bluuebunny/crossref_metadata_2025 huggingface dataset:
The Gaussian Integral for the Normal Distribution in Machine Leaning
Authors: Annamalai Chinnaraji
Published: October 2024

The Gaussian distribution is a normal probability distribution that is a key concept in statistics and the backbone of machine learning. In normal distribution, data are symmetrically distributed with no skew. A data scientist needs to know about the normal distribution for data analysis. In this article, we can learn and understand how to use the Gaussian integral in the probability density function for a normal distribution and applications of machine learning.
Menelaah Penyimpangan “Pengampunan Dosa” Dalam Perspektif Suhento Liauw
Authors: Hia Sozanolo , Harefa Julitinus , Hia Meniati , Tangu Rosanti Yowa , Sari Larosa Ayu Sekar
Published: October 2024

Forgiveness of sins is an essential and fundamental principle in Christian teachings, reflecting the love and compassion of God, which provides humans the opportunity to correct their mistakes and return to Him. However, according to Suhento Liauw's perspective based on local church theology, there are significant differences in understanding and interpretation. This study aims to conduct an in-depth analysis of the concept of forgiveness of sins according to Suhento Liauw within the framework of local church theology, with the objective of understanding and evaluating Suhento Liauw's comprehension as well as its implications and relevance to Christian teaching and spiritual practice. The research method used is a descriptive qualitative approach with literature study, where the data will be analyzed using content analysis and theological analysis methods. The findings indicate that Suhento Liauw's view on the concept of forgiveness of sins in local church theology considers believers as the subjects of forgiveness, so their sins are forgiven and erased before Jesus Christ. Meanwhile, Suhento Liauw rejects the notion that God the Father is also an object for believers seeking forgiveness. This research provides valuable contributions to theological discussions and thoughts regarding the forgiveness of sins, with the hope of producing a more accurate and beneficial understanding for the church and the broader Christian community, as well as enriching the understanding of forgiveness of sins in the context of local church theology.
Makna Kalimat Namun Aku Mengasihi Yakub Tetapi Membenci Esau Dalam Maleakhi 1:2-3
Authors: Ananda Bella Putri , Setyarini Lilis , Widianto Kasiatin
Published: October 2024

The phrase, "Yet I have loved Jacob, but Esau I have hated," found in Malachi 1:2-3, has sparked significant debate, particularly concerning the concept of election in the doctrine of salvation. Therefore, this study aims to explore the intended meaning of the author of the book of Malachi. Utilizing a qualitative exegetical method, alongside several specific analytical steps, this research seeks to produce objective findings that align with the truth of Scripture. After conducting the study through this method, it concludes that the phrase in this verse does not pertain to the concept of election in the doctrine of salvation, but rather reflects the nature of God, who is capable of both love and hatred. Furthermore, the study emphasizes that God's love and hatred cannot be equated with human emotions.
Analisis 1 Samuel 14:52-15:3 Sebuah Pendekatan Aksen Ibrani dan Sintaks
Authors: Chia Philip Suciadi
Published: October 2024

In the book of 1 Samuel, the selection of Saul as king of Israel is influenced by a complex historical and theological context. 1 Samuel 14:52 highlights Saul's reliance on his soldiers in battling the Philistines, which forms the background of his leadership. Conversely, 1 Samuel 15:1-3 underscores Saul's disobedience to God's command, leading to his rejection as king. This study analyzes both aspects Saul's leadership background and his disobedience using Hebrew accent and syntax methodology to explore the theological implications. The Hebrew accent methodology aids in exploring the linguistic emphasis within the text, while Hebrew syntax examines the sentence structure that provides insights into Saul’s character. The analysis reveals that although Saul experienced notable military success, his disobedience to God’s commands was the primary factor in his downfall. There is a clear connection between Saul’s reliance on human strength and his inability to fully submit to God's will. The study concludes that Saul’s rejection was not solely due to disobedience but also reflected a lack of trust in God. These findings are relevant in theological and leadership studies, emphasizing the importance of obedience to God and warning contemporary leaders of the dangers of relying on human strength.
Multi-branch deep learning neural network prediction model for the development of angular biosensors based on sEMG
Authors: Yang Liman , Shi Zhijun , Jia Ruming , Kou Jiange , Du Minghua , Bian Chunrong , Wang Juncheng
Published: October 2024

Introduction

Human gait motion intention recognition is very important for the lower extremity exoskeleton robot to accurately synchronize and respond to the user’s natural motion. And motion intention recognition is generally performed through sEMG. Deep learning neural networks perform well in dealing with high-dimensional data and nonlinear relationships such as sEMG, but different deep learning neural networks have their own advantages in dealing with different types of data. Therefore, a multi-branch deep learning neural network, which enables different neural networks to process different feature items, could achieve more accurate and efficient motion intention recognition. The purpose of this study is to 1) Establish a multi-branch deep learning neural network model to achieve accurate gait recognition and effective estimation of joint angles. 2) Quantify the performance of the multi-branch deep learning neural network model in gait recognition and joint angle prediction using sEMG.

Methodology

This study involved the collection of sEMG and plantar pressure data during walking in human subjects. Firstly, the collected signals are filtered and denoised to ensure the quality and reliability of the data. Calculate the time domain features and the frequency domain features to capture the key information of gait. Then, using the sensitivity difference of different structural neural networks to different feature data, a multi-branch deep learning neural network model is developed, in which the extracted features are used as the input of the model. The output of the model includes gait cycle and joint angle, so as to realize the accurate recognition of human gait and the effective estimation of joint angle.

Results

The results show that the proposed method has high accuracy in identifying human gait and estimating joint angles. The multi-branch neural network model successfully integrates time-domain and frequency-domain features and provides reliable prediction of gait cycle and joint angle. The highest accuracy of gait recognition is 95.42%, the lowest is 90.11%, and the average is 92.16%. The average error of joint angle estimation is 3.19.

Discussion

This study designed a human walking gait recognition and joint angle prediction model to achieve accurate human lower limb motion intention recognition.The model can be integrated into the sEMG sensor to design a angular biosensors, which can predict the human joint angle in real time.
The dual role of autophagy in suppressing and promoting hepatocellular carcinoma
Authors: Mohammed Wasnaa H. , Sulaiman Ghassan M. , Abomughaid Mosleh M. , Klionsky Daniel J. , Abu-Alghayth Mohammed H.
Published: October 2024

The 5-year survival rate for hepatocellular carcinoma (HCC), a deadly form of liver cancer, is quite low. Although drug therapy is successful, patients with advanced liver cancer frequently develop resistance because of the significant phenotypic and genetic heterogeneity of these cells. The overexpression of drug efflux transporters, downstream adaptive responses, malfunctioning DNA damage repair, epigenetic modification, the tumor microenvironment, and the extracellular matrix can all be linked to drug resistance. The evolutionary process of autophagy, which is in charge of intracellular breakdown, is intimately linked to medication resistance in HCC. Autophagy is involved in both the promotion and suppression of cancer by influencing treatment resistance, metastasis, carcinogenesis, and the viability of stem cells. Certain autophagy regulators are employed in anticancer treatment; however, because of the dual functions of autophagy, their use is restricted, and therapeutic failure is increased. By focusing on autophagy, it is possible to reduce HCC expansion and metastasis, and enhance tumor cell reactivity to treatment. Macroautophagy, the best-characterized type of autophagy, involves the formation of a sequestering compartment termed a phagophore, which surrounds and encloses aberrant or superfluous components. The phagophore matures into a double-membrane autophagosome that delivers the cargo to the lysosome; lysosomes and autophagosomes fuse to degrade and recycle the cargo. Macroautophagy plays dual functions in both promoting and suppressing cancer in a variety of cancer types.
The levels of systemic inflammatory markers exhibit a positive correlation with the occurrence of heart failure: a cross-sectional study from NHANES
Authors: Huang Lei , Shen Ronghuan , Yu Hailan , Jin Nake , Hong Jun , Luo Yu , Chen Xudong , Rong Jiacheng
Published: October 2024

Background

We conducted a large-scale epidemiological analysis to investigate the associations between systemic inflammation markers and heart failure (HF). Our aim is to identify potential biomarkers for early detection of HF.

Methods

A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey. We investigated the associations between five systemic inflammation markers (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte ratio [PLR], systemic immune inflammation index [SII], system inflammation response index [SIRI], and aggregate index of systemic inflammation [AISI]) and the risk of HF.

Results

The prevalence rates of HF exhibited a gradual increase across increasing logNLR, logPLR, logSII, logSIRI, and logAISI tertiles. Compared to those in the highest tertiles of logNLR, logSII, logSIRI, and logAISI had a 1.579-fold, 1.341-fold, 1.956-fold, and 1.499-fold increased risk of HF compared to those in the lowest tertile respectively. Conversely, there was no significant correlation between logPLR and HF risk among subjects in the highest tertile. The restricted cubic splines (RCS) analysis revealed a non-linear relationship between the elevation of systemic inflammation markers and HF prevalence. Specifically, a per standard deviation increase in any of these variables is associated with a respective 45%, 29%, 28%, 44% and 29% increase in HF prevalence. The receiver operating characteristic (ROC) analysis demonstrated favorable sensitivity and specificity of these systemic inflammation markers in detecting the presence of HF.

Conclusion

Our cross-sectional study demonstrates significant positive correlations between the NLR, PLR, SII, SIRI, and AISI with the incidence of HF.
Case Report: PROS1 (c.76+2_76+3del) pathogenic mutation causes pulmonary embolism
Authors: Ding Peng , Zhou Yuan , Yang Meijie , Li Sheng , Zhang Song , Zhi Lijia
Published: October 2024

Background

Genetic variation plays an extremely important pathogenic role in the development of venous thromboembolism (VTE). Genetic protein S (PS) deficiency caused by PROS1 gene mutation is an important risk factor for hereditary thrombophilia.

Case introduction

In this case, we report a 28-year-old male patient who developed a severe pulmonary embolism during his visit. The patient had experienced one month of chest pains, coughing and hemoptysis symptoms. CTPA confirmed an acute pulmonary embolism with multiple filling defects in both pulmonary arteries. Ultrasound showed no thrombosis in the veins of both lower limbs. The patient's father and grandfather have a history of lower limb venous thrombosis. The patient was diagnosed with acute pulmonary embolism and pneumonia. The serum PS level significantly decreased (detection result: 10%, normal range: 77–143). Gene sequencing revealed a heterozygous missense mutation in PROS1 c.76+2_76+3del (base deletion), and further testing revealed that the genetic variation originated from his father. The patient was treated with heparin anticoagulant therapy, catheter thrombus aspiration, and catheter thrombolysis. After treatment, the patient's chest pain symptoms were relieved, and there were no symptoms such as difficulty breathing. On the 7th day of admission, the patient was transferred to a general hospital for further treatment.

Conclusion

Hereditary thrombophilia caused by mutations in the PROS1 (c.76+2_76+3del) gene is extremely rare. In clinical practice, heparin and rivaroxaban treatment are beneficial.
Groundwater level rise and geological structure influences on land deformation dynamics: insights from managed aquifer recharge operations in Beijing, China
Authors: Liu Shao-Min , Bai Ming-Zhou
Published: October 2024

Managed Aquifer Recharge (MAR) has been implemented in the upper alluvial plain of the Chaobai River, significantly affecting the groundwater level and causing it to rise. However, the effects of the MAR on land subsidence,remain largely unknown. To elucidate the effects of MAR on land subsidence, a comprehensive analysis was undertaken, integrating interferometric synthetic aperture radar (InSAR) data, extensometer measurements, and groundwater level observations.Our analysis revealed a discernible land rebound phenomenon, with rates escalating from 2.3 mm/a in 2015 to 20 mm/a in 2021. This rebound extends southwestward, following a dispersion pattern that aligns with pre-existing fault structures, suggesting their controlling influence. The groundwater level changes caused by the MAR can cause land rebound, especially near fault footwalls. However,low permeability in fault zones hinders groundwater flow in the hanging wall resulting in slight land deformation. Lithology also affects rebound, with sandy soils showing more significant land rebound, while low-sand areas exhibit limited or delayed rebound. These findings offer crucial insights into the interplay between MAR, groundwater dynamics, and land subsidence in the studied region. They provide a foundation for informed decision-making in groundwater replenishment strategies and precise subsidence prevention and control measures. Future research should maintain a vigilant monitoring of the long-term consequences of MAR on land subsidence to ensure sustainable regional development.
Risk of bone fracture by using dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: a network meta-analysis of population-based cohort studies
Authors: Mostafa Mohamed E. A. , Alrasheed Tariq
Published: October 2024

Background

Type 2 diabetes mellitus (T2DM) is linked to a heightened likelihood of experiencing fractures. It is crucial to ascertain whether medications used to lower blood sugar levels can elevate the risk of fractures. We aimed to investigate and compare the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA), Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) on the fracture risk in patients with T2D in the real world.

Methods

A network meta-analysis conducted an inclusive literature search in PubMed, Scopus, Web of Science, and Cochrane Library to select appropriate population-based cohort studies that investigated the risk of bone fractures of (GLP-1RA), (DPP-4i) or (SGLT-2i) in the real world. A network meta-analysis (NMA) was performed using R software to investigate the risk of total fractures as a primary outcome among patients who used (GLP-1RAs), (SGLT-2i) or (DPP-4i) versus each other or other glucose-lowering medications (GLMs). The odds ratio (OR) and 95% confidence interval (CI) were summarized overall network and for each pairwise direct and indirect comparison. The surface under the cumulative ranking curve (SUCRA) with the P-scores was calculated for each treatment in the network meta-analysis to detect their cumulative ranking probabilities in lowering the risk of total fractures.

Results

In our NMA, we identified a set of 13 population-based cohort studies comprising a total of 1,064,952 patients. The risk of fracture was identified with the follow-up duration for each class. We found a significant decrease in the fracture risk by about 87% associated with patients who used SGLT2 inhibitors in combination with other glucose-lowering medications, followed by SGLT2 inhibitors alone by about 67%, then GLP-1 receptor agonists by about 60%, and at last DPP-4 inhibitors by about 55%.

Conclusion

Our study’s collective findings suggest a significant association of the low risk of fracture with the use of SGLT2i with other GLMs combination, SGLT2i alone, GLP-1RA, and DPP-4i, respectively. This population-based analysis offers the best available evidence and might be helpful for clinicians in the decision of the most suitable T2DM treatment strategies, especially for elderly type 2 diabetic patients, as they may be safe in terms of fracture.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42023448720.
DNA polymorphisms in inflammatory and endocrine signals linked to frailty are also associated with obesity: data from the FRASNET cohort
Authors: Damanti Sarah , Citterio Lorena , Zagato Laura , Brioni Elena , Magnaghi Cristiano , Simonini Marco , De Lorenzo Rebecca , Ruggiero Mariapia , Santoro Simona , Senini Eleonora , Messina Marco , Vitali Giordano , Manunta Paolo , Manfredi Angelo Andrea , Lanzani Chiara , Rovere Querini Patrizia
Published: October 2024

Background

Obesity and frailty are prevalent geriatric conditions that share some pathophysiological mechanisms and are associated with adverse clinical outcomes. The relationship between frailty, obesity, and polymorphism remains inadequately explored. Single nucleotide polymorphisms (SNPs) offer insights into genetic predispositions that may influence the development of both frailty and obesity.

Methods

We aimed at investigating whether SNPs associated with frailty also play a role in obesity. Data were collected from the FRASNET cross-sectional study, which included community-dwelling older individuals residing in Milan and nearby areas. Participants were recruited through random sampling. They underwent multidimensional geriatric assessments, which included the collection of blood samples for SNP analysis. Frailty was assessed using the frailty index, and body composition was evaluated using bioelectrical impedance analysis and anthropometric measures.

Results

SNPs related to frailty and linked to the renin–angiotensin system (CYP11B2 rs1799998, AGT rs5051, and AGTR1 rs2131127), apoptosis pathways (CASP8 rs6747918), growth hormone signaling (GHR rs6180), inflammation (TLR4 rs5030717, CD33 rs3865444, and FN1 rs7567647), adducin (ADD3 rs3731566), and the 9p21–23 region (rs518054) were found to be associated with various measures of obesity in community-dwelling older adults.

Conclusions

Frailty-related SNPs contribute to obesity in community-dwelling older adults. We identified a novel association between adducin SNPs and visceral fat, which has not been previously reported. Detecting genetic predispositions to obesity and frailty early could aid in identifying individuals at risk, facilitating the adoption of preventive interventions. This represents an initial step toward promoting early intervention strategies.
Serum iron status is associated with all-cause mortality in metabolic dysfunction-associated steatotic liver disease: a prospective, observational study
Authors: Xia Ting , Ni Jie , Ni Yuqin , Wu Xinhui , Du Kangming , Wan Xuemei , You Xuli
Published: October 2024

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD.

Methods

A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age.

Results

During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (Poverall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD.

Conclusion

This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status.
A new grid side inertia support control method for cascaded power converters in Bi-directional EV chargers
Authors: Tian Yan , Huang Bo , Fang Jian , Chen Wei , Xin Yu , Lin Haobo , Lin Xiang
Published: October 2024

To provide inertia support to the power grid, the grid side frontend DC/AC inverter of the bidirectional electric vehicle (EV) charging facilities can use the virtual synchronous generator (VSG) control in its grid-side DC/AC converter. However, the existing VSG control cannot actually realize the inertia support due to the limitations of the existing cascaded power converters control structure of the bidirectional EV charger. This paper proposes a new control infrastructure for VSG based bi-directional EV charging facilities. The proposed control instantaneously tracks the inertial supporting surge power by DC/DC so as to stabilize the DC bus voltage. Meanwhile, the droop coefficient based power values are also fed forward to DC/DC controls to support grid frequency control over a larger time scale. Finally, the experiment results show that the proposed method improves the DC bus voltage stability of the EV charger while allowing the EV to participate in the power system frequency regulation, which is a key feature of the Vehicle to Grid applications.
Can agricultural water rights trading promote intensive and economical utilization of water resources in China based on the difference-in-differences model?
Authors: Rong Lili , Cheng Xin
Published: October 2024

Introduction

Improving the level of intensive and economical utilization of water resources is an important step towards water and food security.

Methods

Based on China’s provincial panel data from 2015 to 2021, this study uses a difference-in-differences (DID) model to examine the effect of agricultural water rights trading on intensive and economical utilization of water resources.

Results

The results show that agricultural water rights trading can significantly promote an intensive and economical utilization of water resources at the 1% level, and the results remain valid even after a series of robustness tests. Further analysis indicates that agricultural water rights trading can promote better utilization of water resources by significantly reducing agricultural water consumption at the 1% level and reducing the proportion of agricultural water consumption at the 5% level to optimize water use structure. Moreover, in regions with scarce water resources, strong water resource constraints, more farmland water conservancy projects, and greater economic development, the promoting effect of agricultural water rights trading on the intensive and economical use of water resources is more significant.

Discussion

This study provides evidence of the impact of China’s agricultural water rights trading policy and offers new ideas and experiences to improve China’s water resource utilization efficiency. The contributions of this work are mainly threefold. First, this paper clearly distinguishes the intensive conservation of water resources, presents an evaluation index system, and complements the existing literature on measuring the intensive and economical utilization of water resources. Second, the path of agricultural water rights trading is analyzed to improve the level of intensive and economical utilization of water resources, thus enriching related research on transmission mechanisms. Third, the heterogeneity of the influence of different regional conditions on the level of intensive and economical utilization of water resources is discussed to improve relevant policies.
How are firms motivated to greenly innovate under the pressure of ESG performance? Evidence from Chinese listed firms
Authors: Liu Junliang , Wang Bolin , He Xiaogang
Published: October 2024

The impact of environmental, social, and governance (ESG) performance gaps on firm green innovation is examined in this paper by a panel database of A-share Chinese listed companies from 2011 to 2021. Using multiple linear regression and conducting a series of endogeneity tests and robustness checks, our empirical analysis shows that firm ESG performance gaps have significantly positive effect on green innovation. Both ESG performance below historical aspiration and social aspiration levels enhance a firm’s green innovation. Confucian culture negatively moderates the positive relationship between ESG performance gaps and green innovation, suggesting that firms more influenced by Confucian culture exhibit reduced green innovation than those less influenced. Additionally, firm digitalization positively moderates the positive relationship between ESG performance gaps and green innovation, indicating that firms with higher levels of digitalization are better equipped to improve green innovation when facing ESG performance shortfalls. This study extends the existing knowledge of firm ESG performance and motivation of green innovation. The research findings offer practical insights for leveraging the motivation and capabilities of green innovation to attain firm ESG objectives.
Brucellosis outbreak in a remote village in northwestern Tajikistan in 2023: a matched case-control study
Authors: Qurbonov Emomali , Silemonshoeva Jamila , Horth Roberta , Tilloeva Zulfiya , Yusufi Salomudin , Nabirova Dilyara
Published: October 2024

Background

A sharp increase in reported brucellosis incidence was observed in northwestern Tajikistan (from 1.0/100,000 people in January–May 2022 to 32.7/100,000 in January–May 2023). Most (82%) cases were from the same remote mountainous village (population = 10,712). The aim of this study was to identify risk factors for brucellosis infection and mitigate disease risk.

Methods

Using a case-control design, we conducted face-to-face interviews and collected blood samples during May-June 2023. Fifty-seven cases and 114 controls were recruited. Cases were the first person in a household diagnosed with brucellosis during February–June 2023 with positive serum agglutination test and antibody titers ≥1/160 from blood samples. Two controls were selected for each case (neighbors from different households matched by age and sex). Controls testing positive were excluded and replaced. We conducted conditional multivariable logistic regression to calculate adjusted odds ratio (AOR) and 95% confidence intervals (CI).

Results

Among the 87 brucellosis patients reported, 57 (66%) agreed to participate and didn't have secondary cases in the household. Of the 57 cases, 68% were 15–44 years old, and 44% were male. Cases peaked in May 2023. Common symptoms were joint pain (95%), fever (84%), weakness (72%), and night sweats (65%). Of selected controls, 13% tested positive and were excluded. All cases and 94% of controls owned livestock (mostly cattle, sheep, or goats); no animals had not been vaccinated in the past 5 years. Brucellosis was associated with consumption of both homemade kaymak (clotted cream) and home-raised meat compared with neither (AOR: 59 [95%CI: 4.3–798], p < 0.01), home-raised meat but not kaymak compared with neither (AOR: 54 [4.0–731], p < 0.01), and involvement in animal slaughter compared with no involvement (AOR: 36 [2.8–461], p < 0.01).

Conclusion

Contact with unvaccinated livestock or consumption of their products was a key contributor to this outbreak in a remote village of Tajikistan. With 13% of controls testing positive, true incidence was likely greater than reported. Following our investigation, a brucellosis awareness education campaign and animal vaccination campaigns were carried out in the region and only one case was reported in September 2023.
PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis
Authors: Boumpas Athina , Papaioannou Antonis S. , Bousounis Pavlos , Grigoriou Maria , Bergo Veronica , Papafragkos Iosif , Tasis Athanasios , Iskas Michael , Boon Louis , Makridakis Manousos , Vlachou Antonia , Gavriilaki Eleni , Hatzioannou Aikaterini , Mitroulis Ioannis , Trompouki Eirini , Verginis Panayotis
Published: October 2024

Introduction

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit.

Methods

In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality.

Results

Herein, we reveal that aPD-L1 in tumour-bearing mice targets the HSPCs in the BM, mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice.

Discussion

Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.
Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape
Authors: Xiao Shuo-meng , Xu Rui , Yang Ying-xin , Zhao Rui , Xie Yuan , Lei Xu-dan , Wu Xiao-ting
Published: October 2024

Purpose

The infiltration of immune cells and their roles of the infiltrating-immune cells in gastrointestinal stromal tumor (GIST) is still unclear. We aimed to discover the infiltration cell types and the relationship between the infiltrating-immune cells and the progression of GIST.

Experimental design

Single-cell RNA sequencing were performed to discover types of the infiltrating-immune cells and to analyze CellChat between cells. Immunohistochemistry of 80 GIST samples were used to clarify the relation between macrophages and recurrence risk. In vitro, flow cytometry and Real-time PCR were performed to uncover a potential mechanism of tumor cell regulation of macrophages.

Results

Tumor cells, macrophages, and T-cells were the predominant cell types. The MIF/CXCR4 axis was the most common ligand–receptor interaction between macrophages and tumor cells. As the risk increased, expression levels of CD68, CD206, MIF, and CXCR4 gradually increased. In vitro, we found that GIST882 was able to secrete MIF and GIST882 cell supernatant upregulated M2 polarization. Real-time PCR showed that expression levels of IL-10 mRNA and Arginase-1 mRNA were also the highest in the GIST882 cell supernatant group.

Conclusions

These findings identify that macrophages are the most abundant infiltrating cells in GIST. The MIF/CXCR4 axis is the most common ligand–receptor interaction between macrophages and tumor cells. GIST cells can regulate macrophage M2 polarization through the MIF/CXCR4 axis.
The role of dendritic cells in tertiary lymphoid structures: implications in cancer and autoimmune diseases
Authors: Reste Mariana , Ajazi Kristi , Sayi-Yazgan Ayca , Jankovic Radmila , Bufan Biljana , Brandau Sven , Bækkevold Espen S. , Petitprez Florent , Lindstedt Malin , Adema Gosse J. , Almeida Catarina R.
Published: October 2024

Tertiary Lymphoid Structures (TLS) are organized aggregates of immune cells such as T cells, B cells, and Dendritic Cells (DCs), as well as fibroblasts, formed postnatally in response to signals from cytokines and chemokines. Central to the function of TLS are DCs, professional antigen-presenting cells (APCs) that coordinate the adaptive immune response, and which can be classified into different subsets, with specific functions, and markers. In this article, we review current data on the contribution of different DC subsets to TLS function in cancer and autoimmunity, two opposite sides of the immune response. Different DC subsets can be found in different tumor types, correlating with cancer prognosis. Moreover, DCs are also present in TLS found in autoimmune and inflammatory conditions, contributing to disease development. Broadly, the presence of DCs in TLS appears to be associated with favorable clinical outcomes in cancer while in autoimmune pathologies these cells are associated with unfavorable prognosis. Therefore, it is important to analyze the complex functions of DCs within TLS in order to enhance our fundamental understanding of immune regulation but also as a possible route to create innovative clinical interventions designed for the specific needs of patients with diverse pathological diseases.
Efferocytosis dysfunction in CXCL4-induced M4 macrophages: phenotypic insights in systemic sclerosis in vitro and in vivo
Authors: Le Tallec Erwan , Bellamri Nessrine , Lelong Marie , Morzadec Claudie , Frenger Quentin , Ballerie Alice , Cazalets Claire , Lescoat Alain , Gros Frédéric , Lecureur Valérie
Published: October 2024

Introduction

Systemic sclerosis (SSc) is an autoimmune disease characterized by antinuclear antibody production, which has been linked to an excess of apoptotic cells, normally eliminated by macrophages through efferocytosis. Additionally, circulating levels of CXCL4, a novel SSc biomarker, correlate with more severe fibrotic manifestations of the disease. Considering the defective efferocytosis of macrophages in SSc and the CXCL4-related M4 macrophage phenotype, we hypothesized that CXCL4 could be involved in the alteration of phagocytic functions of macrophages in SSc, including LC3-associated phagocytosis (LAP), another phagocytic process requiring autophagy proteins and contributing to immune silencing.

Methods

In this study, CXCL4 levels were measured by ELISA in vitro in the serum of SSc patients, and also in vivo in the serum and lungs of C57BL/6J SSc mice induced by intradermal injections of hypochloric acid (HOCl) or Bleomycin (BLM), with evaluation of M4 markers. Circulating monocytes from healthy donors were also differentiated in vitro into M4 monocytes-derived macrophages (MDMs) in the presence of recombinant CXCL4. In M4-MDMs, phagocytosis of fluorescent beads and expression level of efferocytic receptors were evaluated by flow cytometry in vitro, while efferocytosis of pHrodo-stained apoptotic Jurkat cells was evaluated by real-time fluorescence microscopy. LAP quantification was made by fluorescence microscopy in M4-MDMs exposed to IgG-coated beads as well as apoptotic Jurkat cells.

Results

Our results demonstrated that efferocytosis was significantly reduced in M0-MDMs from healthy donors exposed to the CXCL4-rich plasma of SSc patients. In vivo, CXCL4 expression was increased in the lungs of both SSc-mouse models, along with elevated M4 markers, while efferocytosis of BLM-mice alveolar macrophages was decreased. In vitro, M4-MDMs exhibited reduced efferocytosis compared to M0-MDMs, notably attributable to lower CD36 receptor expression and impaired phagocytosis capacities, despite enhanced LAP. Autophagic gene expression was increased both in vitro in SSc MDMs and in vivo in BLM mice, thus acting as a potential compensatory mechanism.

Discussion

Altogether, our results support the role of CXCL4 on the impaired efferocytosis capacities of human macrophages from SSc patients and in SSc mice.
Evaluating the mechanical and environmental impact of PEF plastic waste incorporated with graphene nano-platelets in concrete
Authors: Khan Muhammad Basit , Najeh Taoufik , Almujibah Hamad , Al Zouabi Mohammad Ghiath , Benjeddou Omrane
Published: October 2024

There has been a significant surge in the yearly use of plastics, leading to a notable rise in plastic waste generation. Consequently, the recycling of plastic garbage has emerged as a prominent concern around the world. This research explores the feasibility of using polyethylene furanoate (PEF) plastic waste as a substitute for coarse aggregate (CA) in concrete. Graphene nano-platelets (GNPs) were added to the concrete mix in different quantities to improve its structural reliability. The research study used an experimental research design in conducting its investigation. PEF waste plastic was added in concrete in varying proportions of 0%, 5%, 15%, 20%, and 25% as a supplementary material to gravel, and GNPs were added in different percentages of 0%, 0.03%, 0.05%, 0.08%, and 0.1% by weight of cement. Mechanical tests were conducted, which includes compressive strength (CS), split tensile strength (STS), flexural strength (FS), modulus of elasticity (MoE), and ultrasonic pulse velocity (UPV), and the environmental assessment of concrete was done by assessing carbon in concrete and concrete’s eco efficiency (ESE). It was found that 5% addition of PEF as the substitute to CA and 0.1% of GNPs gives the optimum strength, enhancing CS, STS, and FS by 9.10%, 18.18%, and 4.45%, respectively. Response surface technique (RSM) models were created to provide mathematical equations for predicting the predicted outcomes. All models were optimized using a multi-objective optimization approach and then validated.
An integrative predictive model for orthokeratology lens decentration based on diverse metrics
Authors: Xiao Kunhong , Lu Wenrui , Zhang Xuemei , Lin Shenghua , Wei Jingting , Lin Xiangjie , Cai Qingyuan , Ye Yunxi , Yao Yuan , Lin Jiawen , Li Li
Published: October 2024

Purpose

To develop a predictive model for orthokeratology (Ortho-K) lens decentration 1 month after wear.

Methods

This study included myopic children who were fitted with Ortho-K lenses at Fujian Provincial Hospital between December 2022 and May 2024. Corneal topography parameters and other relevant metrics were collected pre- and post-treatment. Feature selection was conducted using univariate logistic regression and Lasso regression analysis. A machine learning approach was used to develop multiple predictive models, including Decision Tree, Logistic Regression, Multilayer Perceptron, Random Forest, and Support Vector Machine. Model performance was evaluated using accuracy, sensitivity, specificity, ROC curves, DCA curves, and calibration curves. SHAP values were employed to interpret the models.

Results

The Logistic Regression model demonstrated the best predictive performance, with an AUC of 0.82 (95% CI: 0.69–0.95), accuracy of 77.59%, sensitivity of 85%, and specificity of 61.11%. The most significant predictors identified were age, 8 mm sag height difference, 5 mm Kx1, and 7 mm Kx2. SHAP analysis confirmed the importance of these features, particularly the 8 mm sag height difference.

Conclusions

The Logistic Regression model successfully predicted the risk of Ortho-K lens decentration using key corneal morphological metrics and age. This model provides valuable support for clinicians in optimizing Ortho-K lens fitting strategies, potentially reducing the risk of adverse outcomes and improving the quality of vision for patients. Further validation in clinical settings is recommended.
Insights into the role of sterol metabolism in antifungal drug resistance: a mini-review
Authors: Tanwar Sunita , Kalra Sapna , Bari Vinay Kumar
Published: October 2024

Sterols are essential for eukaryotic cells and are crucial in cellular membranes’ structure, function, fluidity, permeability, adaptability to environmental stressors, and host-pathogen interactions. Fungal sterol, such as ergosterol metabolism, involves several organelles, including the mitochondria, lipid droplets, endoplasmic reticulum, and peroxisomes that can be regulated mainly by feedback mechanisms and transcriptionally. The majority of sterol transport in yeast occurs via non-vesicular transport pathways mediated by lipid transfer proteins, which determine the quantity of sterol present in the cell membrane. Pathogenic fungi Candida, Aspergillus, and Cryptococcus species can cause a range of superficial to potentially fatal systemic and invasive infections that are more common in immunocompromised patients. There is a significant risk of morbidity and mortality from these infections, which are very difficult to cure. Several antifungal drugs with different modes of action have received clinical approval to treat fungal infections. Antifungal drugs targeting the ergosterol biosynthesis pathway are well-known for their antifungal activity; however, an imbalance in the regulation and transport of ergosterol could lead to resistance to antifungal therapy. This study summarizes how fungal sterol metabolism and regulation can modulate sterol-targeting antifungal drug resistance.
The molecular insights of cyanobacterial bioremediations of heavy metals: the current and the future challenges
Authors: Lourembam Jinita , Haobam Banaraj , Singh Kshetrimayum Birla , Verma Savita , Rajan Jay Prakash
Published: October 2024

In recent years, overexplorations of ore and the growth of industries are the prime factors in the release of heavy metals in environments. As a result, the food crops and water bodies are contaminated with metals which may have several adverse effects on the health of humans and other living species. These metals and metalloids, such as Zn, Cu, Mn, Ni, Cr, Pb, Cd, and As, upset the biochemical pathways of metabolite synthesis in living organisms and contribute to the etiology of different diseases. Microorganisms include bacteria, archaea, viruses, and many unicellular eukaryotes, which can span three domains of life—Archaea, Bacteria, and Eukarya—and some microorganisms, such as cyanobacteria, have shown high efficiency in the biosorption rate of heavy metals. Cyanobacteria are suitable for bioremediation as they can grow in adverse environments, have a less negative impact on the surrounding environment, and are relatively cheaper to manage. The structure of cyanobacteria has shown no extensive internal-bound membranes, so it can directly employ the physiological mechanisms to uptake heavy metals from contamination sites. Such biochemical makeups are suitable for managing and bioremediating heavy metal concentrations in polluted environments. This review aims to explore the potential of cyanobacteria in the bioremediation of heavy metals and metalloids in water bodies. Additionally, we have identified the prospects for enhancing bioremediation effectiveness.
Fungal glyceraldehyde 3-phosphate dehydrogenase GpdC maintains glycolytic mechanism against reactive nitrogen stress-induced damage
Authors: Kadooka Chihiro , Katsuki Nozomi , Masuo Shunsuke , Kojima Saito , Amahisa Madoka , Suzuki Kouta , Doi Yuki , Takeshita Norio , Takaya Naoki
Published: October 2024

Highly reactive nitrogen species (RNS) damage proteins, lipids, and nucleotides, and induce disordered intracellular metabolism. Microorganisms that respond to and defend against RNS include fungal pathogens that invade host tissues. However, the full picture of their mechanisms remains unknown. We identified a novel glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme (GpdC) in the fungus Aspergillus nidulans. This isozyme preferred NADP+, which was unlike glycolytic GpdA that uses NAD+ as a cofactor. Exogenous RNS induced expression of the encoding gpdC gene, which when disrupted, decreased intracellular GAPDH activity, mycelial proliferation, and ethanol fermentation under RNS stress. Under these conditions, fungal growth requires glucose instead of non-fermentable carbon sources, and intact pyruvate decarboxylase (pdcA) and alcohol dehydrogenase (alcC) genes indicated that fungal metabolism shifts from respiratory to glycolytic and ethanolic fermentation. These results indicated that GpdC is an alternative GAPDH isozyme that facilitates NADP+-dependent glycolysis and energy conservation, which constitutes a fungal mechanism of stress tolerance via metabolic adaptation.
Diffusion and functional MRI reveal microstructural and network connectivity impairment in adult-onset neuronal intranuclear inclusion disease
Authors: Zhu Rui , Qu Junyu , Wu Yongsheng , Xu Guihua , Wang Dawei
Published: October 2024

Objectives

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable neuroimaging biomarkers. This study aimed to evaluate microstructural and functional connectivity alterations using diffusion kurtosis imaging (DKI) and resting-state fMRI (rs-fMRI), and to investigate their diagnostic potential as biomarkers.

Methods

Twenty-three patients with NIID and 40 matched healthy controls (HCs) were recruited. Firstly, gray matter (GM) and white matter (WM) changes were assessed by voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). Then we explored modifications in brain functional networks connectivity by independent component analysis. And the relationship between the altered DKI parameters and neuropsychological evaluation was analyzed. Finally, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of different gray matter and white matter parameters.

Results

Compared with the HCs, NIID patients showed reduced mean kurtosis (MK), radial kurtosis (RK), axial kurtosis (AK), and kurtosis fractional anisotropy (KFA) values in deep gray matter regions. Significantly decreased MK, RK, AK, KFA and fractional anisotropy (FA), and increased mean diffusivity (MD) values were observed in extensive white matter fiber tracts. Notable alterations in functional connectivity were also detected. Among all DKI parameters, the diagnostic efficiency of AK in GM and FA in WM regions was the highest.

Conclusion

Adult-onset NIID patients exhibited altered microstructure and functional network connectivity. Our findings suggest that DKI parameters may serve as potential imaging biomarkers for diagnosing adult-onset NIID.