expression of 3 genes was all negatively correlated with methylation and positively with copy number variation (CNV). Finally, an accurate nomogram was constructed with this signature and clinical traits. In short, this study constructed an accurate prognostic signature and identified 3 novel therapeutic targets against ES.