bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring groundwater depletion and land subsidence dynamics in Taiwan’s Choushui river alluvial fan: insights from integrated GNSS and hydrogeological data analysis
Authors: Hung Wei-Chia , Hwang Cheinway , Lin Shao-Hung , Wang Chuan-Sheng , Chen Yi-An , Tsai Pei-Ching , Lin Kuan-Chung
Published: June 2024

The Choushui River Alluvial Fan (CRAF) is a major agricultural area in Taiwan with heavy groundwater usage. The extraction of groundwater here has caused land subsidence, which is now a significant global environmental issue. This study analyzes land subsidence in the CRAF by integrating hydrogeological data from 233 groundwater monitoring stations across four aquifers (CRAF Groundwater_NET) and data from 50 continuous GNSS stations (CRAF GNSS_NET). We developed an automated processing flow for GNSS static surveying within CRAF GNSS_NET, and further employed a time-series fitting method to examine the long-term trends and annual changes for both GNSS and groundwater level data. Our analysis of the time-series data from the past decade identifies areas of significant groundwater level depletion and subsidence hotspots. We explore the relationship between groundwater level variations and surface displacements within CRAF, utilizing GNSS data to analyze horizontal and vertical displacement trends, as well as annual changes. We integrate these findings with hydrogeological data to understand regional subsidence patterns. Our results indicate that CRAF is characterized by distinct hydrogeological features. The study finds that the amplitudes of annual changes in both groundwater level and vertical displacement generally increase from northeast to southwest in the analyzed region. One particular area shows significant groundwater level decline, with the most severe rate recorded at 0.54 m/year. Similarly, GNSS analysis indicates pronounced subsidence trends in the same area, with rates ranging from 4.2 to 5.2 cm/year. These findings highlight the critical need for the development of effective groundwater management strategies to ensure sustainable use of groundwater resources and to implement mitigation measures against land subsidence in similar multiple-aquifer settings.
Effects of inclination angle and confining pressure on triaxial unloading-induced slip behaviors of shale fractures
Authors: Liu Yi , Li Zihan , Zhao Shisen , Jiang Jian , Yuan Chao
Published: June 2024

To explore the effects of fracture inclination angle θ and confining pressure σ3t on the slip behaviors and friction properties of fractures, the triaxial unloading-induced slip experiments were performed on the shale fractures. The results show that the σ3t controls the slip modes of fractures, while the θ affects the occurrence of the stick-slip events during the quasi-static slip stage. With the increase in σ3t, the main slip modes of fracture transform from the stable-slip to stick-slip, and eventually to the creep-slip. The increase in θ facilitated the occurrence of stick-slip events. As the θ increased from 30° to 50°, the number of stick-slip events increased from 0 to 3 and from 2 to 4 for σ3t = 10 MPa and 20 MPa, respectively. For σ3t = 40 MPa, no stick-slip event occurred in the slipping process. The θ and σ3t have great effects on interaction modes between asperities, which directly affected the friction properties of fractures. With increasing σ3t, the void spaces between the asperities were further compacted, resulting in the transition of asperity interaction from overriding mode to shear-off mode. The transition of asperity interaction model therefore brought about the weakening of friction coefficient at the activation point and the onset of dynamic slip stage. There is a competitive relationship between the θ and σ3t for the evolution of the friction properties of fractures. As the θ increase from 30° to 50°, for σ3t = 10 MPa, the mean sheared-off thickness decreased from 0.502 mm to 0.433 mm, while for σ3t = 40 MPa, the mean sheared-off thickness decreased from 0.505 mm to 0.319 mm. With the increment of θ, the anisotropy of joint roughness coefficient was weakened. We suggested that by adjusting the fracturing angle of hydro-fracturing, the earthquakes with large seismic moments may be effectively mitigated.
Satisfaction of Saudi board internal medicine residents with the training program in central Saudi Arabia: a cross-sectional study
Authors: Alsheikh Nejood , Alenezi Shahad , Alshehri Rana , Alshughaithry Fahad , Alamri Orjowan , Khair Haneen , Masud Nazish , Alonazi Jamila
Published: June 2024

Background

The Saudi Internal Medicine (IM) residency program is a 4-year training program that qualifies competent physicians to provide optimal healthcare services. Residents’ satisfaction is a key indicator for a program effectiveness in preparing well-trained physicians. However, no national studies have investigated the perspective of IM residents. This study assessed IM resident’s satisfaction regarding the residency program in several training centers.

Methods

A cross-sectional study with 194 enrolled IM residents was conducted between November 2022 and June 2023 at multiple governmental hospitals in the central region of Saudi Arabia. Data collection was done via an electronic questionnaire. The satisfaction rate was interpreted by a five-point Likert scale (1 “completely unsatisfied” to 5 “extremely satisfied”).

Results

Out of the 184 responses, residents aged 25–27 years comprised 122 (66%) of the sample with male participants being the highest in number at 109 (59%) which was highly significant in accordance to the level of satisfaction (χ2 = 10.07, p = 0.006). Additionally, 89 (54%) junior residents was found to have a significant satisfaction compared to senior residents. In total, 112 (61%) of residents would choose the same IM residency program again if they had the chance and expressed a better level of satisfaction (χ2 = 101, 28, p < 0.001). Overall, the percentage of satisfied residents was around half of the sample 100 (54%). However, workload, quality of life, and teaching opportunities were among the most frequently chosen areas for improvement.

Conclusion

The study concluded that 54% of IM residents were highly satisfied with the program in their respective training center. However, residents have excessive workload, reduced quality of life, and differing unmet learning needs.
Association between weight-adjusted waist index and kidney stones: a propensity score matching study
Authors: Chen Di , Xie Yurun , Luo Quanhai , Fan Wenji , Liu Gang
Published: June 2024

Objective

This study aimed to investigate the association between weight-adjusted waist index (WWI), a novel adiposity index, and kidney stone (KS).

Methods

Data were obtained from the National Health and Nutrition Examination Survey 2007–2018. According to the history of KS, participants were divided into the non-stone group and the stone group. Weighted multivariable logistic regression analyses were used to evaluate the correlation between WWI and KS in unadjusted, partially adjusted, and all-adjusted models. A restricted cubic spline (RCS) analysis assessed the association between continuous WWI and KS risk and obtained the risk function inflection point. Then, subgroup analysis based on the risk function inflection point was conducted to dissect the association in specific subgroups. In addition, the above analyst methods were repeatedly performed in populations after propensity score matching (PSM). The receiver operating characteristic (ROC) curve was applied to compare the ability to predict KS occurrence among WWI, visceral adiposity index (VAI), and body mass index (BMI).

Results

Weighted multivariable logistic regression analyses found a positive association between continuous WWI and KS risk in the all-adjusted model [odds ratio (OR) = 1.03; 95% confidence interval (CI), 1.02–1.04; P < 0.001]. In further analysis, the Q4 WWI group was linked to the highest KS risk when compared to the Q1–Q3 group (OR = 1.06; 95% CI, 1.05–1.08, P < 0.001). RCS analysis found a linear significant correlation between continuous WWI and KS risk, and the risk function inflection point is 11.08 cm/√kg. Subgroup analysis confirmed that WWI was associated with KS risk in different groups. After PSM, increased WWI was still related to a high risk of KS. Moreover, the ROC curve demonstrated that WWI has a higher predictive ability of KS occurrence than VAI and BMI (area under curve, 0.612 vs. 0.581 vs. 0.569).

Conclusion

In the US adult population, elevated WWI value was associated with an increased risk of KS. Furthermore, WWI was a better predictor of KS occurrence than VAI and BMI.
The role of magnesium in the pathogenesis of osteoporosis
Authors: Liu Lin , Luo Pan , Wen Pengfei , Xu Peng
Published: June 2024

Magnesium (Mg), a nutritional element which is essential for bone development and mineralization, has a role in the progression of osteoporosis. Osteoporosis is a multifactorial disease characterized by significant deterioration of bone microstructure and bone loss. Mg deficiency can affect bone structure in an indirect way through the two main regulators of calcium homeostasis (parathyroid hormone and vitamin D). In human osteoblasts (OBs), parathyroid hormone regulates the expression of receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) to affect osteoclast (OC) formation. In addition, Mg may also affect the vitamin D3 -mediated bone remodeling activity. vitamin D3 usually coordinates the activation of the OB and OC. The unbalanced activation OC leads to bone resorption. The RANK/RANKL/OPG axis is considered to be a key factor in the molecular mechanism of osteoporosis. Mg participates in the pathogenesis of osteoporosis by affecting the regulation of parathyroid hormone and vitamin D levels to affect the RANK/RANKL/OPG axis. Different factors affecting the axis and enhancing OC function led to bone loss and bone tissue microstructure damage, which leads to the occurrence of osteoporosis. Clinical research has shown that Mg supplementation can alleviate the symptoms of osteoporosis to some extent.
Advances in research on spexin-mediated regulation of reproductive function in vertebrates
Authors: Chen Xiaojing , Feng Yuyan , Dai Shudi , Guo Binbin , Yan Leyan , Liu Jie , Zhu Huanxi
Published: June 2024

Spexin (SPX, NPQ) is a 14-amino acid neuroactive peptide identified using bioinformatics. This amino acid sequence of the mature spexin peptide has been highly conserved during species evolution and is widely distributed in the central nervous system and peripheral tissues and organs. Therefore, spexin may play a role in various biological functions. Spexin, the cognate ligand for GALR2/3, acting as a neuromodulator or endocrine signaling factor, can inhibit reproductive performance. However, controversies and gaps in knowledge persist regarding spexin-mediated regulation of animal reproductive functions. This review focuses on the hypothalamic-pituitary-gonadal axis and provides a comprehensive overview of the impact of spexin on reproduction. Through this review, we aim to enhance understanding and obtain in-depth insights into the regulation of reproduction by spexin peptides, thereby providing a scientific basis for future investigations into the molecular mechanisms underlying the influence of spexin on reproductive function. Such investigations hold potential benefits for optimizing farming practices in livestock, poultry, and fish industries.
Techno-economic analysis of AMP/PZ solvent for CO2 capture in a biomass CHP plant: towards net negative emissions
Authors: Salman Muhammad , Beguin Brieuc , Nyssen Thomas , Léonard Grégoire
Published: June 2024

Compared to conventional monoethanolamine (MEA), alternative solvents are expected to substantially contribute to reduce the energy demand of post-combustion CO2 capture from flue gases. This study presents a comprehensive techno-economic analysis of a 27 wt% 2-amino-2-methyl-1-propanol (AMP) + 13 wt% piperazine (PZ) aqueous solution for CO2 capture, compared to a 30 wt% MEA solution. The study addresses the retrofit of a carbon capture unit to a biomass-fired combined heat and power (CHP) plant, effectively making it a bioenergy with a carbon capture and storage (BECCS) system. The treated flue gas has a flow rate of 23 tons/hour (t/h) with 11.54 vol% CO2 and a 90% capture rate is aimed for. Aspen Plus V14 was employed for process simulations. Initially, binary interaction parameters for AMP/PZ, AMP/H2O, and PZ/H2O are regressed using vapor-liquid equilibrium (VLE) data, which were retrieved from literature along with reaction kinetics. Validation of parameters from available experimental literature yields an average absolute relative deviation (AARD) of only 5.9%. Afterwards, a process simulation model is developed and validated against experimental data from a reference pilot plant, using a similar AMP/PZ blend, resulting in 5% AARD. Next, a sensitivity analysis optimizes operating conditions, including solvent rate, absorber/stripper packing heights, and stripper pressure, based on regeneration energy impact. Optimized results, compared to MEA, reveal that AMP/PZ reduces the energy consumption from 3.61 to 2.86 GJ/tCO2. The retrofitting of the capture unit onto the selected CHP plant is examined through the development of a dedicated model. Two control strategies are compared to address energy unavailability for supplying the capture unit. The analysis spans 4 months, selected to account for seasonal variations. At nominal capacity, CO2 emissions, rendered negative by biomass combustion and CO2 capture, reach a maximum of −3.4 tCO2/h compared to 0.36 tCO2/h before retrofitting. Depending on the control strategy and CHP plant operating point, the Specific Primary Energy Consumption for CO2 Avoided (SPECCA) ranges from 4.91 MJ/kgCO2 to 1.76 MJ/kgCO2. Finally, an economic comparison based on systematic methodology reveals a 7.87% reduction in capture cost favoring the AMP/PZ blend. Together, these findings highlight AMP/PZ as a highly favorable alternative solvent.
Simulating the effect of haze management using system dynamics: a case study of Beijing
Authors: Lv Furong , Lu Yunjing , Tang Haiping
Published: June 2024

Haze is a pollution phenomenon that has become increasingly frequent in recent years, primarily composed of SO2, NOx, and particulate matter. Since the “PM2.5 Crisis” in 2013, the Beijing-Tianjin-Hebei region has been plagued by haze. After a series of high-intensity management activities, the air quality in Beijing has continued to improve. To investigate the effectiveness of the haze control measures in Beijing, a dynamic management model was constructed using the system dynamics approach and implemented using Stella software. The model is simulated and evaluated the contribution to different governance strategies (increasing investment in science and technology innovation, reducing motor vehicle ownership, reducing coal consumption, and a combination policy) to reduce haze in Beijing from 2010 to 2025. The validity and robustness of the model were verified through model testing and validation. The simulation results showed that: (1) the combination policy has the most significant effect on reducing energy consumption and pollution emissions, which would reduce energy consumption by 38.93 million tons and pollution emissions by 128.33 thousand tons in 2025, (2) among the single treatment measures, reducing industrial coal consumption is the most effective measure to reducing haze, (3) it is necessary to strengthen the joint prevention and control of the Beijing-Tianjin-Hebei region in the future to promote the sustainable development of the regional environment.
A gene edited pig model for studying LGR5+ stem cells: implications for future applications in tissue regeneration and biomedical research
Authors: Hill Amanda B. T. , Murphy Yanet M. , Polkoff Kathryn M. , Edwards Laura , Walker Derek M. , Moatti Adele , Greenbaum Alon , Piedrahita Jorge A.
Published: June 2024

Recent advancements in genome editing techniques, notably CRISPR-Cas9 and TALENs, have marked a transformative era in biomedical research, significantly enhancing our understanding of disease mechanisms and helping develop novel therapies. These technologies have been instrumental in creating precise animal models for use in stem cell research and regenerative medicine. For instance, we have developed a transgenic pig model to enable the investigation of LGR5-expressing cells. The model was designed to induce the expression of H2B-GFP under the regulatory control of the LGR5 promoter via CRISPR/Cas9-mediated gene knock-in. Notably, advancements in stem cell research have identified distinct subpopulations of LGR5-expressing cells within adult human, mouse, and pig tissues. LGR5, a leucine-rich repeat-containing G protein-coupled receptor, enhances WNT signaling and these LGR5+ subpopulations demonstrate varied roles and anatomical distributions, underscoring the necessity for suitable translational models. This transgenic pig model facilitates the tracking of LGR5-expressing cells and has provided valuable insights into the roles of these cells across different tissues and species. For instance, in pulmonary tissue, Lgr5+ cells in mice are predominantly located in alveolar compartments, driving alveolar differentiation of epithelial progenitors via Wnt pathway activation. In contrast, in pigs and humans, these cells are situated in a unique sub-basal position adjacent to the airway epithelium. In fetal stages a pattern of LGR5 expression during lung bud tip formation is evident in humans and pigs but is lacking in mice. Species differences with respect to LGR5 expression have also been observed in the skin, intestines, and cochlea further reinforcing the need for careful selection of appropriate translational animal models. This paper discusses the potential utility of the LGR5+ pig model in exploring the role of LGR5+ cells in tissue development and regeneration with the goal of translating these findings into human and animal clinical applications.
Elucidating causal relationships of diet-derived circulating antioxidants and the risk of osteoporosis: A Mendelian randomization study
Authors: Yuan Kexin , Xie Xingwen , Huang Weiwei , Li Dingpeng , Zhao Yongli , Yang Haodong , Wang Xuetao
Published: June 2024

Background

Osteoporosis (OP) is typically diagnosed by evaluating bone mineral density (BMD), and it frequently results in fractures. Here, we investigated the causal relationships between diet-derived circulating antioxidants and the risk of OP using Mendelian randomization (MR).

Methods

Published studies were used to identify instrumental variables related to absolute levels of circulating antioxidants like lycopene, retinol, ascorbate, and β-carotene, as well as antioxidant metabolites such as ascorbate, retinol, α-tocopherol, and γ-tocopherol. Outcome variables included BMD (in femoral neck, lumbar spine, forearm, heel, total body, total body (age over 60), total body (age 45–60), total body (age 30–45), total body (age 15–30), and total body (age 0–15)), fractures (in arm, spine, leg, heel, and osteoporotic fractures), and OP. Inverse variance weighted or Wald ratio was chosen as the main method for MR analysis based on the number of single nucleotide polymorphisms (SNPs). Furthermore, we performed sensitivity analyses to confirm the reliability of the findings.

Results

We found a causal relationship between absolute retinol levels and heel BMD (p = 7.6E-05). The results of fixed effects IVW showed a protective effect of absolute retinol levels against heel BMD, with per 0.1 ln-transformed retinol being associated with a 28% increase in heel BMD (OR: 1.28, 95% CI: 1.13–1.44). In addition, a sex-specific effect of the absolute circulating retinol levels on the heel BMD has been observed in men. No other significant causal relationship was found.

Conclusion

There is a positive causal relationship between absolute retinol levels and heel BMD. The implications of our results should be taken into account in future studies and in the creation of public health policies and OP prevention tactics.
A causal association between lipid-lowering medications and rotator cuff syndrome: a drug-targeted mendelian randomization study
Authors: Liu Meng-meng , Chen Xiang , Yu Chuan-wen , Chen Jin-wei , Zhen Pu-xiang , Liu Zhi-peng
Published: June 2024

Background: Previous research has suggested that dyslipidemia may be a risk factor for rotator cuff syndrome (RCS), and lipid-lowering drugs may aid in its treatment, though conclusions have not been definitive. Mendelian randomization is a statistical method that explores the causal relationships between exposure factors and diseases. It overcomes the confounding issues inherent in traditional observational studies, thereby providing more reliable causal inferences. We employed this method to investigate whether hyperlipidemia is a risk factor for rotator cuff syndrome and whether lipid-lowering drugs can effectively treat this condition.

Methods: Genetic variations linked to lipid traits low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) were acquired from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in rotator cuff syndrome were obtained from FinnGen, including 24,061 patients and 275,212 controls. In the next step, we carried out two-sample Mendelian randomization analyses to determine whether lipid traits correlate with rotator cuff syndrome risk. Additionally, we performed drug-target Mendelian randomization (MR) analyses on 10 drug targets related to rotator cuff syndrome. For the drug targets that showed significant results, further analysis was done using Summary-data-based Mendelian Randomization (SMR) and colocalization techniques. We performed a mediation analysis to identify potential mediators between HMG-CoA reductase (HMGCR) and RCS.

Results: No causative link was established between these lipid traits and rotator cuff syndrome. However, a significant association has been identified where HMGCR inhibition corresponds to a reduced risk of rotator cuff disease (OR = 0.68, [95% CI, 0.56–0.83], p = 1.510 × 10−4). Additionally, enhanced expression of HMGCR in muscle tissues is also linked to a decreased risk of rotator cuff syndrome (OR = 0.88, [95% CI, 0.76–0.99], p = 0.03). Body mass index (BMI) mediated 22.97% of the total effect of HMGCR on RCS.

Conclusion: This study does not support low-density LDL-C, TG, and TC as risk factors for rotator cuff syndrome. HMGCR represents a potential pharmaceutical target for preventing and treating rotator cuff syndrome. The protective action of statins on the rotator cuff syndrome might not be associated with their lipid-lowering properties.
Identification of oxidative phosphorylation-related genes in moyamoya disease by combining bulk RNA-sequencing analysis and machine learning
Authors: Han Zhiguang , Zhang Junze , Su Yutao , Zhou Zhenyu , Wang Yanru , Xu Shaoqi , Zhao Yuanli , He Shihao , Wang Rong
Published: June 2024

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular disease that can lead to ischemia and hemorrhagic stroke. The relationship between oxidative phosphorylation (OXPHOS) and MMD pathogenesis remains unknown.

Methods: The gene expression data of 60 participants were acquired from three Gene Expression Omnibus (GEO) datasets, including 36 and 24 in the MMD and control groups. Differentially expressed genes (DEGs) between MMD patients MMD and control groups were identified. Machine learning was used to select the key OXPHOS-related genes associated with MMD from the intersection of DEGs and OXPHOS-related gene sets. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), gene set enrichment analysis (GSEA), Immune infiltration and microenvironments analysis were used to analyze the function of key genes. Machine learning selected four key OXPHOS-related genes associated with MMD: CSK, NARS2, PTPN6 and SMAD2 (PTPN6 was upregulated and the other three were downregulated).

Results: Functional enrichment analysis showed that these genes were mainly enriched in the Notch signaling pathway, GAP junction, and RNA degradation, which are related to several biological processes, including angiogenesis, proliferation of vascular smooth muscle and endothelial cells, and cytoskeleton regulation. Immune analysis revealed immune infiltration and microenvironment in these MMD samples and their relationships with four key OXPHOS-related genes. APC co-inhibition (p = 0.032), HLA (p = 0.001), MHC I (p = 0.013), T cellco- inhibition (p = 0.032) and Type I IFN responses (p < 0.001) were significantly higher in the MMD groups than those in the control groups. The CSK positively correlated with APC co-inhibition and T cell-co-inhibition. The NARS2 negatively correlated with Type I IFN response. The SMAD2 negatively correlated with APC co-inhibition and Type I IFN response. The PTPN6 positively correlated with HLA, MHC I and Type I IFN responses.

Discussion: This study provides a comprehensive understanding of the role of OXPHOS in MMD and will contribute to the development of new treatment methods and exploration of MMD pathogenesis.
Determinants of home delivery among reproductive age women in Bore District, East Guji Zone, Ethiopia: a case–control study
Authors: Teressa Beka , Legesse Elsabeth , Nigussie Tadesse , Deriba Berhanu Senbeta , Guye Ararso Hordofa , Girma Derara , Dejene Hiwot , Adugna Leta , Birhanu Belete , Eshetu Hana , Tadele Amanu’el , Mideksa Gachena
Published: June 2024

Introduction

Home delivery, which is the process of childbirth at one's residence rather than in a health facility, is a major reason for maternal mortality caused by obstetric complications, such as sepsis, hypertensive disorders, and hemorrhage. Maternal and child mortality remains high in developing countries despite efforts made to reduce these outcomes. This is mainly due to poor utilization of institution-based healthcare services. Moreover, there is a limited number of studies that have addressed the determinants of home delivery in Ethiopia, including the study area. This study aims to identify the determinants of home delivery in Bore District, East Guji Zone, Southern Ethiopia, in 2022.

Methods

A community-based unmatched case–control study was conducted from 18 May to 5 July 2022 among 498 women (249 cases and 249 controls) who gave birth in Bore District. The case group included women who gave birth at home, while the control group included those who gave their last birth at health institutions. A multistage sampling technique was employed to select the study participants. Data were collected using the KoboToolbox digital software and exported to SPSS Version 26.0 for analysis. A multivariable logistic regression analysis was done to declare the statistical significance of the association of the the independent variables and home delivery.

Results

The study included a total of 496 respondents with a mean age of 32.5 (SD = ±5.5) for the case group and 33.7 (SD = ±5.2) for the control group. Among the assessed determinants of home delivery were not attending antenatal care (ANC) visits [adjusted odds ratio (AOR) =  5.6, 95% CI: 2.0–15.16], missing pregnant women's conferences (AOR = 3.2, 95% CI: 1.65–8.32), not receiving health education on pregnancy-related complications (AOR = 2.2, 95% CI: 1.1–4.3), inadequate knowledge of pregnancy-related danger signs (AOR = 6.0, CI: 3.0–11.9), inadequate knowledge about pregnancy-related complications (AOR = 3.0, CI: 1.55–6.13), and unfavorable attitude (AOR = 6.9, 95% CI: 2.16–22.6).

Conclusion

In this study, not attending ANC visits, missing pregnant women's conferences, not receiving health education on pregnancy-related complications, inadequate knowledge of pregnancy-related danger signs, inadequate knowledge about pregnancy-related complications, and unfavorable attitudes were identified as determinants of home delivery. The district health office and other stakeholders should work on strengthening maternal health service delivery through appropriate ANC visits and participation in pregnant women's conferences and improving community awareness about pregnancy at all levels.
SWIFT clustering analysis of intracellular cytokine staining flow cytometry data of the HVTN 105 vaccine trial reveals high frequencies of HIV-specific CD4+ T cell responses and associations with humoral responses
Authors: Mosmann Tim R. , Rebhahn Jonathan A. , De Rosa Stephen C. , Keefer Michael C. , McElrath M. Juliana , Rouphael Nadine G. , Pantaleo Giuseppe , Gilbert Peter B. , Corey Lawrence , Kobie James J. , Thakar Juilee
Published: June 2024

Introduction

The HVTN 105 vaccine clinical trial tested four combinations of two immunogens - the DNA vaccine DNA-HIV-PT123, and the protein vaccine AIDSVAX B/E. All combinations induced substantial antibody and CD4+ T cell responses in many participants. We have now re-examined the intracellular cytokine staining flow cytometry data using the high-resolution SWIFT clustering algorithm, which is very effective for enumerating rare populations such as antigen-responsive T cells, and also determined correlations between the antibody and T cell responses.

Methods

Flow cytometry samples across all the analysis batches were registered using the swiftReg registration tool, which reduces batch variation without compromising biological variation. Registered data were clustered using the SWIFT algorithm, and cluster template competition was used to identify clusters of antigen-responsive T cells and to separate these from constitutive cytokine producing cell clusters.

Results

Registration strongly reduced batch variation among batches analyzed across several months. This in-depth clustering analysis identified a greater proportion of responders than the original analysis. A subset of antigen-responsive clusters producing IL-21 was identified. The cytokine patterns in each vaccine group were related to the type of vaccine – protein antigens tended to induce more cells producing IL-2 but not IFN-γ, whereas DNA vaccines tended to induce more IL-2+ IFN-γ+ CD4 T cells. Several significant correlations were identified between specific antibody responses and antigen-responsive T cell clusters. The best correlations were not necessarily observed with the strongest antibody or T cell responses.

Conclusion

In the complex HVTN105 dataset, alternative analysis methods increased sensitivity of the detection of antigen-specific T cells; increased the number of identified vaccine responders; identified a small IL-21-producing T cell population; and demonstrated significant correlations between specific T cell populations and serum antibody responses. Multiple analysis strategies may be valuable for extracting the most information from large, complex studies.
The cytoskeletal protein profilin is an important allergen in saltwort (Salsola kali)
Authors: Peterkova Ludmila , Trifonova Daria , Gattinger Pia , Focke-Tejkl Margarete , Garib Victoria , Magbulova Nigora , Djambekova Gulnara , Zakhidova Nodira , Ismatova Mokhigul , Sekerel Bulent Enis , Tuten Dal Sevda , Tulaev Mikhail , Kundi Michael , Keller Walter , Karaulov Alexander , Valenta Rudolf
Published: June 2024

Pollen from Salsola kali, i.e., saltwort, Russian thistle, is a major allergen source in the coastal regions of southern Europe, in Turkey, Central Asia, and Iran. S. kali-allergic patients mainly suffer from hay-fever (i.e., rhinitis and conjunctivitis), asthma, and allergic skin symptoms. The aim of this study was to investigate the importance of individual S. kali allergen molecules. Sal k 1, Sal k 2, Sal k 3, Sal k 4, Sal k 5, and Sal k 6 were expressed in Escherichia coli as recombinant proteins containing a C-terminal hexahistidine tag and purified by nickel affinity chromatography. The purity of the recombinant allergens was analyzed by SDS-PAGE. Their molecular weight was determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and their fold and secondary structure were studied by circular dichroism (CD) spectroscopy. Sera from clinically well-characterized S. kali-allergic patients were used for IgE reactivity and basophil activation experiments. S. kali allergen-specific IgE levels and IgE levels specific for the highly IgE cross-reactive profilin and the calcium-binding allergen from timothy grass pollen, Phl p 12 and Phl p 7, respectively, were measured by ImmunoCAP. The allergenic activity of natural S. kali pollen allergens was studied in basophil activation experiments. Recombinant S. kali allergens were folded when studied by CD analysis. The sum of recombinant allergen-specific IgE levels and allergen-extract-specific IgE levels was highly correlated. Sal k 1 and profilin, reactive with IgE from 64% and 49% of patients, respectively, were the most important allergens, whereas the other S. kali allergens were less frequently recognized. Specific IgE levels were highest for profilin. Of note, 37% of patients who were negative for Sal k 1 showed IgE reactivity to Phl p 12, emphasizing the importance of the ubiquitous cytoskeletal actin-binding protein, profilin, for the diagnosis of IgE sensitization in S. kali-allergic patients. rPhl p 12 and rSal k 4 showed equivalent IgE reactivity, and the clinical importance of profilin was underlined by the fact that profilin-monosensitized patients suffered from symptoms of respiratory allergy to saltwort. Accordingly, profilin should be included in the panel of allergen molecules for diagnosis and in molecular allergy vaccines for the treatment and prevention of S. kali allergy.
Exploring the protective association between COVID-19 infection and laryngeal cancer: insights from a Mendelian randomization study
Authors: Wang Heng , Fang Ning , Mozumder Prithweeraj , Jiang Richeng , Wang Xin
Published: June 2024

Introduction

Viral infections have been implicated as a risk factor for laryngeal cancer. Given the possible effects of Corona virus disease 2019 (COVID-19) on the laryngeal tissue, we investigated the causal link between COVID-19 and laryngeal cancer using a two-sample Mendelian randomization (MR) approach.

Methods

We utilized genetic data from the 5th Genome-wide association studies (GWAS) edition of the COVID-19 Host Genetics Initiative (published on January 18, 2021) and a large-scale laryngeal cancer GWAS comprising 180 cases and 218,612 controls of European ancestry. We applied inverse variance weighting, MR Egger, and weighted median methods to infer causality. We performed sensitivity analysis using the “leave-one-out” method to verify robustness.

Results

We found no evidence of a causal association between gene-predicted COVID-19 and laryngeal cancer [Odds ratio (OR)=0.24 (95% Confidence intervals (CI), 0.05–1.26), P=0.09]. However, we observed significant inverse associations between gene-predicted COVID-19 hospitalization [OR=0.51 (95% CI, 0.28–0.95), P=0.03] and severe patients [OR=0.62 (95% CI, 0.43–0.90), P=0.01] and laryngeal cancer. Notably, the study detected important genetic variants, such as rs13050728, that modulate the expression of interferon alpha receptor 2 (IFNAR2), indicating possible roles for immune response pathways in both COVID-19 and cancer.

Discussion

This study reveals a potential interaction between COVID-19 severity, genetic factors, and laryngeal cancer, underscoring the importance of investigating the immune response mechanisms in both conditions. These findings contribute to the understanding of the complex interactions between COVID-19 and laryngeal cancer and may guide future research on the role of immune response, particularly involving IFNAR2.
Innate and germline immune memory: specificity and heritability of the ancient immune mechanisms for adaptation and survival
Authors: Boraschi Diana , Toepfer Elfi , Italiani Paola
Published: June 2024

The immune memory is one of the defensive strategies developed by both unicellular and multicellular organisms for ensuring their integrity and functionality. While the immune memory of the vertebrate adaptive immune system (based on somatic recombination) is antigen-specific, encompassing the generation of memory T and B cells that only recognize/react to a specific antigen epitope, the capacity of vertebrate innate cells to remember past events is a mostly non-specific mechanism of adaptation. This “innate memory” can be considered as germline-encoded because its effector tools (such as innate receptors) do not need somatic recombination for being active. Also, in several organisms the memory-related information is integrated in the genome of germline cells and can be transmitted to the progeny for several generations, but it can also be erased depending on the environmental conditions. Overall, depending on the organism, its environment and its living habits, innate immune memory appears to be a mechanism for achieving better protection and survival against repeated exposure to microbes/stressful agents present in the same environment or occurring in the same anatomical district, able to adapt to changes in the environmental cues. The anatomical and functional complexity of the organism and its lifespan drive the generation of different immune memory mechanisms, for optimal adaptation to changes in the living/environmental conditions. The concept of innate immunity being non-specific needs to be revisited, as a wealth of evidence suggests a significant degree of specificity both in the primary immune reaction and in the ensuing memory-like responses. This is clearly evident in invertebrate metazoans, in which distinct scenarios can be observed, with both non-specific (immune enhancement) or specific (immune priming) memory-like responses. In the case of mammals, there is evidence that some degree of specificity can be attained in different situations, for instance as organ-specific protection rather than microorganism-specific reaction. Thus, depending on the challenges and conditions, innate memory can be non-specific or specific, can be integrated in the germline and transmitted to the progeny or be short-lived, thereby representing an exceptionally plastic mechanism of defensive adaptation for ensuring individual and species survival.
Toll-like receptor signaling in multiple myeloma cells promotes the expression of pro-survival genes B-cell lymphoma 2 and MYC and modulates the expression of B-cell maturation antigen
Authors: Tryggestad Synne Stokke , Roseth Ingrid Aass , Aass Kristin Roseth , Ørning Nadia Elise Helene , Mjelle Robin , Hella Hanne , Standal Therese
Published: June 2024

Infections are common in plasma cell cancer multiple myeloma (MM) due to disease-related immune deficiencies and cancer treatment. Myeloma cells express Toll-like receptors (TLRs), and TLR activation has been shown to induce proliferative and pro-survival signals in cancer cells. MM is a complex and heterogeneous disease, and expression levels of TLRs as well as downstream signaling components are likely to differ between patients. Here, we show that in a large cohort of patients, TLR1, TLR4, TLR6, TLR9, and TLR10 are the most highly expressed in primary CD138+ cells. Using an MM cell line expressing TLR4 and TLR9 as a model, we demonstrate that TLR4 and TLR9 activation promoted the expression of well-established pro-survival and oncogenes in MM such as MYC, IRF4, NFKB, and BCL2. TLR4 and TLR9 activation inhibited the efficacy of proteasome inhibitors bortezomib and carfilzomib, drugs used in the treatment of MM. Inhibiting the autophagosome–lysosome protein degradation pathway by hydroxychloroquine (HCQ) diminished the protective effect of TLR activation on proteasome inhibitor-induced cytotoxicity. We also found that TLR signaling downregulated the expression of TNFRSF17, the gene encoding for B-cell maturation antigen (BCMA). MYC, BCL2, and BCL2L1 were upregulated in approximately 50% of primary cells, while the response to TLR signaling in terms of TNFRSF17 expression was dichotomous, as an equal fraction of patients showed upregulation and downregulation of the gene. While proteasome inhibitors are part of first-line MM treatment, several of the new anti-MM immune therapeutic drugs target BCMA. Thus, TLR activation may render MM cells less responsive to commonly used anti-myeloma drugs.
Case report: Rapid clinical improvement in acute exacerbation of MuSK-MG with efgartigimod
Authors: Zhu Geke , Ma Yongbo , Zhou Han , Nie Xiangtao , Qi Wenjing , Hao Lei , Guo Xiuming
Published: June 2024

Myasthenia gravis with positive MuSK antibody often involves the bulbar muscles and is usually refractory to acetylcholinesterase inhibitors. For MuSK-MG patients who experience acute exacerbations and do not respond to conventional treatments, there is an urgent need to find more suitable treatment options. With the advent of biologic agents, efgartigimod has shown promising results in the treatment of MG. We report a 65-year-old MuSK-MG patient who presented with impaired eye movements initially, and the symptoms rapidly worsened within a week, affecting the limbs and neck muscles, and had difficulties in chewing and swallowing. Lymphoplasmapheresis did not achieve satisfactory results, but after a cycle of efgartigimod treatment, the patient’s symptoms gradually improved and remained in a good clinical state for several months.
Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis
Authors: Cavalcante Paola , Mantegazza Renato , Antozzi Carlo
Published: June 2024

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms’ distribution, disease severity, age at onset, thymic histopathology and response to therapies. Current treatment of MG based on international consensus guidelines allows to effectively control symptoms, but most patients do not reach complete stable remission and require life-long immunosuppressive (IS) therapies. Moreover, a proportion of them is refractory to conventional IS treatment, highlighting the need for more specific and tailored strategies. Precision medicine is a new frontier of medicine that promises to greatly increase therapeutic success in several diseases, including autoimmune conditions. In MG, B cell activation, antibody recycling and NMJ damage by the complement system are crucial mechanisms, and their targeting by innovative biological drugs has been proven to be effective and safe in clinical trials. The switch from conventional IS to novel precision medicine approaches based on these drugs could prospectively and significantly improve MG care. In this review, we provide an overview of key immunopathogenetic processes underlying MG, and discuss on emerging biological drugs targeting them. We also discuss on future direction of research to address the need for patients’ stratification in endotypes according with genetic and molecular biomarkers for successful clinical decision making within precision medicine workflow.
Case report: Bilateral facial palsy with paresthesias and positive anti-GT1a antibodies
Authors: Xu Xiaoxuan , Wang Zhihan , Su Chang , Cong Lin , Zheng Dongming
Published: June 2024

Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.
Pathogenic roles of follicular helper T cells in IgG4-related disease and implications for potential therapy
Authors: Xu Jingyi , Zhai Jiayu , Zhao Jinxia
Published: June 2024

IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.
Revisiting the interaction between complement lectin pathway protease MASP-2 and SARS-CoV-2 nucleoprotein
Authors: Bally Isabelle , Drumont Guillaume , Rossi Véronique , Guseva Serafima , Botova Maiia , Reiser Jean-Baptiste , Thépaut Michel , Dergan Dylon Sebastian , Dumestre-Pérard Chantal , Gaboriaud Christine , Fieschi Franck , Blackledge Martin , Poignard Pascal , Thielens Nicole M.
Published: June 2024

Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a strong inflammatory response. Involvement of the lectin complement pathway, a major actor of the innate immune anti-viral defense, has been reported previously. It is initiated by recognition of the viral surface Spike glycoprotein by mannose-binding lectin (MBL), which induces activation of the MBL-associated protease MASP-2 and triggers the proteolytic complement cascade. A role for the viral nucleoprotein (N) has also been reported, through binding to MASP-2, leading to protease overactivation and potentiation of the lectin pathway. In the present study, we reinvestigated the interactions of the SARS-CoV-2 N protein, produced either in bacteria or secreted by mammalian cells, with full-length MASP-2 or its catalytic domain, in either active or proenzyme form. We could not confirm the interaction of the N protein with the catalytic domain of MASP-2 but observed N protein binding to proenzyme MASP-2. We did not find a role of the N protein in MBL-mediated activation of the lectin pathway. Finally, we showed that incubation of the N protein with MASP-2 results in proteolysis of the viral protein, an observation that requires further investigation to understand a potential functional significance in infected patients.