bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Learning Resulting from Students’ Experiences in Shaping Their Identity and Perception of the Significance of Smart Tourism Destination
Authors: CHIREAC Silvia-Maria , GARCÍA PERIS Vicent
Published: March 2024

This research presents an analysis of the participation and interaction of 129 students from the Faculty of Teacher Training Education (University of Valencia) with tourist places cultural heritage from the Valencia city. The analysis of our students’ affective evaluation and interpretation of a touristic place through smart tourism was a major factor that impacted their perception of the cultural heritage significance of a certain place. Therefore, our findings suggest that there is a strong correlation between students’ cultural experiences, awareness and perception of a touristic place and their interpretation of the economic, social and cultural significance of the touristic places. Tourism experiences of our students contributed to transformative learning acquired by immersion in a new knowledge as a result of travelling and living in one of the most visited regions in Spain.
Pengaruh Profitabilitas, Leverage, Ukuran Perusahaan, dan Intensitas Aset Tetap terhadap Penghindaran Pajak (Studi Empiris pada Perusahaan Subsektor Makanan dan Minuman Yang Terdaftar Di Bursa Efek Indonesia)
Authors: Irsyad Alfin , Endah Suwarni  , Basuki Rachmat
Published: March 2024

The purpose of this study is to investigate the influence of Profitability, Leverage, Company Size and Intensity of  Fixed Assets on the Tax Avoidance of subsector food and beverage companies. The research used Purposive Sampling as the data collection technique. From the 30 companies, there were only 14 companies which met the criteria. The data analysis method used a multipe linear regressions. The used 26th version of  IBM SPSS Statistics as a data analysis tool. The result of the research showed that there was a postive and significant influence of Company Size on the Tax Avoidance. Meanwhile, Profitability, Leverage, and Intensity of Fixed Assets partially have not significant effect on the Tax Avoidance. The result of simultaneous test showed that there was a not significant influence of Profitability, Leverage, and Intensity of Fixed Assets  on the Tax Avoidance.
Written Corrective Feedback and EFL Students’ Use of Prepositions, Articles, Punctuation and Capitalization
Authors: Al Harthy Said Rashid , Darwish Abdullah , Yacoub Mohamed , Alnwairan Met'eb
Published: March 2024

This study investigates the effect of direct and indirect written corrective feedback (WCF) on EFL students’ use of prepositions, articles, punctuation, and capitalization. The importance of focusing on WCF is due to its role in enhancing students’ writing accuracy and making their writing more suitable to their respective discourse communities. Using a quantitative approach, data was collected over a period of two months in a university in the Sultanate of Oman through pre- and post-tests including two stages of treatments. A total of 45 students voluntarily participated in the study: control group (n=15), direct group (n=15), and indirect group (n=15). While the control group (CG) received no feedback and did not receive interventions, the direct group (DG) received feedback on their pre-test, treatment one and treatment two. For DG, errors were underlined and correct forms were given immediately. The indirect group (IG) received feedback on their pre-test, treatment one and treatment two, as well, but their errors were only underlined with no corrections given to encourage students to find the correct forms themselves. The results of this study suggest that direct written corrective feedback (WCF) is more effective than indirect feedback in improving the use of prepositions, articles, punctuation, and capitalization among Omani undergraduate students majoring in literature. The control group did not show any significant improvements, indicating that written corrective feedback is necessary for improving writing skills among EFL students.
The relationship between lateral femoral condyle ratio measured by MRI and anterior cruciate ligament injury
Authors: Sun Yang , Tang Yun
Published: March 2024

Background:

Previous studies have shown that the lateral femoral condyle ratio (LFCR) measured by X-ray has a significant relationship with the anterior cruciate ligament (ACL) injury. However, few relevant studies have been performed on LFCR measured by magnetic resonance imaging (MRI).

Purpose:

(1) To evaluate the relationship between LFCR measured by MRI and ACL injury or rerupture. (2) To compare the LFCR measured by MRI with existing bony morphological risk factors and screen out the most predictive risk factors for primary ACL injury or rerupture.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

Totally 147 patients who underwent knee arthroscopic surgery from 2015 to 2019 with minimum follow-up of 48 months were retrospectively evaluated. Patients were placed into three groups: 1) the control group of patients with simple meniscus tears without ligament injury; 2) the primary noncontact ACL injury group; 3) ACL rerupture group (ACL reconstruction failure). The LFCR measured by MRI and other previous known risk factors associated with MRI (notch width index, medial tibial slope, lateral tibial slope, medial tibial depth, lateral tibial height) were performed to evaluate their predictive value for ACL injury and rerupture. All the risk factors with p < 0.01 according to univariate analysis were included in the logistic regression models. Receiver operating characteristic (ROC) curves were analyzed for sensitivity, specificity, cut-off, and area under the curve (AUC). Z tests were used to compare the AUC values.

Results:

The LFCR measured by MRI was obviously higher in primary ACL injury group (0.628 ± 0.020) and in ACL rerupture group (0.625 ± 0.021) than that in the control group (0.593 ± 0.030). The best risk factor was the LFCR with a cut-off of 0.602 (AUC, 0.818; 95% CI, 0.748–0.878; sensitivity, 90%; specificity, 66%). When combined with lateral tibial slope (cutoff, 7°) and lateral tibial height (cutoff, 3.6 mm), the diagnostic performance was improved significantly (AUC, 0.896; 95% CI, 0.890–0.950; sensitivity, 87%; specificity, 80%).

Conclusion:

The increased LFCR measured by MRI was associated with a significantly higher risk for ACL injury or rerupture. The combination of LFCR, lateral tibial slope and lateral tibial height were the most predictive risk factors. This may help clinicians identify susceptible individuals and allow precision approaches for better prevention, treatment and management of this disease.
Caught in action: how MSCs modulate atherosclerotic plaque
Authors: Egea Virginia
Published: March 2024

Atherosclerosis (AS) is a medical condition marked by the stiffening and constriction of the arteries. This is caused by the accumulation of plaque, a substance made up of fat, cholesterol, calcium, and other elements present in the blood. Over time, this plaque solidifies and constricts the arteries, restricting the circulation of oxygen-rich blood to the organs and other body parts. The onset and progression of AS involve a continuous inflammatory response, including the infiltration of inflammatory cells, foam cells derived from monocytes/macrophages, and inflammatory cytokines and chemokines. Mesenchymal stromal cells (MSCs), a type of multipotent stem cells originating from various body tissues, have recently been demonstrated to have a protective and regulatory role in diseases involving inflammation. Consequently, the transplantation of MSCs is being proposed as a novel therapeutic strategy for atherosclerosis treatment. This mini-review intends to provide a summary of the regulatory effects of MSCs at the plaque site to lay the groundwork for therapeutic interventions.
Staphylococcus aureus oleate hydratase produces ligands that activate host PPARα
Authors: Radka Christopher D. , Frank Matthew W. , Simmons Tyler S. , Johnson Cydney N. , Rosch Jason W. , Rock Charles O.
Published: March 2024

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages. Cell-based transcriptional reporter assays show h18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-14C]h18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of h18:0 released into the media. The catabolism of h18:0 was >10-fold lower in bone marrow-derived macrophages isolated from Ppara−/− knockout mice, and we recover 74-fold fewer S. aureus cells from the skin infection site of Ppara−/− knockout mice compared to wildtype mice. These data identify PPARα as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARα signaling axis that functions to suppress the innate immune response to S. aureus.
Pore-forming peptide C14R exhibits potent antifungal activity against clinical isolates of Candida albicans and Candida auris
Authors: Vélez Norida , Argel Andreys , Kissmann Ann-Kathrin , Alpízar-Pedraza Daniel , Escandón Patricia , Rosenau Frank , Ständker Ludger , Firacative Carolina
Published: March 2024

Introduction

Invasive candidiasis is a global public health problem as it poses a significant threat in hospital-settings. The aim of this study was to evaluate C14R, an analog derived from peptide BP100, as a potential antimicrobial peptide against the prevalent opportunistic yeast Candida albicans and the emergent multidrug-resistant yeast Candida auris.

Methods

Antifungal susceptibility testing of C14R against 99 C. albicans and 105 C. auris clinical isolates from Colombia, was determined by broth microdilution. Fluconazole was used as a control antifungal. The synergy between C14R and fluconazole was assessed in resistant isolates. Assays against fungal biofilm and growth curves were also carried out. Morphological alterations of yeast cell surface were evaluated by scanning electron microscopy. A permeability assay verified the pore-forming ability of C14R.

Results

C. albicans and C. auris isolates had a geometric mean MIC against C14R of 4.42 µg/ml and 5.34 µg/ml, respectively. Notably, none of the isolates of any species exhibited growth at the highest evaluated peptide concentration (200 µg/ml). Synergistic effects were observed when combining the peptide and fluconazole. C14R affects biofilm and growth of C. albicans and C. auris. Cell membrane disruptions were observed in both species after treatment with the peptide. It was confirmed that C14R form pores in C. albicans’ membrane.

Discussion

C14R has a potent antifungal activity against a large set of clinical isolates of both C. albicans and C. auris, showing its capacity to disrupt Candida membranes. This antifungal activity remains consistent across isolates regardless of their clinical source. Furthermore, the absence of correlation between MICs to C14R and resistance to fluconazole indicates the peptide’s potential effectiveness against fluconazole-resistant strains. Our results suggest the potential of C14R, a pore-forming peptide, as a treatment option for fungal infections, such as invasive candidiasis, including fluconazole and amphotericin B -resistant strains.
The added value of three-dimensional transthoracic echocardiography in mitral annular disjunction: a case report
Authors: Papadopoulos Konstantinos , Ikonomidis Ignatios , Vannan Mani A.
Published: March 2024

Background

Mitral annular disjunction (MAD) refers to the arrhythmic mitral valve prolapse (MVP) syndrome associated with ventricular arrhythmias and sudden cardiac death. Although the pathophysiology of this disease is still under investigation, specific imaging criteria that establish the diagnosis have been recognized. In this article, we demonstrate most of these criteria using three-dimensional transthoracic echocardiography (3D-TTE) and provide added value in the management of MAD syndrome.

Case presentation

A 50-year-old male patient with recent syncope and a history of mitral regurgitation (MR) and MAD was admitted to our clinic for further investigation. According to our protocol, the patient underwent a complete 3D-TTE, laboratory blood exams, and 24 h ambulatory electrocardiogram (ECG). Our investigation confirmed the presence of MAD syndrome with bileaflet prolapse, severe MR, and non-sustained ventricular tachycardia, necessitating an implantable cardioverter defibrillator (ICD) and surgical mitral valve repair. The 3D-TTE analysis of the mitral valve demonstrated mitral annular systolic expansion and systolic flattening of the saddle-shaped annulus and quantified the extent of the disjunction arc. Additionally, four-dimensional (4D) strain analysis of the left ventricle revealed the presence of fibrosis of the posteromedial papillary muscle and basal inferolateral wall, which are variables that are required for the diagnosis and therapeutic management of MAD syndrome.

Conclusions

3D-TTE and 4D strain offer valuable insights for diagnosing and managing patients with MAD syndrome. This method seems to correlate well with the other imaging modalities and could be included in the management protocol of MAD syndrome.
Enhancing elementary school teachers’ competence in recognizing and supporting gifted students with learning disabilities in Saudi Arabia
Authors: Alsamiri Yasir A.
Published: March 2024

This research investigates the competence of elementary school teachers in Saudi Arabia in recognizing and supporting gifted students with learning disabilities. Two research questions guided the inquiry: RQ1: How do elementary school teachers in Saudi Arabia perceive the impact of professional development, on increasing awareness about students with giftedness and learning disabilities? RQ2: How do elementary school teachers in Saudi Arabia perceive the academic challenges addressed by the series of workshops that created collaborative groups for the discussion of student needs? Using a qualitative approach, in-depth interviews were conducted with 10 certified elementary teachers in Medina City. The study identified two key themes through thematic analysis. The first theme emphasizes the impact of professional development on increasing teachers’ awareness of students with giftedness and learning disabilities. Training provided insights into identifying students with learning disabilities and recognizing those with giftedness, emphasizing the need for ongoing training and collaboration. The second theme emerged from workshops creating collaborative groups for discussing student needs, highlighting the power of recognizing individual differences and collaborative efforts for supporting diverse needs. The findings underscore the importance of ongoing professional development and collaboration in improving the capacity of elementary school teachers in Saudi Arabia. These insights have implications for enhancing teacher training programs and developing inclusive educational policies for twice-exceptional learners.
Research progress on the mechanism of TCM regulating intestinal microbiota in the treatment of DM mellitus
Authors: Ping Yang , Liu Jianing , Wang Lihong , Qiu Hongbin , Zhang Yu
Published: March 2024

In recent years, with the improvement of people’s living standards, the incidence of DM has increased year by year in China. DM is a common metabolic syndrome characterized by hyperglycemia caused by genetic, environmental and other factors. At the same time, long-term suffering from DM will also have an impact on the heart, blood vessels, eyes, kidneys and nerves, and associated serious diseases. The human body has a large and complex gut microbiota, which has a significant impact on the body’s metabolism. Research shows that the occurrence and development of DM and its complications are closely related to intestinal microbiota. At present, western medicine generally treats DM with drugs. The hypoglycemic effect is fast and strong, but it can have a series of side effects on the human body. Compared with western medicine, Chinese medicine has its unique views and methods in treating DM. TCM can improve symptoms and treat complications by improving the imbalance of microbiota in patients with DM. Its characteristics of health, safety, and reliability are widely accepted by the general public. This article reviews the relationship between intestinal microbiota and DM, as well as the mechanism of TCM intervention in DM by regulating intestinal microbiota.
Global, regional, and national burden of chronic kidney disease attributable to high fasting plasma glucose from 1990 to 2019: a systematic analysis from the global burden of disease study 2019
Authors: Wei Huizhi , Ren Jinhong , Li Rui , Qi Xiaoming , Yang Fan , Li Qingshan
Published: March 2024

Purpose

Given the rising prevalence of high fasting plasma glucose (HFPG) over the past three decades, it is crucial to assess its global, national, and regional impact on chronic kidney disease (CKD). This study aims to investigate the burden of CKD attributed to HFPG and its distribution across various levels.

Methods and materials

The data for this research was sourced from the Global Burden of Diseases Study 2019. To estimate the burden of CKD attributed to HFPG, we utilized DisMod-MR 2.1, a Bayesian meta-regression tool. The burden was measured using age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years (DALYs) rate. Correlation analysis was performed using the Spearman rank order correlation method. Temporal trends were analyzed by estimating the estimated annual percentage change (EAPC).

Results

Globally in 2019, there were a total of 487.97 thousand deaths and 13,093.42 thousand DALYs attributed to CKD attributed to HFPG, which represent a substantial increase of 153.8% and 120%, respectively, compared to 1990. Over the period from 1990 to 2019, the burden of CKD attributable to HFPG increased across all regions, with the highest increases observed in regions with high socio-demographic index (SDI) and middle SDI. Regions with lower SDI exhibited higher ASMR and age-standardized DALYs (ASDR) compared to developed nations at the regional level. Additionally, the EAPC values, which indicate the rate of increase, were significantly higher in these regions compared to developed nations. Notably, high-income North America, belonging to the high SDI regions, experienced the greatest increase in both ASMR and ASDR over the past three decades. Furthermore, throughout the years from 1990 to 2019, males bore a greater burden of CKD attributable to HFPG.

Conclusion

With an increasing population and changing dietary patterns, the burden of CKD attributed to HFPG is expected to worsen. From 1990 to 2019, males and developing regions have experienced a more significant burden. Notably, the EAPC values for both ASMR and ASDR were higher in males and regions with lower SDI (excluding high-income North America). This emphasizes the pressing requirement for effective interventions to reduce the burden of CKD attributable to HFPG.
The association between Chinese visceral adiposity index and cardiometabolic multimorbidity among Chinese middle-aged and older adults: a national cohort study
Authors: Ye Xiaomei , Zhang Guangru , Han Chenyu , Wang Ping , Lu Jiaping , Zhang Min
Published: March 2024

Objective

This study aimed to explore the association between the Chinese visceral adiposity index (CVAI) and cardiometabolic multimorbidity in middle-aged and older Chinese adults.

Methods

The data used in this study were obtained from a national cohort, the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018 wave). The CVAI was measured using previously validated biomarker estimation formulas, which included sex, age, body mass index, waist circumference, triglycerides, and high-density lipoprotein cholesterol. The presence of two or more of these cardiometabolic diseases (diabetes, heart disease, and stroke) is considered as cardiometabolic multimorbidity. We used Cox proportional hazard regression models to examine the association between CVAI and cardiometabolic multimorbidity, adjusting for a set of covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to show the strength of the associations. We also conducted a subgroup analysis between age and sex, as well as two sensitivity analyses. Receiver operator characteristic curves (ROC) were used to test the predictive capabilities and cutoff value of the CVAI for cardiometabolic multimorbidity.

Results

A total of 9028 participants were included in the final analysis, with a mean age of 59.3 years (standard deviation: 9.3) and women accounting for 53.7% of the sample population. In the fully-adjusted model, compared with participants in the Q1 of CVAI, the Q3 (HR = 2.203, 95% CI = 1.039 – 3.774) and Q4 of CVAI (HR = 3.547, 95% CI = 2.100 – 5.992) were associated with an increased risk of cardiometabolic multimorbidity. There was no evidence of an interaction between the CVAI quartiles and sex or age in association with cardiometabolic multimorbidity (P >0.05). The results of both sensitivity analyses suggested that the association between CVAI and cardiometabolic multimorbidity was robust. In addition, the area under ROC and ideal cutoff value for CVAI prediction of cardiometabolic multimorbidity were 0.685 (95% CI = 0.649-0.722) and 121.388.

Conclusion

The CVAI is a valid biomarker with good predictive capability for cardiometabolic multimorbidity and can be used by primary healthcare organizations in the future for early warning, prevention, and intervention with regard to cardiometabolic multimorbidity.
Emergency materials management of petrochemical accidents considering the randomness and uncertainty base on stochastic programming
Authors: Jiang Wei , Yang Yuxiang , Hu Ansen , Liu Yulin , Hong Siyan
Published: March 2024

Petroleum is the pillar industry of the national economy, but safety accidents are frequent all over the world. The government attaches more importance to the safety production management of enterprises to reduce the occurrence of accidents that infringe on personal safety. The management of emergency supplies, which can effectively respond to the occurrence of safety production accidents, is a key measure for handling emergency accidents. Rapid response to accidents means reducing accident rescue costs and protecting personal and property safety. This paper proposes a material stochastic model with the randomness of accident demand for materials. The enterprise and the government can obtain the material management scheme and the quantitative evaluation standard of accident preventive measures from the model results respectively. The model covers as many accident scenarios as possible through multi-scenario modeling to reduce the impact of accident uncertainty. Finally, the feasibility is proved by an example of a petroleum enterprise in Zhoushan City. When the accident demand fluctuates randomly between 80% and 120%, the model proposes a material management scheme that the dispatching time of materials and the cost in rescue work do not exceed 31.33 min and 11.68 million CNY respectively. With the assistance of the model, the enterprise saves the cost of safe production and improves the efficiency of rescue. The government has strengthened the supervision and evaluation of enterprise safety production management. Finally, the mission of protecting the property and life safety of the people will be realized.
Simulation of grid/standalone solar energy supplied reduced switch converter with optimal fuzzy logic controller using golden BallAlgorithm
Authors: Srilakshmi Koganti , Sundaragiri Dheeraj , Gaddameedhi Sravanthy , Vangalapudi Ramprasad , Balachandran Praveen Kumar , Colak Ilhami , Selvarajan Shitharath
Published: March 2024

This article presents the utilization of a shunt active power filter (SHAPF) in combination with an Energy Storage System (ESS) and a Solar Energy System (SES). Voltage source converters (VSC) are connected in parallel to a direct current (DC) bus. The membership function (MSF) of fuzzy logic controller (FLC) for the shunt control system is optimally adjusted using the golden balloptimization algorithm (GBOA). The present effort aims to achieve the following primary objectives: 1) Quick implementation to stabilize the voltage of the DC Link capacitor (DCLCV); 2) Mitigation of harmonics and improvement of power factor (PF); 3) Satisfactory performance under load as well as solar power varying conditions. The effectiveness of the optimally designed controller is evaluated by studying four test scenarios with grid and standalone conditions. The results are then compared to the existing sliding mode (SMC) and fuzzy logic controllers (FLC).
Experimental study of ultra-low IFT foam flooding for low permeability reservoirs
Authors: Lang Liyuan , Zhao Shuang , Liu Lu
Published: March 2024

Foam flooding is an effective oil displacement technique to improve fluid sweep efficiency and increase oil recovery. The objective of this paper is to investigate the applicability of ultra-low IFT foam flooding for low permeability oil recovery under the conditions of WX reservoir block in Tuha oilfield (84°C, 86,072 mg/L). A modified amphoteric hydroxy sulfobetaine surfactant (Cn-HSB) was formulated as a foaming agent based on the principle of compatibility with crude oil that could achieve the ultra-low interfacial tension (IFT) and strong foamability simultaneously. This is shown to reduce the oil/water dynamic IFT (DIFT) to an ultra-low value of the order of 10−5 mN/m (0.10wt%), as well as produce a foam volume and half-life of 448 mL and 2567 s, respectively. In addition, results of IFT and foam quality tests indicate that the modified Cn-HSB has good thermal stability and excellent salinity-resistance. Moreover, the ultra-low IFT foam flooding has an ideal injectivity and oil displacement efficiency in low permeability porous media that can mobilize the trapped oil in k = 1.50 × 10−3μm2 with a threshold pressure gradient of 0.115 MPa/m. This improves oil displacement efficiency about 15%OOIP. Fundamental knowledge gained from this research gives insight into the application of ultra-low IFT foam flooding in low-permeability reservoirs under a combination of specific reservoir conditions.
The prognostic significance of LncRNA BLACAT1 overexpression in various tumors: a meta-analysis
Authors: Yan Xuefen , Zhang Nana , Wang Gang , Wang Jiaheng
Published: March 2024

Objective:

Recent studies have revealed increasing evidence that the long non-coding RNA bladder cancer associated transcript 1 (LncRNA BLACAT1) plays an essential role in the emergence of different malignancies. This meta-analysis aimed to evaluate the prognostic significance of LncRNA BLACAT1 in various cancers.

Methods:

Six electronic databases (PubMed, Embase, Medline, Web of Science, China National Knowledge Infrastructure (CNKI), and the Chinese WanFang database) were comprehensively searched for relevant studies. The analysis of overall survival (OS) and clinicopathological characteristics was conducted.

Results:

Nineteen studies with 1,559 patients were eventually eligible to be included in this meta-analysis. High expression level of LncRNA BLACAT1 was identified to be linked with shorter OS (HR: 2.02, 95% CI: 1.66–2.46, p < 0.001) and PFS (HR: 2.424, 95% CI: 1.827–3.020, p < 0.001) in cancer patients as opposed to low expression levels. Subgroup analysis showed that analysis model (multivariate or univariate), cut-off value (mean or median), sample size (more or fewer than 100), and cancer type had little effect on OS in multiple tumors. Moreover, high LncRNA BLACAT1 expression was associated with positive lymph node metastasis (HR: 2.29, 95% CI: 1.66–3.16, p < 0.00001), advanced clinical stage (HR: 2.29, 95% CI: 1.65–3.19, p < 0.00001) and worse differentiation status (HR: 0.58, 95% CI: 0.37–0.92, p = 0.02), compared to low LncRNA BLACAT1 expression.

Conclusion:

The findings highlight that high LncRNA BLACAT1 expression might be detrimental and induce a worse prognosis for cancer patients.
Functional analysis of RRAS2 pathogenic variants with a Noonan-like phenotype
Authors: Iida Takaya , Igarashi Arisa , Fukunaga Kae , Aoki Taiga , Hidai Tomomi , Yanagi Kumiko , Yamamori Masahiko , Satou Kazuhito , Go Hayato , Kosho Tomoki , Maki Ryuto , Suzuki Takashi , Nitta Yohei , Sugie Atsushi , Asaoka Yoichi , Furutani-Seiki Makoto , Kimura Tetsuaki , Matsubara Yoichi , Kaname Tadashi
Published: March 2024

Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like low-molecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis.

Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed.

Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway.

Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-of-function RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients.
The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes
Authors: Martínez-Gómez Laura Edith , Martinez-Armenta Carlos , Tusie-Luna Teresa , Vázquez-Cárdenas Paola , Vidal-Vázquez Rosa P. , Ramírez-Hinojosa Juan P. , Gómez-Martín Diana , Vargas-Alarcón Gilberto , Posadas-Sánchez Rosalinda , Fragoso José Manuel , de la Peña Aurora , Rodríguez-Pérez José Manuel , Mata-Miranda Mónica M. , Vázquez-Zapién Gustavo J. , Martínez-Cuazitl Adriana , Martínez-Ruiz Felipe de J. , Zayago-Angeles Dulce M. , Ramos-Tavera Luis , Méndez-Aguilera Alberto , Camacho-Rea María del C. , Ordoñez-Sánchez María L. , Segura-Kato Yayoi , Suarez-Ahedo Carlos , Olea-Torres Jessel , Herrera-López Brígida , Pineda Carlos , Martínez-Nava Gabriela A. , López-Reyes Alberto
Published: March 2024

Introduction

Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes.

Methods

To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity).

Results

According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02).

Discussion

Our data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.
Effect of smoking-related features and 731 immune cell phenotypes on esophageal cancer: a two-sample and mediated Mendelian randomized study
Authors: Yang Kaiqi , Li Shaoya , Ding Yuchen , Meng Xiaodie , Zhang Changhao , Sun Xiujing
Published: March 2024

Introduction

Numerous observational studies have indicated that smoking is a substantial risk factor for esophageal cancer. However, there is a shortage of research that delves into the specific causal relationship and potential mediators between the two. Our study aims to validate the correlation between smoking-related traits and esophageal cancer while exploring the possible mediating effects of immune factors.

Methods

Initially, we conducted bidirectional univariate Mendelian Randomization (MR) analyses to forecast the causal effects linking smoking-related traits and esophageal cancer. Subsequently, we employed a two-step MR analysis to scrutinize immune cell phenotypes that could mediate these effects. Finally, the coefficient product method was employed to determine the precise mediating impact. Additionally, we have refined our sensitivity analysis to ensure the reliability of the outcomes.

Results

After analysis, Smoking status: Never had a significant negative association with the incidence of esophageal cancer (inverse-variance weighted (IVW) method, p=1.82e-05, OR=0.10, 95%CI=0.04~0.29). Ever smoked (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) and Current tobacco smoking (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) showed the promoting effect on the pathogenesis of esophageal cancer. Through further examination, researchers discovered 21 immune cell phenotypes that have a causal relationship with esophageal cancer. After careful screening, two immune cell phenotypes were found to have potential mediating effects. In particular, it was observed that in the case of the preventive effect of Smoking status: Never on esophageal cancer, the absolute count of CD62L plasmacytoid dendritic cells mediated a reduction of 4.21%, while the mediating effect of CD27 in CD20-CD38-B cells was -4.12%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy.

Conclusion

The study provides new evidence for the causal relationship between smoking-related features and esophageal cancer and proposes immune factors with potential mediating effects. However, this finding needs to be further demonstrated by more extensive clinical studies.
A generalizable and easy-to-use COVID-19 stratification model for the next pandemic via immune-phenotyping and machine learning
Authors: He Xinlei , Cui Xiao , Zhao Zhiling , Wu Rui , Zhang Qiang , Xue Lei , Zhang Hua , Ge Qinggang , Leng Yuxin
Published: March 2024

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has affected billions of people worldwide, and the lessons learned need to be concluded to get better prepared for the next pandemic. Early identification of high-risk patients is important for appropriate treatment and distribution of medical resources. A generalizable and easy-to-use COVID-19 severity stratification model is vital and may provide references for clinicians.

Methods

Three COVID-19 cohorts (one discovery cohort and two validation cohorts) were included. Longitudinal peripheral blood mononuclear cells were collected from the discovery cohort (n = 39, mild = 15, critical = 24). The immune characteristics of COVID-19 and critical COVID-19 were analyzed by comparison with those of healthy volunteers (n = 16) and patients with mild COVID-19 using mass cytometry by time of flight (CyTOF). Subsequently, machine learning models were developed based on immune signatures and the most valuable laboratory parameters that performed well in distinguishing mild from critical cases. Finally, single-cell RNA sequencing data from a published study (n = 43) and electronic health records from a prospective cohort study (n = 840) were used to verify the role of crucial clinical laboratory and immune signature parameters in the stratification of COVID-19 severity.

Results

Patients with COVID-19 were determined with disturbed glucose and tryptophan metabolism in two major innate immune clusters. Critical patients were further characterized by significant depletion of classical dendritic cells (cDCs), regulatory T cells (Tregs), and CD4+ central memory T cells (Tcm), along with increased systemic interleukin-6 (IL-6), interleukin-12 (IL-12), and lactate dehydrogenase (LDH). The machine learning models based on the level of cDCs and LDH showed great potential for predicting critical cases. The model performances in severity stratification were validated in two cohorts (AUC = 0.77 and 0.88, respectively) infected with different strains in different periods. The reference limits of cDCs and LDH as biomarkers for predicting critical COVID-19 were 1.2% and 270.5 U/L, respectively.

Conclusion

Overall, we developed and validated a generalizable and easy-to-use COVID-19 severity stratification model using machine learning algorithms. The level of cDCs and LDH will assist clinicians in making quick decisions during future pandemics.
HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation
Authors: Senev Aleksandar , Tambur Anat R. , Kosmoliaptsis Vasilis , Copley Hannah Charlotte , García-Sánchez Cynthia , Usenko Crystal , Ildstad Suzanne T. , Leventhal Joseph R.
Published: March 2024

Introduction

We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT).

Methods

All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), de novo DSA, and graft rejection.

Results

Follow-up time of this cohort was 6–13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30–0.61] vs. 0.24 [IQR, 0.18–0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM.

Conclusion

Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings.

Clinical trial registration

https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.
Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity
Authors: Dennis Emily , Murach Maria , Blackburn Cassidy M.R. , Marshall Melissa , Root Katherine , Pattarabanjird Tanyaporn , Deroissart Justine , Erickson Loren D. , Binder Christoph J. , Bekiranov Stefan , McNamara Coleen A.
Published: March 2024

Recent studies have demonstrated a role for Ten-Eleven Translocation-2 (TET2), an epigenetic modulator, in regulating germinal center formation and plasma cell differentiation in B-2 cells, yet the role of TET2 in regulating B-1 cells is largely unknown. Here, B-1 cell subset numbers, IgM production, and gene expression were analyzed in mice with global knockout of TET2 compared to wildtype (WT) controls. Results revealed that TET2-KO mice had elevated numbers of B-1a and B-1b cells in their primary niche, the peritoneal cavity, as well as in the bone marrow (B-1a) and spleen (B-1b). Consistent with this finding, circulating IgM, but not IgG, was elevated in TET2-KO mice compared to WT. Analysis of bulk RNASeq of sort purified peritoneal B-1a and B-1b cells revealed reduced expression of heavy and light chain immunoglobulin genes, predominantly in B-1a cells from TET2-KO mice compared to WT controls. As expected, the expression of IgM transcripts was the most abundant isotype in B-1 cells. Yet, only in B-1a cells there was a significant increase in the proportion of IgM transcripts in TET2-KO mice compared to WT. Analysis of the CDR3 of the BCR revealed an increased abundance of replicated CDR3 sequences in B-1 cells from TET2-KO mice, which was more clearly pronounced in B-1a compared to B-1b cells. V-D-J usage and circos plot analysis of V-J combinations showed enhanced usage of VH11 and VH12 pairings. Taken together, our study is the first to demonstrate that global loss of TET2 increases B-1 cell number and IgM production and reduces CDR3 diversity, which could impact many biological processes and disease states that are regulated by IgM.
Response of the copepod community to interannual differences in sea-ice cover and water masses in the northern Barents Sea
Authors: Gawinski Christine , Daase Malin , Primicerio Raul , Amargant-Arumí Martí , Müller Oliver , Wold Anette , Ormańczyk Mateusz Roman , Kwasniewski Slawomir , Svensen Camilla
Published: March 2024

The reduction of Arctic summer sea ice due to climate change can lead to increased primary production in parts of the Barents Sea if sufficient nutrients are available. Changes in the timing and magnitude of primary production may have cascading consequences for the zooplankton community and ultimately for higher trophic levels. In Arctic food webs, both small and large copepods are commonly present, but may have different life history strategies and hence different responses to environmental change. We investigated how contrasting summer sea-ice cover and water masses in the northern Barents Sea influenced the copepod community composition and secondary production of small and large copepods along a transect from 76°N to 83°N in August 2018 and August 2019. Bulk abundance, biomass, and secondary production of the total copepod community did not differ significantly between the two years. There were however significant spatial differences in the copepod community composition and production, with declining copepod abundance from Atlantic to Arctic waters and the highest copepod biomass and production on the Barents Sea shelf. The boreal Calanus finmarchicus showed higher abundance, biomass, and secondary production in the year with less sea-ice cover and at locations with a clear Atlantic water signal. Significant differences in the copepod community between areas in the two years could be attributed to interannual differences in sea-ice cover and Atlantic water inflow. Small copepods contributed more to secondary production in areas with no or little sea ice and their production was positively correlated to water temperature and ciliate abundance. Large copepods contributed more to secondary production in areas with extensive sea ice and their production was positively correlated with chlorophyll a concentration. Our results show how pelagic communities might function in a future ice-free Barents Sea, in which the main component of the communities are smaller-sized copepod species (including smaller-sized Calanus and small copepods), and the secondary production they generate is available in energetically less resource-rich portions.
Changes in hydrodynamics and nutrient load of the coastal bay induced by Typhoon Talim (2023)
Authors: Chen Chunqing , Lao Qibin , Zhou Xin , Zhu Qingmei , Chen Fajin
Published: March 2024

Typhoons can greatly alter the hydrodynamic and nutrient supply in coastal oceans. However, due to the complex conditions of typhoons, such as their intensity, even slight changes may cause substantial changes in hydrodynamics and nutrient supply, which needs to be better understood. In this study, we conducted two cruises before and after Typhoon Talim (2023) to quantitatively investigate changes in hydrodynamics and nutrient supply in Zhanjiang Bay using dual water isotopes. Before the typhoon, strong stratification occurred in the bay. However, the strong external force of the typhoon destroyed the stratification and substantially changed the water mixing in the bay after the typhoon. In the upper bay, massive freshwater input remarkably decreased the salinity during the post-typhoon period (freshwater increased by 18%). In contrast, the salinity variation in the lower bay was minimal, mainly due to massive seawater intrusion from the outer bay induced by the typhoon; the seawater mixed with freshwater columns from the upper bay, forming a strong ocean front. The intensity of ocean fronts induced by typhoons directly depended on the typhoon intensity landing in Zhanjiang Bay, as stronger typhoons will cause more intrusion of high-salinity seawater from the outer bay. Due to the formation of the ocean front, freshwater and terrestrial nutrients from the upper bay are prevented from being transported downwards, resulting in a large amount of accumulated pollutants within the bay. By contrast, due to the impact of high-salinity seawater intrusion, the contribution of seawater from the outer bay has increased, thereby diluting the nutrients in the lower bay. This study provides a new insight into the responses of coastal marine eco-environment systems to typhoons.