bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive Selection in Gene Regulatory Factors Suggests Adaptive Pleiotropic Changes During Human Evolution
Authors: Jovanovic Vladimir M. , Sarfert Melanie , Reyna-Blanco Carlos S. , Indrischek Henrike , Valdivia Dulce I. , Shelest Ekaterina , Nowick Katja
Published: May 2021

Gene regulatory factors (GRFs), such as transcription factors, co-factors and histone-modifying enzymes, play many important roles in modifying gene expression in biological processes. They have also been proposed to underlie speciation and adaptation. To investigate potential contributions of GRFs to primate evolution, we analyzed GRF genes in 27 publicly available primate genomes. Genes coding for zinc finger (ZNF) proteins, especially ZNFs with a Krüppel-associated box (KRAB) domain were the most abundant TFs in all genomes. Gene numbers per TF family differed between all species. To detect signs of positive selection in GRF genes we investigated more than 3,000 human GRFs with their more than 70,000 orthologs in 26 non-human primates. We implemented two independent tests for positive selection, the branch-site-model of the PAML suite and aBSREL of the HyPhy suite, focusing on the human and great ape branch. Our workflow included rigorous procedures to reduce the number of false positives: excluding distantly similar orthologs, manual corrections of alignments, and considering only genes and sites detected by both tests for positive selection. Furthermore, we verified the candidate sites for selection by investigating their variation within human and non-human great ape population data. In order to approximately assign a date to positively selected sites in the human lineage, we analyzed archaic human genomes. Our work revealed with high confidence five GRFs that have been positively selected on the human lineage and one GRF that has been positively selected on the great ape lineage. These GRFs are scattered on different chromosomes and have been previously linked to diverse functions. For some of them a role in speciation and/or adaptation can be proposed based on the expression pattern or association with human diseases, but it seems that they all contributed independently to human evolution. Four of the positively selected GRFs are KRAB-ZNF proteins, that induce changes in target genes co-expression and/or through arms race with transposable elements. Since each positively selected GRF contains several sites with evidence for positive selection, we suggest that these GRFs participated pleiotropically to phenotypic adaptations in humans.
Association of RYR2 Mutation With Tumor Mutation Burden, Prognosis, and Antitumor Immunity in Patients With Esophageal Adenocarcinoma
Authors: Liu Zaoqu , Liu Long , Jiao Dechao , Guo Chunguang , Wang Libo , Li Zhaonan , Sun Zhenqiang , Zhao Yanan , Han Xinwei
Published: May 2021

Background: Esophageal adenocarcinoma (EAC) remains a leading cause of cancer-related deaths worldwide and demonstrates a predominant rising incidence in Western countries. Recently, immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, with the benefit in EAC thus far been limited to a small fraction of patients.

Methods: Using somatic mutation data of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium, we delineated the somatic mutation landscape of EAC patients from US and England. Based on the expression data of TCGA cohort, multiple bioinformatics algorithms were utilized to perform function annotation, immune cell infiltration analysis, and immunotherapy response assessment.

Results: We found that RYR2 was a common frequently mutated gene in both cohorts, and patients with RYR2 mutation suggested higher tumor mutation burden (TMB), better prognosis, and superior expression of immune checkpoints. Moreover, RYR2 mutation upregulated the signaling pathways implicated in immune response and enhanced antitumor immunity in EAC. Multiple bioinformatics algorithms for assessing immunotherapy response demonstrated that patients with RYR2 mutation might benefit more from immunotherapy. In order to provide additional reference for antitumor therapy of different RYR2 status, we identified nine latent antitumor drugs associated with RYR2 status in EAC.

Conclusion: This study reveals a novel gene whose mutation could be served as a potential biomarker for prognosis, TMB, and immunotherapy of EAC patients.
Prednisolone Suppresses the Extracellular Release of HMGB-1 and Associated Inflammatory Pathways in Kawasaki Disease
Authors: Ueno Kentaro , Nomura Yuichi , Morita Yasuko , Kawano Yoshifumi
Published: May 2021

Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitisin vitro. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1β and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.
Quantification of Cytokine Storms During Virus Infections
Authors: Yuan Shu , Jiang Si-Cong , Zhang Zhong-Wei , Fu Yu-Fan , Hu Jing , Li Zi-Lin
Published: May 2021

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) − 2.48 − 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.
The Role of Inflammation and Immune Activation on Circulating Endothelial Progenitor Cells in Chronic HIV Infection
Authors: Zhu Ziang , Li Tong , Chen Jinya , Kumar Jai , Kumar Princy , Qin Jing , Hadigan Colleen , Sereti Irini , Baker Jason V. , Catalfamo Marta
Published: May 2021

Endothelial inflammation and damage are the main drivers of cardiovascular risk/disease. Endothelial repair is mediated in part by recruitment of bone marrow endothelial progenitor/endothelial colony forming cells (EPC/ECFC). People with HIV (PWH) have increased cardiovascular risk and the impact of infection in endothelial repair is not well defined. The low frequencies and challenges to in vitro isolation and differentiation of EPC/ECFC from PBMCs had made it difficult to study their role in this context. We hypothesized that HIV driven inflammation induces phenotypic changes that reflects the impact of infection. To test this hypothesis, we evaluated expression of markers of trafficking, endothelial differentiation, and angiogenesis, and study their association with biomarkers of inflammation in a cohort of PWH. In addition, we investigated the relationship of circulating endothelial progenitors and angiogenic T cells, a T cell subset with angiogenic function. Using a flow cytometry approach, we identified two subsets of circulating progenitors LIN4-CD45-CD34+ and LIN4-CD45dimCD34+ in PWH. We found that the phenotype but not frequencies were associated with biomarkers of inflammation. In addition, the percentage of LIN4-CD45dimCD34+ was associated with serum levels of lipids. This data may provide a new tool to better address the impact of HIV infection in endothelial inflammation and repair.
RBM39 Alters Phosphorylation of c-Jun and Binds to Viral RNA to Promote PRRSV Proliferation
Authors: Song Yinna , Guo Yanyu , Li Xiaoyang , Sun Ruiqi , Zhu Min , Shi Jingxuan , Tan Zheng , Zhang Lilin , Huang Jinhai
Published: May 2021

As transcriptional co-activator of AP-1/Jun, estrogen receptors and NF-κB, nuclear protein RBM39 also involves precursor mRNA (pre-mRNA) splicing. Porcine reproductive and respiratory syndrome virus (PRRSV) causes sow reproductive disorders and piglet respiratory diseases, which resulted in serious economic losses worldwide. In this study, the up-regulated expression of RBM39 and down-regulated of inflammatory cytokines (IFN-β, TNFα, NF-κB, IL-1β, IL-6) were determined in PRRSV-infected 3D4/21 cells, and accompanied with the PRRSV proliferation. The roles of RBM39 altering phosphorylation of c-Jun to inhibit the AP-1 pathway to promote PRRSV proliferation were further verified. In addition, the nucleocytoplasmic translocation of RBM39 and c-Jun from the nucleus to cytoplasm was enhanced in PRRSV-infected cells. The three RRM domain of RBM39 are crucial to support the proliferation of PRRSV. Several PRRSV RNA (nsp4, nsp5, nsp7, nsp10-12, M and N) binding with RBM39 were determined, which may also contribute to the PRRSV proliferation. Our results revealed a complex mechanism of RBM39 by altering c-Jun phosphorylation and nucleocytoplasmic translocation, and regulating binding of RBM39 with viral RNA to prompt PRRSV proliferation. The results provide new viewpoints to understand the immune escape mechanism of PRRSV infection.
Comparative Analysis on Abnormal Methylome of Differentially Expressed Genes and Disease Pathways in the Immune Cells of RA and SLE
Authors: Fang Qinghua , Li Tingyue , Chen Peiya , Wu Yuzhe , Wang Tingting , Mo Lixia , Ou Jiaxin , Nandakumar Kutty Selva
Published: May 2021

We identified abnormally methylated, differentially expressed genes (DEGs) and pathogenic mechanisms in different immune cells of RA and SLE by comprehensive bioinformatics analysis. Six microarray data sets of each immune cell (CD19+ B cells, CD4+ T cells and CD14+ monocytes) were integrated to screen DEGs and differentially methylated genes by using R package “limma.” Gene ontology annotations and KEGG analysis of aberrant methylome of DEGs were done using DAVID online database. Protein-protein interaction (PPI) network was generated to detect the hub genes and their methylation levels were compared using DiseaseMeth 2.0 database. Aberrantly methylated DEGs in CD19+ B cells (173 and 180), CD4+ T cells (184 and 417) and CD14+ monocytes (193 and 392) of RA and SLE patients were identified. We detected 30 hub genes in different immune cells of RA and SLE and confirmed their expression using FACS sorted immune cells by qPCR. Among them, 12 genes (BPTF, PHC2, JUN, KRAS, PTEN, FGFR2, ALB, SERB-1, SKP2, TUBA1A, IMP3, and SMAD4) of RA and 12 genes (OAS1, RSAD2, OASL, IFIT3, OAS2, IFIH1, CENPE, TOP2A, PBK, KIF11, IFIT1, and ISG15) of SLE are proposed as potential biomarker genes based on receiver operating curve analysis. Our study suggests that MAPK signaling pathway could potentially differentiate the mechanisms affecting T- and B- cells in RA, whereas PI3K pathway may be used for exploring common disease pathways between RA and SLE. Compared to individual data analyses, more dependable and precise filtering of results can be achieved by integrating several relevant data sets.
Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis
Authors: Diaz-Jimenez David , Kolb Joseph P. , Cidlowski John A.
Published: May 2021

Our immune system has evolved as a complex network of cells and tissues tasked with maintaining host homeostasis. This is evident during the inflammatory responses elicited during a microbial infection or traumatic tissue damage. These responses seek to eliminate foreign material or restore tissue integrity. Even during periods without explicit disturbances, the immune system plays prominent roles in tissue homeostasis. Perhaps one of the most studied cells in this regard is the macrophage. Tissue-resident macrophages are a heterogenous group of sensory cells that respond to a variety of environmental cues and are essential for organ function. Endogenously produced glucocorticoid hormones connect external environmental stress signals with the function of many cell types, producing profound changes in immune cells, including macrophages. Here, we review the current literature which demonstrates specific effects of glucocorticoids in several organ systems. We propose that tissue-resident macrophages, through glucocorticoid signaling, may play an underappreciated role as regulators of organ homeostasis.
Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response
Authors: Zhou Qiongqiong , Yan Bingfang , Sun Wanying , Chen Qi , Xiao Qiling , Xiao Yuncai , Wang Xiliang , Shi Deshi
Published: May 2021

Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E2. Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.
Interleukin-27 and Its Diverse Effects on Bacterial Infections
Authors: Morita Yugo , Masters Elysia A. , Schwarz Edward M. , Muthukrishnan Gowrishankar
Published: May 2021

Innate and adaptive immune responses against pathogens are known to be carefully orchestrated by specific cytokines that initiate and down regulate immune cell functions from the initial infection through tissue repair and homeostasis. However, some cytokines, including interleukin-27, are expressed at multiple phases of the infection, such that their pro and anti-inflammatory functions have been difficult to interpret. As elucidation of specific cytokine functions throughout infection is central to our understanding of protective vs. susceptible immunity and return to homeostasis vs. prolonged inflammation leading to septic shock, here we review the literature on IL-27 signaling and the various functions of this heterodimeric ligand member of the IL-12 cytokine family. Canonically, IL-27 is produced by antigen-presenting cells, and is thought of as an immunostimulatory cytokine due to its capacity to induce Th1 differentiation. However, many studies have also identified various immunosuppressive effects of IL-27 signaling, including suppression of Th17 differentiation and induction of co-inhibitory receptors on T cells. Thus, the exact role of IL-27 in the context of infectious diseases remains a topic of debate and active research. Additionally, as recent interest has focused on clinical management of acute vs. chronic infections, and life-threatening “cytokine storm” from sepsis, we propose a hypothetical model to explain the biphasic role of IL-27 during the early and late phases of immune responses to reconcile its known pro and anti-inflammatory functions, which could be therapeutically regulated to improve patient outcomes of infection.
Lactobacillus casei CCFM1074 Alleviates Collagen-Induced Arthritis in Rats via Balancing Treg/Th17 and Modulating the Metabolites and Gut Microbiota
Authors: Fan Zhexin , Ross R. Paul , Stanton Catherine , Hou Bao , Zhao Jianxin , Zhang Hao , Yang Bo , Chen Wei
Published: May 2021

Gut microbiota and their influence on metabolites are receiving increasing attentions in autoimmune diseases including rheumatoid arthritis (RA). Probiotics become a promising manipulator to prevent or attenuate the progression of arthritis, some evidences suggesting that lactobacilli treatment influence the responses to RA therapy but the underlying mechanisms are limited. By using a collagen-induced arthritis (CIA) rats, the study assessed the effects of two L. casei strains (CCFM1074, CCFM1075) on the immune responses, gut microbiota and plasma metabolites via an integrated cross-omics approach including fecal 16S rRNA high-throughput sequencing and plasma metabolomics. The genome of the two strains was analyzed and compared using whole-genome sequencing approach to further confirm biology functions. CCFM1074 reduced arthritic symptoms while CCFM1075 did not, though both strains down-regulated the plasma IL-6 and Th17 cells proportion. CCFM1074 enhanced the proportion of Treg cells in mesenteric lymph nodes which was significantly associated with SCFAs upregulation, as well as with genomic evidence that CCFM1074 possesses more functional genes involved in carbohydrate metabolism. Moreover, CCFM1074 regulated the gut microbiota, including modulating community structure, decreasing the abundance of Alistipes and Parabacteroides and increasing the abundance of Oscillibacter. The differential metabolites modulated by CCFM1074 including eicosapentaenoic acid and docosapentaenoic acid which involved in unsaturated fatty acids metabolism. Furthermore, alterations of gut microbial community were correlated with the plasma metabolome. In summary, L. casei CCFM1074 alleviated arthritis via rebalancing gut microbiota, immune responses and plasma metabolites.
miRNA-Mediated Control of B Cell Responses in Immunity and SLE
Authors: Schell Stephanie L. , Rahman Ziaur S. M.
Published: May 2021

Loss of B cell tolerance is central to autoimmune diseases such as systemic lupus erythematosus (SLE). As such, the mechanisms involved in B cell development, maturation, activation, and function that are aberrantly regulated in SLE are of interest in the design of targeted therapeutics. While many factors are involved in the generation and regulation of B cell responses, miRNAs have emerged as critical regulators of these responses within the last decade. To date, miRNA involvement in B cell responses has largely been studied in non-autoimmune, immunization-based systems. However, miRNA profiles have also been strongly associated with SLE in human patients and these molecules have proven critical in both the promotion and regulation of disease in mouse models and in the formation of autoreactive B cell responses. Functionally, miRNAs are small non-coding RNAs that bind to complementary sequences located in target mRNA transcripts to mediate transcript degradation or translational repression, invoking a post-transcriptional level of genetic regulation. Due to their capacity to target a diverse range of transcripts and pathways in different immune cell types and throughout the various stages of development and response, targeting miRNAs is an interesting potential therapeutic avenue. Herein, we focus on what is currently known about miRNA function in both normal and SLE B cell responses, primarily highlighting miRNAs with confirmed functions in mouse models. We also discuss areas that should be addressed in future studies and whether the development of miRNA-centric therapeutics may be a viable alternative for the treatment of SLE.
Bioactivity of Biosilica Obtained From North Atlantic Deep-Sea Sponges
Authors: Dudik Olesia , Amorim Sara , Xavier Joana R. , Rapp Hans Tore , Silva Tiago H. , Pires Ricardo A. , Reis Rui L.
Published: May 2021

Demosponges are a well-known source of a plethora of bioactive compounds. In particular, they are able to form a skeleton by direct deposition of silica in a process catalyzed by silicatein. Herein, we isolated biosilicas from five different Atlantic deep-sea sponges Geodia atlantica (GA), Geodia barretti (GB), Stelletta normani (SN), Axinella infundibuliformis (AI), and Phakellia ventilabrum (PV) to explore the bioactivity and osteogenic capacity of its silica-based materials. We chemically characterized the isolated biosilicas and evaluated them for their bioactivity to deposit Ca and P on their surface (by immersion in simulated body fluid, SBF). GB-, SN-, AI-, and PV-based biosilicas did not generate a stable calcium phosphate (CaP) layer over time in the presence of SBF, however, the GA-derived one was able to form a CaP surface layer (at a Ca/P ratio of ∼1.7, similar to the one observed for hydroxyapatite), that was stable during the 28 days of testing. In addition, no cytotoxicity toward L929 and SaOs2 cells was observed for the GA-based biosilica up to a concentration of 10 mg/mL. Overall, the GA-based biosilica presents the characteristics to be used in the development of biomaterials for bone tissue engineering (BTE).
Comparative Reproductive Biology of Deep-Sea Ophiuroids Inhabiting Polymetallic-Nodule Fields in the Clarion-Clipperton Fracture Zone
Authors: Laming Sven R. , Christodoulou Magdalini , Martinez Arbizu Pedro , Hilário Ana
Published: May 2021

Deep-sea mining in the Pacific Clarion-Clipperton Fracture Zone (CCZ), a low-energy sedimentary habitat with polymetallic nodules, is expected to have considerable and long-lasting environmental impact. The CCZ hosts extraordinarily high species diversity across representatives from all Domains of Life. Data on species biology and ecology remain scarce, however. The current study describes the reproductive biology of Ophiosphalma glabrum (Ophiosphalmidae) and Ophiacantha cosmica (Ophiacanthidae), two ophiuroids frequently found in the CCZ. Specimens collected in Spring 2015 and 2019 in four contract areas were examined morphologically and histologically. Size-class frequencies (disc diameter and oocytes feret diameters), sex ratios, gametogenic status, putative reproductive mode, and a simple proxy for fecundity are presented. Habitat use differs in each. While O. glabrum is epibenthic, occurring as single individuals, O. cosmica often forms size-stratified groups living on stalked sponges, suggesting gregarious settlement or retention of offspring (though no brooding individuals were found). Further molecular analyses are needed to establish whether O. cosmica groups are familial. In O. glabrum, for which sample sizes were larger, sex ratios approximated a 1:1 ratio with no size-structuring. In both species, individuals were at various stages of gametogenic maturity, but no ripe females were identified. Based on this, O. glabrum is most probably gonochoric. Reproductive mode remains inconclusive for O. cosmica. Both species are presumptively lecithotrophic, with vitellogenic-oocyte feret diameters exceeding 250 μm. Oocyte feret diameters at times exceeded 400 μm in O. glabrum, indicating substantial yolk reserves. Estimates of instantaneous fecundity (vitellogenic specimens of O. glabrum only) were confounded by interindividual variability in gonad characteristics. The well-furnished lecithotrophic larvae of O. glabrum would be capable of dispersing even under food-impoverished conditions. The current study examines ophiuroid reproductive biology over multiple localities in the CCZ concurrently for the first time, at sites characterised by differing productivity regimes. The reproductive biology of each species is thus discussed with reference to past evolutionary (habitat stability), contemporary (food supply), and future environmental drivers (potential impacts of deep-sea mining).
Use of an Under-Water Compressed Air Energy Storage (UWCAES) to Fully Power the Sicily Region (Italy) With Renewable Energy: A Case Study
Authors: Tiano Francesco Antonio , Rizzo Gianfranco
Published: May 2021

The high concentration of CO2 in the atmosphere and the increase in sea and land temperatures make the use of renewable energy sources increasingly urgent. To overcome the problem of non-programmability of renewable sources, this study analyzes an energy storage system consisting of under water compressed air energy storage (UWCAES). A case study for fully power the Sicily region (Italy) with renewable energy source (wind and photovoltaic) is presented. From the real annual capacity values of the renewable plants installed in Sicily, a sizing of both the energy production and the storage system and its auxiliary services is evaluated. The optimization of the operation of the system as a whole, modeled with mathematical models already validated in previous studies, is obtained through dynamic programming. The electricity consumed annually by the region, equal to 19048.4 GWh, can be entirely satisfied by renewable energy sources. A sizing of plants powered by renewable sources for a nominal power of 15, 000 MW equally divided between photovoltaic and wind power is considered. The underwater air storage system has a maximum volume of 2.1 × 108 m3, while the compression and generation units have a total nominal power of 6, 900 and 3, 100 MW, respectively. The study finally presents a sensitivity analysis for the evaluation of the effects of the variation of the power produced by renewable energy sources and of Sicily energy consumption. The results show that carbon-free feeding is possible and that all the boundary conditions on the operation of the system can be met.
Numerical Investigation of Axonal Damage for Regular and Irregular Axonal Distributions
Authors: Kazempour Morteza , Kazempour Amin , Baniassadi Majid , Remond Yves , Baghani Mostafa
Published: May 2021

Recently, various researches have revealed the importance of the investigations performed for evaluating mechanical properties and damages of the brain tissues while dealing with the production of surgical ligaments and helmets. Therefore, it is vital to study the structure of the brain both experimentally and numerically. By experimental tests, despite being costly, it is almost impossible to establish stress distribution in micro scale, which causes injury. Micromechanical predictions are effective ways to assess brain behavior. They can be applied to compensate for some experimental test limitations. In this work, a numerical study of the axonal injury in different heterogeneous porcine brain parts with different axon distributions under quasi-static loading is provided. In order to produce a heterogeneous structure, axons are distributed in regular, semi-regular, and irregular patterns inside the representative volume element. To accurately examine the brain tissue time-dependent behavior, a visco-hyperelastic constitutive model is developed. Also, axonal damage is studied under different conditions by applying different levels of load and rate. Because of geometrical complexities, a self-consistent method was applied to study the damage in higher volume fractions of the axon. The results reveal that the regions of the brain enjoying a regular axon distribution would have higher strength. In addition, among the two influential load and loading rate parameters, the brain tissue in all regions shows more sensitivity toward the applying load.
Effectiveness of Thermal Properties in Thermal Energy Storage Modeling
Authors: Torres Sevilla Law , Radulovic Jovana
Published: May 2021

This paper studies the influence of material thermal properties on the charging dynamics in a low temperature Thermal Energy Storage, which combines sensible and latent heat. The analysis is based on a small scale packed bed with encapsulated PCMs, numerically solved using COMSOL Multiphysics. The PCMs studied are materials constructed based on typical thermal properties (melting temperature, density, specific heat capacity (solid and liquid), thermal conductivity (solid and liquid) and the latent heat) of storage mediums in literature. The range of values are: 25–65°C for the melting temperature, 10–500 kJ/kg for the latent heat, 600–1,000 kg/m3 for the density, 0.1–0.4 W/mK (solid and liquid) for the thermal conductivity and 1,000–2,200 J/kgK (solid and liquid) for the specific heat capacity. The temperature change is monitored at three different positions along the tank. The system consists of a 2D tank with L/D ratio of 1 at a starting temperature of 20°C. Water, as the heat transfer fluid, enters the tank at 90°C. Results indicate that latent heat is a leading parameter in the performance of the system, and that the thermal properties of the PCM in liquid phase influence the overall heat absorption more than its solid counterpart.
An Overview of Lung Cancer in Women and the Impact of Estrogen in Lung Carcinogenesis and Lung Cancer Treatment
Authors: Rodriguez-Lara Vianey , Avila-Costa Maria Rosa
Published: May 2021

Lung cancer incidence and mortality have significantly increased in women worldwide. Lung adenocarcinoma is the most common form of lung cancer globally. This type of lung cancer shows differences by sex, including the mutational burden, behavior, clinical characteristics, and response to treatment. The effect of sex on lung cancer patients' survival is still controversial; however, lung adenocarcinoma is considered a different disease in women and men. Moreover, lung adenocarcinoma is strongly influenced by estrogen and is also different depending on the hormonal status of the patient. Young pre-menopausal women have been explored as an independent group. They presented in more advanced stages at diagnosis, exhibited more aggressive tumors, and showed poor survival compared to men and post-menopausal women, supporting the role of sex hormones in this pathology. Several reports indicate the estrogen's role in lung carcinogenesis and tumor progression. Thus, there are currently some clinical trials testing the efficacy of antihormonal therapy in lung cancer treatment. This mini review shows the updated data about lung cancer in women, its characteristics, the etiological factors that influence carcinogenesis, and the critical role of estrogen in lung cancer and treatment.
A Decreased Level of Soluble Klotho Can Predict Cardiovascular Death in No or Mild Abdominal Aortic Calcification Hemodialysis Patients
Authors: Cai Hong , Zhu Xuying , Lu Jiayue , Zhu Minxia , Liu Shang , Zhan Yaping , Ni Zhaohui , Gu Leyi , Zhang Weiming , Mou Shan
Published: May 2021

Background: Soluble Klotho plays an important role in cardiovascular disease and death in chronic kidney disease (CKD). We assessed the relationship between serum soluble Klotho (sKL) level and outcome in MHD patients.

Methods: Soluble Klotho was detected by ELISA. Cox regression analysis and Kaplan-Meier analysis showed the relationship between sKL and cardiovascular disease (CVD) mortality in maintenance hemodialysis (MHD) patients.

Results: There were 45 cases (35.2%) of all-cause death and 36 cases (28.1%) of CVD mortality. Multivariate linear regression analysis showed that Log[iPTH] (γ = −0.224, P = 0.015) was an independent predictor of sKL level. Cox regression showed that lower sKL was associated with higher CVD mortality rate [OR = 0.401, 95% CI (0.183–0.867), P = 0.022]. Kaplan-Meier analysis showed that the CVD mortality rate increased significantly in patients with low sKL (P = 0.006). Compared with high sKL patients, low sKL patients with no or mild vascular calcification [aortic calcification score (AACs) ≤ 4] had no significant difference in all-cause mortality rate. The CVD mortality rate was significantly lower in high sKL patients (P = 0.004) than in those with low sKL. In the severe calcification group (AACs ≥ 5), all-cause and CVD mortality rates were similar between different sKL groups (P = 0.706 and 0.488, respectively). The area under the receiver-operating characteristic curve (AUC) of soluble Klotho for predicting the CVD in MHD patients with AACs ≤ 4 was 0.796 (0.647–0.946, P = 0.017), sensitivity was 0.921, and specificity was 0.50 for a cutoff value of 307.69 pg/ml.

Conclusions: Lower sKL was associated with higher CVD mortality rate. Lower sKL concentration in MHD patients with no or mild calcification can predict CVD mortality.
Development and Validation of a Machine-Learning Model for Prediction of Extubation Failure in Intensive Care Units
Authors: Zhao Qin-Yu , Wang Huan , Luo Jing-Chao , Luo Ming-Hao , Liu Le-Ping , Yu Shen-Ji , Liu Kai , Zhang Yi-Jie , Sun Peng , Tu Guo-Wei , Luo Zhe
Published: May 2021

Background: Extubation failure (EF) can lead to an increased chance of ventilator-associated pneumonia, longer hospital stays, and a higher mortality rate. This study aimed to develop and validate an accurate machine-learning model to predict EF in intensive care units (ICUs).

Methods: Patients who underwent extubation in the Medical Information Mart for Intensive Care (MIMIC)-IV database were included. EF was defined as the need for ventilatory support (non-invasive ventilation or reintubation) or death within 48 h following extubation. A machine-learning model called Categorical Boosting (CatBoost) was developed based on 89 clinical and laboratory variables. SHapley Additive exPlanations (SHAP) values were calculated to evaluate feature importance and the recursive feature elimination (RFE) algorithm was used to select key features. Hyperparameter optimization was conducted using an automated machine-learning toolkit (Neural Network Intelligence). The final model was trained based on key features and compared with 10 other models. The model was then prospectively validated in patients enrolled in the Cardiac Surgical ICU of Zhongshan Hospital, Fudan University. In addition, a web-based tool was developed to help clinicians use our model.

Results: Of 16,189 patients included in the MIMIC-IV cohort, 2,756 (17.0%) had EF. Nineteen key features were selected using the RFE algorithm, including age, body mass index, stroke, heart rate, respiratory rate, mean arterial pressure, peripheral oxygen saturation, temperature, pH, central venous pressure, tidal volume, positive end-expiratory pressure, mean airway pressure, pressure support ventilation (PSV) level, mechanical ventilation (MV) durations, spontaneous breathing trial success times, urine output, crystalloid amount, and antibiotic types. After hyperparameter optimization, our model had the greatest area under the receiver operating characteristic (AUROC: 0.835) in internal validation. Significant differences in mortality, reintubation rates, and NIV rates were shown between patients with a high predicted risk and those with a low predicted risk. In the prospective validation, the superiority of our model was also observed (AUROC: 0.803). According to the SHAP values, MV duration and PSV level were the most important features for prediction.

Conclusions: In conclusion, this study developed and prospectively validated a CatBoost model, which better predicted EF in ICUs than other models.
Comparative Genomic Analysis of the Foodborne Pathogen Burkholderia gladioli pv. cocovenenans Harboring a Bongkrekic Acid Biosynthesis Gene Cluster
Authors: Peng Zixin , Dottorini Tania , Hu Yue , Li Menghan , Yan Shaofei , Fanning Séamus , Baker Michelle , Xu Jin , Li Fengqin
Published: May 2021

The environmental bacterium Burkholderia gladioli pv. cocovenenans (B. cocovenenans) has been linked to fatal food poisoning cases in Asia and Africa. Bongkrekic acid (BA), a mitochondrial toxin produced by B. cocovenenans, is thought to be responsible for these outbreaks. While there are over 80 species in the Burkholderia genus, B. cocovenenans is the only pathovar capable of producing BA and causing human death. However, the genomic features of B. gladioli and the evolution of the BA biosynthesis gene cluster, bon, in B. cocovenenans remain elusive. In this study, 239 whole genome sequences (WGSs) of B. gladioli, isolated from 12 countries collected over 100 years, were used to analyze the intra-species genomic diversity and phylogenetic relationships of B. gladioli and to explore the origin and evolution of the bon gene cluster. Our results showed that the genome-wide average nucleotide identity (ANI) values were above 97.29% for pairs of B. gladioli genomes. Thirty-six of the 239 (15.06%) B. gladioli genomes, isolated from corn, rice, fruits, soil, and patients from Asia, Europe, North America, and South America, contained the bon gene cluster and formed three clades within the phylogenetic tree. Pan- and core-genome analysis suggested that the BA biosynthesis genes were recently acquired. Comparative genome analysis of the bon gene cluster showed that complex recombination events contributed to this toxin biosynthesis gene cluster’s evolution and formation. This study suggests that a better understanding of the genomic diversity and evolution of this lethal foodborne pathovar will potentially contribute to B. cocovenenans food poisoning outbreak prevention.
Experimental Warming Reduces Survival, Cold Tolerance, and Gut Prokaryotic Diversity of the Eastern Subterranean Termite, Reticulitermes flavipes (Kollar)
Authors: Arango Rachel A. , Schoville Sean D. , Currie Cameron R. , Carlos-Shanley Camila
Published: May 2021

Understanding the effects of environmental disturbances on insects is crucial in predicting the impact of climate change on their distribution, abundance, and ecology. As microbial symbionts are known to play an integral role in a diversity of functions within the insect host, research examining how organisms adapt to environmental fluctuations should include their associated microbiota. In this study, subterranean termites [Reticulitermes flavipes (Kollar)] were exposed to three different temperature treatments characterized as low (15°C), medium (27°C), and high (35°C). Results suggested that pre-exposure to cold allowed termites to stay active longer in decreasing temperatures but caused termites to freeze at higher temperatures. High temperature exposure had the most deleterious effects on termites with a significant reduction in termite survival as well as reduced ability to withstand cold stress. The microbial community of high temperature exposed termites also showed a reduction in bacterial richness and decreased relative abundance of Spirochaetes, Elusimicrobia, and methanogenic Euryarchaeota. Our results indicate a potential link between gut bacterial symbionts and termite’s physiological response to environmental changes and highlight the need to consider microbial symbionts in studies relating to insect thermosensitivity.
Cyprus Sausages’ Bacterial Community Identification Through Metataxonomic Sequencing: Evaluation of the Impact of Different DNA Extraction Protocols on the Sausages’ Microbial Diversity Representation
Authors: Kamilari Eleni , Efthymiou Marina , Anagnostopoulos Dimitrios A. , Tsaltas Dimitrios
Published: May 2021

Cyprus traditional sausages from the Troodos mountainous region of Pitsilia gained the protected geographical indication (PGI) designation from the European Committee (EU 2020/C 203/06). Still, we lack authentication protocols for the distinction of “Pitsilia” from industrially produced Cyprus sausages. Microbial activity is an essential contributor to traditional sausages’ sensorial characteristics, but whether the microbial patterns might be associated with the area of production is unclear. In the present research, we applied high-throughput sequencing (HTS) to provide a linkage between the area of production and Cyprus sausages’ bacterial diversity. To strengthen our findings, we used three different DNA extraction commercial kits: (i) the DNeasy PowerFood Microbial Kit (QIAGEN); (ii) the NucleoSpin Food Kit (MACHEREY-NAGEL); and (iii) the blackPREP Food DNA I Kit (Analytik Jena), in which we applied three different microbial cell wall lysis modifications. The modifications included heat treatment, bead beating, and enzymatic treatment. Results regarding metagenomic sequencing were evaluated in terms of number of reads, alpha diversity indexes, and taxonomic composition. The efficacy of each method of DNA isolation was assessed quantitatively based on the extracted DNA yield and the obtained copy number of (a) the 16S rRNA gene, (b) the internal transcribed spacer (ITS) region, and (c) three Gram-positive bacteria that belong to the genera Latilactobacillus (formerly Lactobacillus), Bacillus, and Enterococcus via absolute quantification using qPCR. Compared with some examined industrial sausages, Pitsilia sausages had significantly higher bacterial alpha diversity (Shannon and Simpson indexes). Principal coordinates analysis separated the total bacterial community composition (beta diversity) of the three Pitsilia sausages from the industrial sausages, with the exception of one industrial sausage produced in Pitsilia, according to the manufacturer. Although the eight sausages shared the abundant bacterial taxa based on 16S rDNA HTS, we observed differences associated with bacterial diversity representation and specific genera. The findings indicate that the microbial communities may be used as an additional tool for identifying of the authenticity of Cypriot sausages.
Paracrine IFN Response Limits ZIKV Infection in Human Sertoli Cells
Authors: Strange Daniel P. , Jiyarom Boonyanudh , Sadri-Ardekani Hooman , Cazares Lisa H. , Kenny Tara A. , Ward Michael D. , Verma Saguna
Published: May 2021

Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The testes have been implicated as sites of long-term ZIKV replication, and our previous studies have identified Sertoli cells (SC), the nurse cells of the seminiferous epithelium that govern spermatogenesis, as major targets of ZIKV infection. To improve our understanding of the interaction of ZIKV with human SC, we analyzed ZIKV-induced proteome changes in these cells using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data demonstrated that interferon (IFN) signaling was the most significantly enriched pathway and the antiviral proteins MX1 and IFIT1 were among the top upregulated proteins in SC following ZIKV infection. The dynamic between IFN response and ZIKV infection kinetics in SC remains unclear, therefore we further determined whether MX1 and IFIT1 serve as antiviral effectors against ZIKV. We found that increased levels of MX1 at the later time points of infection coincided with diminished ZIKV infection while the silencing of MX1 and IFIT1 enhanced peak ZIKV propagation in SC. Furthermore, although IFN-I exposure was found to significantly hinder ZIKV replication in SC, IFN response was attenuated in these cells as compared to other cell types. The data in this study highlight IFN-I as a driver of the antiviral state that limits ZIKV infection in SC and suggests that MX1 and IFIT1 function as antiviral effectors against ZIKV in SC. Collectively, this study provides important biological insights into the response of SC to ZIKV infection and the ability of the virus to persist in the testes.
Alternative Animal Models of Aging Research
Authors: Holtze Susanne , Gorshkova Ekaterina , Braude Stan , Cellerino Alessandro , Dammann Philip , Hildebrandt Thomas B. , Hoeflich Andreas , Hoffmann Steve , Koch Philipp , Terzibasi Tozzini Eva , Skulachev Maxim , Skulachev Vladimir P. , Sahm Arne
Published: May 2021

Most research on mechanisms of aging is being conducted in a very limited number of classical model species, i.e., laboratory mouse (Mus musculus), rat (Rattus norvegicus domestica), the common fruit fly (Drosophila melanogaster) and roundworm (Caenorhabditis elegans). The obvious advantages of using these models are access to resources such as strains with known genetic properties, high-quality genomic and transcriptomic sequencing data, versatile experimental manipulation capabilities including well-established genome editing tools, as well as extensive experience in husbandry. However, this approach may introduce interpretation biases due to the specific characteristics of the investigated species, which may lead to inappropriate, or even false, generalization. For example, it is still unclear to what extent knowledge of aging mechanisms gained in short-lived model organisms is transferable to long-lived species such as humans. In addition, other specific adaptations favoring a long and healthy life from the immense evolutionary toolbox may be entirely missed. In this review, we summarize the specific characteristics of emerging animal models that have attracted the attention of gerontologists, we provide an overview of the available data and resources related to these models, and we summarize important insights gained from them in recent years. The models presented include short-lived ones such as killifish (Nothobranchius furzeri), long-lived ones such as primates (Callithrix jacchus, Cebus imitator, Macaca mulatta), bathyergid mole-rats (Heterocephalus glaber, Fukomys spp.), bats (Myotis spp.), birds, olms (Proteus anguinus), turtles, greenland sharks, bivalves (Arctica islandica), and potentially non-aging ones such as Hydra and Planaria.