bluuebunny/crossref_metadata_2025 huggingface dataset:
An open-source platform integrating emerging data sources to support multi-modal active pharmacovigilance
Authors: Dimitriadis Vlasios K. , Dimitsaki Stella , Chytas Achilleas , Gavriilidis George I. , Kakalou Christine , Bonotis Panos , Natsiavas Pantelis
Published: January 2023

As new data sources have emerged, the data space which Pharmacovigilance (PV) processes can use has significantly expanded. However, still, the currently available tools do not widely exploit data sources beyond Spontaneous Report Systems built to collect Individual Case Safety Reports (ICSRs). This article presents an open-source platform enabling the integration of heterogeneous data sources to support the analysis of drug safety related information. Furthermore, the results of a comparative study as part of the project’s pilot phase are also presented. Data sources were integrated in the form of four “workspaces”: (a) Individual Case Safety Reports—obtained from OpenFDA, (b) Real-World Data (RWD) —using the OMOP-CDM data model, (c) social media data—collected via Twitter, and (d) scientific literature—retrieved from PubMed. Data intensive analytics are built for each workspace (e.g., disproportionality analysis metrics are used for OpenFDA data, descriptive statistics for OMOP-CDM data and twitter data streams etc.). Upon these workspaces, the end-user sets up “investigation scenarios” defined by Drug-Event Combinations (DEC). Specialized features like detailed reporting which could be used to support reports for regulatory purposes and also “quick views” are provided to facilitate use where detailed statistics might not be needed and a qualitative overview of the available information might be enough (e.g., clinical environment). The platform’s technical features are presented as Supplementary Material via a walkthrough of an example “investigation scenario”. The presented platform is evaluated via a comparative study against the EVDAS system, conducted by PV professionals. Results from the comparative study, show that there is indeed a need for relevant technical tools and the ability to draw recent data from heterogeneous data sources is appreciated. However, a reluctance by end-users is also outlined as they feel technical improvements and systematic training are required before the potential adoption of the presented software. As a whole, it is concluded that integrating such a platform in real-world setting is far from trivial, requiring significant effort on training and usability aspects.
Experimental and numerical model of anisotropic permeability and CO2 injectivity of coal during CO2 enhanced coalbed methane recovery process
Authors: Niu Qinghe , Hu Mingwei , Leng Bing , He Xiang , Su Wenjie , Wang Wei , Wang Qizhi , Chang Jiangfang , Ji Zhongmin , Qi Xiaofei
Published: January 2023

Guaranteeing CO2 injectivity has been the precondition for implementing the CO2-enhanced coalbed methane recovery (CO2-ECBM), however, it dramatically decreases during the CO2 injection process because it is influenced by the dynamic change of the anisotropic permeability of coal. To reveal and evaluate the CO2 injectivity of coal, the anisotropic permeability test and the CO2 injectivity simulation test were first conducted, then the corresponding numerical models were established and verified by the experimental data. The results show that the permeability of coal in parallel face cleat direction is the largest, followed by the permeability of coal in parallel butt cleat direction and that in vertical bedding direction is the minimum. The peak value of the instantaneous injectivity rate is enhanced and the injection time is prolonged with the increase of the CO2 injection pressure. The total CO2 injectivity rate is nonlinearly increased from 13.61 to 311.87 cm2/MPa min when the CO2 injection pressure raises from 2 to 10 MPa. The anisotropic permeability model is appropriate to describe the dynamic evolution of permeability under different boundary conditions, the CO2 injectivity prediction model can be used to evaluate the CO2 injectivity during the CO2 injection process. Increasing the CO2 injection pressure may temporarily promote CO2 injectivity, while the CO2 injection increment is limited. The CO2 fracturing by phase transition may be an available reservoir stimulation method for enhancing the CO2 injection and should be focused on in the future.
The triglyceride and glucose index and risk of nonalcoholic fatty liver disease: A dose–response meta-analysis
Authors: Ling Qin , Chen Jiawei , Liu Xiao , Xu Yi , Ma Jianyong , Yu Peng , Zheng Kai , Liu Fuwei , Luo Jun
Published: January 2023

Background

The triglyceride and glucose (TyG) index is associated with the risk of nonalcoholic fatty liver disease (NAFLD), but the dose−response relationship between them is still unknown. We conducted a comprehensive meta-analysis to study the dose−response association between the TyG index and the risk of NAFLD.

Methods

We systematically searched the Cochrane Library, PubMed, and Embase databases until July 2022 for relevant studies. The robust error meta-regression method was used to investigate the dose−response association between the TyG index and NAFLD. Summary relative risks (ORs) and 95% CIs were estimated by using a random-effects model.

Results

A total of 4 cohort and 8 cross-sectional studies were included, with 28,788 NAFLD cases among the 105,365 participants. A positive association for the risk of NAFLD was observed for each additional unit of the TyG index with a linear association (p=0.82), and the summary OR was 2.84 (95% CI, 2.01-4.01). In the subgroup analyses, a stronger association of the TyG index with NAFLD was shown in females than in males (men: OR=2.97, 95% CI 2.55-3.46, women: OR=4.80, 95% CI 3.90-5.90, Psubgroup<0.001).

Conclusion

The TyG index may be a novel independent risk factor for NAFLD beyond traditional risk factors.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero, identifier (CRD42022347813).
Qingrequzhuo capsule alleviated methionine and choline deficient diet-induced nonalcoholic steatohepatitis in mice through regulating gut microbiota, enhancing gut tight junction and inhibiting the activation of TLR4/NF-κB signaling pathway
Authors: Lv Shuquan , Zhang Zhongyong , Su Xiuhai , Li Wendong , Wang Xiaoyun , Pan Baochao , Li Hanzhou , Zhang Hui , Wang Yuansong
Published: January 2023

Qingrequzhuo capsule (QRQZ), composed of Morus alba L., Coptis chinensis Franch., Anemarrhena asphodeloides Bunge, Alisma plantago-aquatica subsp. orientale (Sam.) Sam., Citrus × aurantium L., Carthamus tinctorius L., Rheum palmatum L., Smilax glabra Roxb., Dioscorea oppositifolia L., Cyathula officinalis K.C.Kuan, has been used to treat nonalcoholic steatohepatitis (NASH) in clinic. However, the mechanism of QRQZ on NASH remains unclear. Recent studies have found that the dysfunction of gut microbiota could impair the gut barrier and induce the activation of TLR4/NF-kB signaling pathway, and further contribute to the inflammatory response in NASH. Modulating the gut microbiota to reduce inflammation could prevent the progression of NASH. In this study, a mouse model of NASH was generated by methionine and choline deficient diet (MCD) and treated with QRQZ. First, we evaluated the therapeutic effects of QRQZ on liver injury and inflammation in the NASH mice. Second, the changes in the gut microbiota diversity and abundance in each group of mice were measured through 16S rRNA sequencing. Finally, the effects of QRQZ on gut mucosal permeability, endotoxemia, and liver TLR4/NF-kB signaling pathway levels were examined. Our results showed that QRQZ significantly reduced the lipid accumulation in liver and the liver injury in NASH mice. In addition, QRQZ treatment decreased the levels of inflammatory cytokines in liver. 16S rRNA sequencing showed that QRQZ affected the diversity of gut microbiota and a f f e c t e d t h e r e l a t i v e a b u n d a n c e s o f D u b o s i e l l a , Lachnospiraceae_NK4A136_group, and Blautiain NASH mice. Besides, QRQZ could increase the expression of tight junction proteins (zonula occludens-1 and occludin) in gut and decrease the lipopolysaccharide (LPS) level in serum. Western blot results also showed that QRQZ treatment decreased the protein expression ofTLR4, MyD88 and the phosphorylation of IkB and NF-kBp65 and qPCR results showed that QRQZ treatment down-regulated the gene expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a in liver. In conclusion, our study demonstrated that QRQZ could reduce the lipid accumulation and inflammatory response in NASH model mice. The mechanisms of QRQZ on NASH were associated with modulating gut microbiota, thereby inducing the tight junction of gut barrier, reducing the endotoxemia and inhibiting the activation of TLR4/NFkB signaling pathway in liver.
Functional regulation of syntaxin-1: An underlying mechanism mediating exocytosis in neuroendocrine cells
Authors: Yang Xinquan , Tu Weifeng , Gao Xuzhu , Zhang Qi , Guan Jinping , Zhang Junlong
Published: January 2023

The fusion of the secretory vesicle with the plasma membrane requires the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complexes formed by synaptobrevin, syntaxin-1, and SNAP-25. Within the pathway leading to exocytosis, the transitions between the “open” and “closed” conformations of syntaxin-1 function as a switch for the fusion of vesicles with the plasma membranes; rapid assembly and disassembly of syntaxin-1 clusters on the plasma membrane provide docking and fusion sites for secretory vesicles in neuroendocrine cells; and the fully zippered trans-SNARE complex, which requires the orderly, rapid and accurate binding of syntaxin-1 to other SNARE proteins, play key roles in triggering fusion. All of these reactions that affect exocytosis under physiological conditions are tightly regulated by multiple factors. Here, we review the current evidence for the involvement of syntaxin-1 in the mechanism of neuroendocrine cell exocytosis, discuss the roles of multiple factors such as proteins, lipids, protein kinases, drugs, and toxins in SNARE complex-mediated membrane fusion, and present an overview of syntaxin-1 mutation-associated diseases with a view to developing novel mechanistic therapeutic targets for the treatment of neuroendocrine disorders.
Methylglyoxal products in pre-symptomatic type 1 diabetes
Authors: Shuck Sarah C. , Achenbach Peter , Roep Bart O. , Termini John S. , Hernandez-Castillo Carlos , Winkler Christiane , Weiss Andreas , Ziegler Anette-Gabriele
Published: January 2023

Introduction

Progression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 diabetes progression and to supplement existing predictive biomarkers. Methylglyoxal (MG) is a reactive product produced from protein, lipid, and sugar metabolism, providing a more comprehensive measure of metabolic changes compared to hyperglycemia alone. MG forms covalent adducts on nucleic and amino acids, termed MG-advanced glycation end products (AGEs) that associate with type 1 diabetes.

Methods

We tested their ability to predict risk of disease and discriminate which individuals with autoimmunity will progress to type 1 diabetes. We measured serum MG-AGEs from 141 individuals without type 1 diabetes and 271 individuals with type 1 diabetes enrolled in the Fr1da cohort. Individuals with type 1 diabetes were at stages 1, 2, and 3.

Results

We examined the association of MG-AGEs with type 1 diabetes. MG-AGEs did not correlate with HbA1c or differ between stages 1, 2, and 3 type 1 diabetes. Yet, RNA MG-AGEs were significantly associated with the rate of progression to stage 3 type 1 diabetes, with lower serum levels increasing risk of progression.

Discussion

MG-AGEs were able to discriminate which individuals with autoantibodies would progress at a faster rate to stage 3 type 1 diabetes providing a potential new clinical biomarker for determining rate of disease progression and pointing to contributing metabolic pathways.
The protective effects of lipoxin A4 on type 2 diabetes mellitus: A Chinese prospective cohort study
Authors: Wang Sudan , Qian Xiaoyan , Shen Chao , Sun Qian , Jing Yang , Liu Bingyue , Zhang Kexin , Li Mengyuan , Wang Junrong , Zhou Hui , Dong Chen
Published: January 2023

Background

Several cellular and animal studies have suggested that lipoxin A4 (LXA4) has a protective effect on type 2 diabetes mellitus (T2DM) development. However, little is known about whether LXA4 influences T2DM development at the population level.

Methods

We included 2755 non-diabetic participants from a cohort study in China who were followed for about seven years. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association between LXA4 and incident T2DM. Mediation models were used to examine how serum lipids as mediators impact the association between LXA4 and T2DM.

Results

In total, 172 newly diagnosed T2DM cases were identified. Multivariate-adjusted HR for T2DM in the fourth compared with the first quartile of LXA4 was 0.62 (95% CI: 0.40-0.96). When used the optimal cutoff value determined by the receiver operating characteristic curve, the results showed participants with LXA4 > 2.84 ng/mL had a decreased T2DM risk compared to those with LXA4 ≤ 2.84 ng/mL (HR: 0.63, 95% CI: 0.45-0.89). The effect of LXA4 on incident T2DM was significantly modified by gender (P-interaction = 0.024) and family history of diabetes (P-interaction = 0.025). Additionally, the association between LXA4 and incident T2DM was partially suppressed by the TyG and TG/HDL-c ratio, with a suppression proportion of 22.2% and 16.0%, respectively.

Conclusions

Higher LXA4 levels are significantly associated with a lower risk of T2DM development. The present findings would be helpful in understanding the effect of LXA4 on T2DM development at the population level.
Nomogram for predicting central lymph node metastasis in T1-T2 papillary thyroid cancer with no lateral lymph node metastasis
Authors: Sun Yubo , Sun Wei , Xiang Jingzhe , Zhang Hao
Published: January 2023

Objective

Whether routine central lymph node dissection (CLND) is necessary for T1-T2 papillary thyroid carcinoma (PTC) patients without certain lateral lymph node metastases (LLNM) remains controversial. This study aims to construct a nomogram that predicts central lymph node metastasis (CLNM) for T1-T2 PTC patients without LLNM.

Methods

We retrospectively reviewed adult T1-T2 PTC patients with no LLNM retrieved from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. We also collected data from patients treated at the First Hospital of China Medical University between February and April 2021 for external validation. Logistic regression model was used to construct a risk prediction model nomogram. The receiver-operating characteristic (ROC) curve, calibration plot, and decision curve analyses (DCA) were used for assessing the nomogram.

Results

5,094 patients from the SEER database and 300 patients from our department were finally included in this study. Variables such as age, gender, race, tumor size, multifocality, and minimal extrathyroidal extension (mETE) were found to be associated with CLNM and were subsequently incorporated into our nomogram. The C-index of our constructed model was 0.704, while the internal and external validation C-indexes were 0.693 and 0.745, respectively. The nomogram was then evaluated using calibration and decision curve analyses.

Conclusion

A visualized nomogram was successfully developed to predict CLNM in T1-T2 PTC patients without LLNM and assist clinicians in making personalized clinical decisions.
Inverter fault diagnosis based on Fourier transform and evolutionary neural network
Authors: Yang Hongxin , Peng Zishun , Xu Qijin , Huang Tingxuan , Zhu Xiangou
Published: January 2023

The fault diagnosis of the inverter is fundamental to energy intelligence. Due to the complex characteristics of the inverter (e.g., high-dimensional decision and poor stability), it is challenging to solve the problem using traditional fault diagnosis methods. Recently, artificial intelligence (AI)-based approaches have emerged as the most promising methods. However, they often require to set hyperparameters manually, which hinders further AI-based applications in fault diagnosis of inverters. To fill the gap, we propose an inverter fault diagnosis method using fast Fourier Transform (FFT) and evolutionary neural network. This method combines the amplitude of low-frequency harmonic component of the three-phase inverter output current which is obtained by FFT and the average value in a period of three-phase inverter output current into the fault eigenvector. This method uses an evolutionary neural network trained by combining genetic algorithm (GA), ant colony optimization (ACO) algorithm and Back-propagation (BP) algorithm to realize fault diagnosis. This method can effectively resist noise interference and reduce the number of independent variables in the part of feature extraction, so that it can simplify the network model. In addition, this method can avoid the network training from trapping in local optima in the part of fault classification, with high accuracy and fast response speed. The experimental results show that the proposed algorithm and method of fault feature extraction can effectively detect and locate the insulated-gate bipolar transistor (IGBT) with open circuit (OC) fault in three-phase inverter, and can be applied to online monitoring.
Optimal capacity allocation of wind-light-water multi-energy complementary capacity based on improved multi-objective optimization algorithm
Authors: Wang Ying , Liu Jiajun
Published: January 2023

As a basic industry for national economic development, the power industry is closely related to the overall economic and environmental development of China. At present, China is still dominated by thermal power generation. In order to reduce carbon emissions, promote the realization of the “double carbon” goal, and improve the level of clean energy utilization and the operating efficiency of the power system, a wind-light-water storage complementary power generation system is built, and a mathematical model of multi energy complementation is established. The minimum economic cost and the minimum battery capacity are proposed as the objective functions of system capacity configuration. Then a multi-objective evolutionary algorithm based on Pareto optimal space of the NDWA-GA and the PCA is proposed for optimal capacity allocation of multi energy complementary systems in this paper. Compared with the traditional multi-objective optimization algorithm, the correctness and effectiveness of the proposed method are verified. In addition, according to the actual research object, the optimal capacity configuration of the multi energy complementary system is given, which can guide the production and has an important promotion significance for energy saving and emission reduction.
The justice and policy implications of clean energy transition in Africa
Authors: Nsafon Benyoh Emmanuel Kigha , Same Noel Ngando , Yakub Abdulfatai Olatunji , Chaulagain Deepak , Kumar Nallapaneni Manoj , Huh Jeung-Soo
Published: January 2023

Despite the low local energy access rates, Africa is considered a key player in the global energy transition due to its large supply of fossil fuels and a large reserve of critical minerals essential for manufacturing renewable energy components in the energy sector and storage devices in the transportation and electronics sectors. But building a sustainable society at all levels across nations would only come when there exists a just and inclusive energy transition based on the idea of “leave no one behind”. While many African countries have embarked on ambitious and transformative transition strategies, and many energy projects classified as “clean” have economic, environmental, and social implications that jeopardize the wellbeing of those already vulnerable to the impacts of climate change. This paper explores the policy implications of the just transition to ensure that efforts to steer Africa towards a lower carbon future are supported by fair, equity, and justice considerations. Our analyses provide valuable evidence for considering a just transition in Africa that will not exacerbate the current socio-economic challenges the region is facing but will support sustained poverty reduction and the achievement of faster economic growth. Our findings show that the African continent’s multiple challenges of energy security, economic growth, and affordable access must feature in its clean energy transition. We draw conclusions that an incremental transition emphasizing low-carbon development is the most feasible and pragmatic approach to transform the region’s economy and address climate change challenges.
Effects of biochar and wood ash amendments in the soil-water-plant environment of two temperate forest plantations
Authors: Moragues-Saitua Lur , Arias-González Ander , Blanco Fernando , Benito-Carnero Garazi , Gartzia-Bengoetxea Nahia
Published: January 2023

Forest biomass is considered an alternative to fossil fuels in energy production, as part of global strategies for climate change mitigation. Application of by-products such as wood ash (WA) and biochar (BC) to soil could replace the nutrients removed by tree harvesting and could also increase soil carbon stocks. However, the extent to which these amendments can provide benefits depends on how the by-products interact with the soil-water-plant system. We studied the short-term responses of WA and BC application in two different mineral soil-water-plant systems in temperate forests: A. Typic Udorthent (TU) with mature Pinus radiata; B. Typic Dystrudept (TD) with young Quercus pyrenaica, to test the following hypotheses: (1) the application of WA and BC will increase nutrient uptake by plants, but (2) these products could induce toxicity in the soil-water-plant system, and (3) in case of no toxicity, plant biomass growth in these temperate forest soils will increase due to increased plant nutrient uptake. Biochar was applied at rates of 3.5, 10, and 20 Mg ha–1 and WA at rates of 1.5, 4.5, and 9 Mg ha–1 (calcium equivalent). A nitrogen enriched treatment was applied with the intermediate doses. Ecotoxicity testing indicated that WA and BC were not toxic, although Ni uptake increased in biomass of the TU after BC + N application. BC increased SOC stocks of both sites, depending on treatment. In TD BC increased K uptake by plants, but did not increase biomass. In summary, this study shows that the application of BC and WA had different effects on the soil -water-plant system in two different forest soils. This difference was attributed to (i) the soil characteristics, (ii) the application rates and (iii) whether or not nitrogen was applied. Long-term field experiments are required to test the performance and potential toxicity of these by-products as soil enhancers.
Identification of miRNA-mediated gene regulatory networks in L-methionine exposure counteracts cocaine-conditioned place preference in mice
Authors: Wang Yan , Yang Lvyu , Zhou Hansheng , Zhang Kunlin , Zhao Mei
Published: January 2023

Background and Aims: Methionine has been proven to inhibit addictive behaviors of cocaine dependence. This study aimed to identify the potential mechanisms of MET relating to its inhibitory effects on cocaine induced cellular and behavioral changes.

Methods: MRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine conditioned place preference (CPP) combined with L-methionine was performed. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) regulated by cocaine and inhibited by L-methionine were identified. DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, the identified DEGs were subjected to the DAVID webserver for functional annotation. Finally, miRNA-mRNA regulatory network and miRNA-mRNA-TF regulatory networks were established to screen key DE-miRNAs and coregulation network in Cytoscape.

Results: Sequencing data analysis showed that L-methionine reversely regulated genes and miRNAs affected by cocaine. Pathways associated with drug addiction only enriched in CS-down with MC-up genes targeted by DE-miRNAs including GABAergic synapse, Glutamatergic synapse, Circadian entrainment, Axon guidance and Calcium signaling pathway. Drug addiction associated network was formed of 22 DEGs including calcium channel (Cacna1c, Cacna1e, Cacna1g and Cacng8), ephrin receptor genes (Ephb6 and Epha8) and ryanodine receptor genes (Ryr1 and Ryr2). Calcium channel gene network were identified as a core gene network modulated by L-methionine in response to cocaine dependence. Moreover, it was predicted that Grin1 and Fosb presented in TF-miRNA-mRNA coregulation network with a high degree of interaction as hub genes and interacted calcium channels.

Conclusion: These identified key genes, miRNA and coregulation network demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP. To a certain degree, it may provide some hints to better understand the underlying mechanism on L-methionine in response to cocaine abuse.
A 31-plex panel for high-dimensional single-cell analysis of murine preclinical models of solid tumors by imaging mass cytometry
Authors: Glasson Yaël , Chépeaux Laure-Agnès , Dumé Anne-Sophie , Jay Philippe , Pirot Nelly , Bonnefoy Nathalie , Michaud Henri-Alexandre
Published: January 2023

Currently, the study of resistance mechanisms and disease progression in cancer relies on the capacity to analyze tumors as a complex ecosystem of healthy and malignant cells. Therefore, one of the current challenges is to decipher the intra-tumor heterogeneity and especially the spatial distribution and interactions of the different cellular actors within the tumor. Preclinical mouse models are widely used to extend our understanding of the tumor microenvironment (TME). Such models are becoming more sophisticated and allow investigating questions that cannot be addressed in clinical studies. Indeed, besides studying the tumor cell interactions within their environment, mouse models allow evaluating the efficacy of new drugs and delivery approaches, treatment posology, and toxicity. Spatially resolved analyses of the intra-tumor heterogeneity require global approaches to identify and localize a large number of different cell types. For this purpose, imaging mass cytometry (IMC) is a major asset in the field of human immuno-oncology. However, the paucity of validated IMC panels to study TME in pre-clinical mouse models remains a critical obstacle to translational or basic research in oncology. Here, we validated a panel of 31 markers for studying at the single-cell level the TME and the immune landscape for discovering/characterizing cells with complex phenotypes and the interactions shaping the tumor ecosystem in mouse models.
Olive leaves extract alleviates inflammation and modifies the intrinsic apoptotic signal in the leukemic bone marrow
Authors: Nath Priyatosh , Modak Snehashish , Aktar Tamanna , Maiti Sharanya , Ghosh Anisha , Singh Riddha , Debnath Mousumi , Saha Bhaskar , Maiti Debasish
Published: January 2023

Introduction

Current anti-leukemic chemotherapies with multiple targets suffer from side effects. Synthetic drugs with huge off-target effects are detrimental to leukemic patients. Therefore, natural plant-based products are being increasingly tested for new anti-leukemic therapy with fewer or no side effects. Herein, we report the effect of ethanolic olive leaves extract (EOLE) on the K562 cell line and on the bone marrow (BM) of N-ethyl-N-nitrosourea (ENU)-induced leukemic mice.

Methods

Using standard methodologies, we assessed viability, chromatin condensation, and induction of apoptosis in EOLE-treated K562 cells in-vitro. The anti-leukemic activity of EOLE was assayed by measuring ROS, levels of various cytokines, expression of iNOS and COX-2 gene, and changes in the level of important apoptosis regulatory and cell signaling proteins in-vivo.

Result

K562 cells underwent apoptotic induction after exposure to EOLE. In the BM of leukemic mice, EOLE therapy decreased the number of blast cells, ROS generation, and expression of NF-κB and ERK1/2. IL-6, IL-1β, TNF-α, iNOS, and COX-2 were among the inflammatory molecules that were down-regulated by EOLE therapy. Additionally, it decreased the expression of anti-apoptotic proteins BCL2A1, BCL-xL, and MCL-1 in the BM of leukemic mice.

Discussion

Chronic inflammation and anomalous apoptotic mechanism both critically contribute to the malignant transformation of cells. Inflammation in the tumor microenvironment promotes the growth, survival, and migration of cancer cells, accelerating the disease. The current investigation showed that EOLE treatment reduces inflammation and alters the expression of apoptosis regulatory protein in the BM of leukemic mice, which may halt the progression of the disease.
The dietary inflammatory index and its association with the prevalence of hypertension: A cross-sectional study
Authors: Zhou Nan , Xie Zhi-Ping , Liu Qing , Xu Yun , Dai Si-Cheng , Lu Juan , Weng Jia-Yi , Wu Li-Da
Published: January 2023

Aims

We aim to investigate the association of the Dietary Inflammatory Index (DII) with the prevalence of hypertension in a large multiracial population in the United States.

Methods

Participants from the National Health and Nutrition Examination Survey (NHANES) (1999–2018) were included in this cross-sectional study. Dietary information was obtained and used to calculate DII. Blood pressures of participants were measured by experienced examiners. The NHANES used the method of “stratified multistage probability sampling,” and this study is a weight analysis following the NHANES analytic guidance. Weight logistic regression analysis was adopted to investigate the association of hypertension with DII. Least Absolute Shrinkage and Selection Operator (LASSO) regression was carried out to screen the most important dietary factors associated with the risk of hypertension. Moreover, a nomogram model based on key dietary factors was established; the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic power of the nomogram model for screening hypertension risk.

Results

A total of 45,023 participants were included in this study, representing 191 million residents in the United States. Participants with hypertension had an elevated DII compared with those without hypertension. Weight logistic regression showed that an increment of DII was strongly associated with hypertension after adjusting for confounding factors. The nomogram model, based on key dietary factors screened by LASSO regression, showed a favorable discriminatory power with an area under the curve (AUC) of 78.5% (95% CI: 78.5%–79.3%). Results of the sensitivity analysis excluding participants who received any drug treatment were consistent with those in the main analysis.

Conclusion

An increment of DII is associated with the risk of hypertension. For better prevention and treatment of hypertension, more attention should be paid to controlling dietary inflammation.
Endoplasmic reticulum-associated protein degradation contributes to Toll innate immune defense in Drosophila melanogaster
Authors: Zhu Yangyang , Liu Lei , Zhang Chuchu , Zhang Chao , Han Tingting , Duan Renjie , Jin Yiheng , Guo Huimin , She Kan , Xiao Yihua , Goto Akira , Cai Qingshuang , Ji Shanming
Published: January 2023

In Drosophila, the endoplasmic reticulum-associated protein degradation (ERAD) is engaged in regulating pleiotropic biological processes, with regard to retinal degeneration, intestinal homeostasis, and organismal development. The extent to which it functions in controlling the fly innate immune defense, however, remains largely unknown. Here, we show that blockade of the ERAD in fat bodies antagonizes the Toll but not the IMD innate immune defense in Drosophila. Genetic approaches further suggest a functional role of Me31B in the ERAD-mediated fly innate immunity. Moreover, we provide evidence that silence of Xbp1 other than PERK or Atf6 partially rescues the immune defects by the dysregulated ERAD in fat bodies. Collectively, our study uncovers an essential function of the ERAD in mediating the Toll innate immune reaction in Drosophila.
Prediction and validation of murine MHC class I epitopes of the recombinant virus VSV-GP
Authors: Vijver Saskia V. , Danklmaier Sarah , Pipperger Lisa , Gronauer Raphael , Floriani Gabriel , Hackl Hubert , Das Krishna , Wollmann Guido
Published: January 2023

Oncolytic viruses are currently tested as a novel platform for cancer therapy. These viruses preferentially replicate in and kill malignant cells. Due to their microbial origin, treatment with oncolytic viruses naturally results in anti-viral responses and general immune activation. Consequently, the oncolytic virus treatment also induces anti-viral T cells. Since these can constitute the dominant activated T cell pool, monitoring of the anti-viral T cell response may aid in better understanding of the immune responses post oncolytic virotherapy. This study aimed to identify the anti-viral T cells raised by VSV-GP virotherapy in C57BL/6J mice, one of the most widely used models for preclinical studies. VSV-GP is a novel oncolytic agent that recently entered a clinical phase I study. To identify the VSV-GP epitopes to which mouse anti-viral T cells react, we used a multilevel adapted bioinformatics viral epitope prediction approach based on the tools netMHCpan, MHCflurry and netMHCstabPan, which are commonly used in neoepitope identification. Predicted viral epitopes were ranked based on consensus binding strength categories, predicted stability, and dissimilarity to the mouse proteome. The top ranked epitopes were selected and included in the peptide candidate matrix in order to use a matrix deconvolution approach. Using ELISpot, we showed which viral epitopes presented on C57BL/6J mouse MHC-I alleles H2-Db and H2-Kb trigger IFN-γ secretion due to T cell activation. Furthermore, we validated these findings using an intracellular cytokine staining. Collectively, identification of the VSV-GP T cell epitopes enables monitoring of the full range of anti-viral T cell responses upon VSV-GP virotherapy in future studies with preclinical mouse models to more comprehensively delineate anti-viral from anti-tumor T cell responses. These findings also support the development of novel VSV-GP variants expressing immunomodulatory transgenes and can improve the assessment of anti-viral immunity in preclinical models.
Prediction of celiac disease associated epitopes and motifs in a protein
Authors: Tomer Ritu , Patiyal Sumeet , Dhall Anjali , Raghava Gajendra P. S.
Published: January 2023

Introduction

Celiac disease (CD) is an autoimmune gastrointestinal disorder causes immune-mediated enteropathy against gluten. Gluten immunogenic peptides have the potential to trigger immune responses which leads to damage the small intestine. HLA-DQ2/DQ8 are major alleles that bind to epitope/antigenic region of gluten and induce celiac disease. There is a need to identify CD associated epitopes in protein-based foods and therapeutics.

Methods

In this study, computational tools have been developed to predict CD associated epitopes and motifs. Dataset used for training, testing and evaluation contain experimentally validated CD associated and non-CD associate peptides. We perform positional analysis to identify the most significant position of an amino acid residue in the peptide and checked the frequency of HLA alleles. We also compute amino acid composition to develop machine learning based models. We also developed ensemble method that combines motif-based approach and machine learning based models.

Results and Discussion

Our analysis support existing hypothesis that proline (P) and glutamine (Q) are highly abundant in CD associated peptides. A model based on density of P&Q in peptides has been developed for predicting CD associated peptides which achieve maximum AUROC 0.98 on independent data. We discovered motifs (e.g., QPF, QPQ, PYP) which occurs specifically in CD associated peptides. We also developed machine learning based models using peptide composition and achieved maximum AUROC 0.99. Finally, we developed ensemble method that combines motif-based approach and machine learning based models. The ensemble model-predict CD associated motifs with 100% accuracy on an independent dataset, not used for training. Finally, the best models and motifs has been integrated in a web server and standalone software package “CDpred”. We hope this server anticipate the scientific community for the prediction, designing and scanning of CD associated peptides as well as CD associated motifs in a protein/peptide sequence (https://webs.iiitd.edu.in/raghava/cdpred/).
The adjuvant effect of bacterium-like particles depends on the route of administration
Authors: Sudo Haruka , Tokunoh Nagisa , Tsujii Ayato , Kawashima Sarana , Hayakawa Yuta , Fukushima Hiroki , Takahashi Keita , Koshizuka Tetsuo , Inoue Naoki
Published: January 2023

Direct administration of vaccines to mucosal surfaces, such as via oral or nasal vaccination, represents an attractive alternative, or complement, to current parenteral vaccination because it has a potential to induce antigen-specific immunity both at mucosal and systemic tissues. Although bacterium-like particles (BLPs), peptidoglycan structures derived from lactic acid bacteria, have been investigated as a novel adjuvant for oral or nasal vaccines, it remains unclear whether the administration routes differ the adjuvant effect of BLPs. Here, we showed that the adjuvant effect of BLPs from Lactococcus lactis NZ9000 is greater with the nasal administration than with the oral administration. We conjugated BLPs with Tir, a virulence factor of Citrobacter rodentium, as a model adjuvant-antigen complex, and found that nasal, but not oral, immunization of mice with BLP-Tir induced robust antigen-specific IgA responses at the respiratory and intestinal mucosa, IgG2b-skewed systemic responses, and Th17 cellular responses. As one of the underlying mechanisms, we demonstrated that the nasal administration has a greater delivery efficiency (~1,000-fold) of the BLPs-conjugated antigens to mucosal-associated lymphoid tissues than the oral administration. Furthermore, the nasal, but not oral, administration of BLP-Tir elicited robust innate immune responses that were characterized by the expression of various pro-inflammatory cytokines and chemokines in the mucosal-associated lymphoid tissues. Considering these findings together, we anticipate that BLPs can be an attractive novel adjuvant for nasal vaccines targeting not only respiratory but also gastrointestinal infectious diseases.
Maternal synapsin autoantibodies are associated with neurodevelopmental delay
Authors: Bünger Isabel , Makridis Konstantin L. , Kreye Jakob , Nikolaus Marc , Sedlin Eva , Ullrich Tim , Hoffmann Christian , Tromm Johannes Vincent , Rasmussen Helle Foverskov , Milovanovic Dragomir , Höltje Markus , Prüss Harald , Kaindl Angela M.
Published: January 2023

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.
Epifriedelanol is the key compound to antibacterial effects of extracts of Synadenium glaucescens (Pax) against medically important bacteria
Authors: Msengwa Zaituni , Rwegoshora Frank , David Credo , Mwesongo James , Mafuru Magesa , Mabiki Faith P. , Mwang’onde Beda J. , Mtambo Madundo M. , Kusiluka Lughano J. M. , Mdegela Robinson H. , Olsen John E.
Published: January 2023

Introduction

Synadenium glaucescens has been used for the treatment of bacterial infections in many parts of the world. We investigated the antibacterial and cytotoxicity activities of secondary metabolites of this plant.

Methods

Hexane, dichloromethane, methanol, and water were used as extraction solvents. The extract of the root bark was fractionated with ethyl acetate and methanol. The isolation of compounds from root barks, leaves and stem wood extracts were carried out using column chromatography. Antibacterial activities were characterized based on growth curves, killing curves and MIC determinations. Haemolytic effect towards sheep red blood cells (RBCs) was analysed with spectrophotometer at the wavelength of 540nm.

Results and Discussion

Extracts from whole root and root bark showed strong activity against Staphylococcus aureus, and Streptococci and Enterococci species, and moderate to weak activity against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella species, Shigella sonnei and Yersinia enterocolitica. Staphylococcus aureus was the most susceptible, and E. coli and Klebsiella pneumonia were the least susceptible ones. Likewise, extracts, fractions, sub-fractions and epifriedelanol demonstrated bacteriostatic activity against S. aureus. The haemolytic activity of the extracts, fractions, sub-fractions and epifriedelanol was significantly low compared to the positive control, hydrogen peroxide. But extract from leaves showed high haemolytic effects at the concentrations of 500 μg/mL and 1000 μg/mL. Thus, extracts of S. glaucescens have antibacterial activity against several Gram-positive bacteria including Methicillin Resistant S. aureus with low haemolytic activity. At high concentrations, the extracts from leaves have toxicity risk. More studies for the active compounds are required for biological testing.
Physiological and immunological responses of Nile tilapia fed dietary supplementation of sweet basil ethanolic and aqueous extracts
Authors: Mansour Abdallah Tageldein , Diab Amany M. , Khalil Riad H. , Eldessouki Elsayed A. , El-Sabbagh Nasser , Elsamannoudy Salma I. , Younis Nehal A.
Published: January 2023

The use of phytotherapy in aquaculture is rapidly increasing for more environmentally sustainable measures. The present work aimed to investigate the effects of different dietary levels of sweet basil, Ocimum basilicum, leaves ethanol (BEE) or aqueous (BAE) extracts (0, 200, 300, and 500 mg/kg) on Oreochromis niloticus growth, digestive enzyme activities, hemato-biochemical profile, antioxidant status, immune responses, and resistance against Streptococcus agalactiae. Oreochromis niloticus fingerlings (40.00 ± 1.00 g/fish, n = 210) were randomly divided into seven triplicated groups (control, BEE200, BEE300, BEE500, BAE200, BAE300, and BAE500) and fed the experimental diets for 8 weeks. The results revealed that dietary inclusion of BEE and BAE significantly improved final weight, weight gain, survival, and digestive enzyme activities. The growth response revealed a dose-dependent in favor of fish fed BEE. The hemato-biochemical biomarkers showed a significant improvement in RBCs, WBCs, hemoglobin, and lymphocyte, and a significant decrease in aminotransferases, creatinine, and cholesterol levels with dietary basil extracts. The cellular and humoral immune responses (phagocytic activity, phagocytic index, lysozyme activity, immunoglobulin) were significantly improved with increasing BEE and BAE in a dose-dependent manner. The expression of IL-1β and TNF-α genes were increased, while TGF-β was decreased in a dose-dependent manner and BEE500 have the highest expression. The antioxidant balance was improved with increasing basil extracts supplementation, and the BEE500 group showed the best antioxidant status. Dietary BEE and BAE increased Nile tilapia resistance to S. agalactiae. In conclusion, the dietary supplementation of both ethanolic and aqueous extracts could improve the growth performance and physiological, and immune-antioxidant status of Nile tilapia.
How does heat stress affect sponge microbiomes? Structure and resilience of microbial communities of marine sponges from different habitats
Authors: De Castro-Fernández Paula , Ballesté Elisenda , Angulo-Preckler Carlos , Biggs Jason , Avila Conxita , García-Aljaro Cristina
Published: January 2023

Introduction

Sponges are key components of marine benthic communities, providing many ecosystem functions and establishing close relationships with microorganisms, conforming the holobiont. These symbiotic microbiotas seem to be host species-specific and highly diverse, playing key roles in their sponge host. The effects of elevated seawater temperature on sponges and their microbiota are still poorly known, and whether sponges from polar areas are more sensitive to these impacts respect to temperate and tropical species is totally unknown.

Methods

We analyzed the microbiomes of different sponge species in their natural habitat and after exposure to heat stress in aquaria by 16S rRNA amplicon sequencing to (1) characterize the sponge microbiota covering a latitudinal gradient (polar, temperate and tropical environments), and (2) asses the effects of thermal stress on their microbial communities.

Results

Bacterial communities’ structure was different in the different sponge species and also respect the surrounding seawater. The core microbiome is maintained in most sponge species after a heat stress, although whether they would recover to the normal conditions previous to the stress remains yet to be further investigated. We observed increased abundances of transient bacteria from unknown origin in sponge species exposed to heat stress.

Discussion

Some of the transient bacteria may be opportunistic bacteria that may benefit from the heat stress-associated dysregulation in the sponge by occupying new niches in the holobiont. According to our results, sponges from Antarctic waters could be more resilient than tropical and temperate sponges. Both the microbiome composition and the changes produced by the heat stress seem to be quite host species-specific, and thus, depend on the sponge species. Under a global change scenario, the microbiomes of the tropical and temperate sponges will probably be those suffering the most the heat stress, and therefore the effects of global change may be dramatic for benthic ecosystems since sponges are a fundamental part of them.