bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 Pandemic and Public Restrictions on Outcomes After Catheter Ablation of Atrial Fibrillation
Authors: Kim Daehoon , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: March 2022

Background

Here we aimed to analyze changes in the outcomes of atrial fibrillation (AF) catheter ablation (AFCA) during the coronavirus disease 2019 (COVID-19) pandemic and examine the relationship between rhythm outcomes and the stringency of government social distancing measures.

Methods

We included 453 patients who underwent de novo AFCA between May 2018 and October 2019 (pre-COVID-19 era) and 601 between November 2019 and April 2021 (COVID-19 era). The primary outcome was late recurrence, defined as any episode of AF or atrial tachycardia documented after a 3-month blanking period. A multivariable Cox regression analysis was performed to estimate the relative hazards of AF recurrence in the two eras.

Results

In the study population (24.3% women; median age, 60 years), 660 (62.6%) patients had paroxysmal AF. Among those with paroxysmal AF, the late recurrence rate was significantly lower in the COVID-19 era than in the pre-COVID-19 era [9.4% vs. 17.0%, respectively, log-rank P = 0.004; adjusted hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.35–0.90] during a median follow-up of 11 months. In patients with persistent AF, the late recurrence rate did not significantly differ between the pre-COVID-19 and COVID-19 era groups (18.9% vs. 21.5%, respectively; log-rank P = 0.523; adjusted HR 0.84, 95% CI 0.47–1.53) during the median follow-up of 11 months.

Conclusion

A decrease in AF recurrence after catheter ablation was observed in patients with paroxysmal AF during the COVID-19 outbreak, whereas no change was observed in those with persistent AF.
Receptor-Interacting Protein Kinase 3 Suppresses Mitophagy Activation via the Yes-Associated Protein/Transcription Factor EB Pathways in Septic Cardiomyopathy
Authors: Zhu Pingjun , Chen Yangxiaocao , Wang Junyan , Lin Geng , Wang Runsheng , Que Yifan , Zhou Jin , Xu Guogang , Luo Jiang , Du Yingzhen
Published: March 2022

Mitophagy, known as the main mechanism of mitochondrial quality control, determines the pathophysiology of septic cardiomyopathy, although the precise regulatory mechanisms remain elusive. Data from the present study suggested that receptor-interacting protein kinase 3 (RIPK3) expression could be enhanced in response to lipopolysaccharide (LPS) challenge. Upregulated RIPK3 expression was accompanied by severe cardiac injury and cardiac dysfunction. Further examination revealed that elevated RIPK3 expression subsequently inhibited the Yes-associated protein (YAP) pathway, which was accompanied by reduced transcription factor EB (TFEB) expression. Inhibition of TFEB would reduce mitophagy, which ultimately induced cardiomyocyte death under LPS challenge. In contrast, loss of RIPK3 induced the YAP/TFEB/mitophagy pathway alleviated the sensitivity of cardiomyocytes to LPS-induced cytotoxicity. Collectively, the RIPK3/YAP/TFEB axis was confirmed to be responsible for the pathogenesis of septic cardiomyopathy by inhibiting mitophagy. These findings have potential significance for the progression of new approaches to the treatment of septic cardiomyopathy.
Long Atrial Fibrillation Duration and Early Recurrence Are Reliable Predictors of Late Recurrence After Radiofrequency Catheter Ablation
Authors: Li Zhitong , Wang Shihao , Hidru Tesfaldet H. , Sun Yuanjun , Gao Lianjun , Yang Xiaolei , Xia Yunlong
Published: March 2022

Background

Recurrence after atrial fibrillation (AF) ablation is still common.

Objective

This study aimed to evaluate the predictive abilities of AF duration and early recurrence (ER) to discriminate high-risk patients for recurrence.

Methods

We enrolled 1,763 consecutive patients with AF who were scheduled to receive the index radiofrequency catheter ablation (RFCA) from January 2016 to August 2021 in Dalian, China. Long AF duration (LAFD) was considered if the course of AF lasted for ≥ 12 months. ER was defined as any atrial tachycardia (AT) or AF event longer than 30 s occurring within a 3-month post-RFCA.

Results

Late recurrence occurred in 643 (36.5%) of the 1,763 patients at a median of 35 months after RFCA. Multivariate analysis identified LAFD (hazard ratio (HR): 1.80, 95% confidence interval (CI): 1.38–2.35, p < 0.001) and ER (HR: 2.34, 95% CI: 1.82–3.01, p < 0.001) as strong independent predictors of late recurrence in non-paroxysmal AF. Similarly, LAFD (HR: 1.48, 95% CI: 1.20–1.84, p < 0.001) and ER (HR: 3.40, 95% CI: 2.68–4.30, p < 0.001) were significantly associated with late recurrence in paroxysmal AF. Receiver operating curve analyses revealed that the CAAP-AF (CAD, Atrial diameter, Age, Persistent or longstanding AF, Antiarrhythmic drugs failed, Female) had the highest predict power [area under ROC curve (AUC) 0.586]. The addition of ER and LAFD to the CAAP-AF score significantly improved risk discrimination for late recurrence after AF ablation from 0.586 to 0.686.

Conclusion

Long AF duration and ER were independently associated with late recurrence. The prediction performance of the CAAP-AF model for recurrence was improved by the addition of LAFD and ER.
Dissolved Organic Carbon (DOC) in Ground Ice on Northeastern Tibetan Plateau
Authors: Yang Yuzhong , Guo Xiaoyan , Wang Qingfeng , Jin Huijun , Yun Hanbo , Wu Qingbai
Published: March 2022

Ground ice in permafrost stores substantial amounts of dissolved organic carbon (DOC) upon thaw, which may perpetuate a carbon feedback in permafrost regions, yet little is known to date about the dynamics of DOC and source variability of ground ice on the Tibetan Plateau. Here, the high-resolution data of DOC in ground ice (4.8 m in depth) from two permafrost profiles on the Northeastern Tibetan Plateau (NETP) were firstly presented. We quantified the DOC concentrations (mean: 9.7–21.5 mg/L) of ground ice and revealed sizeable—by a factor of 7.0–36.0—enrichment of the ground ice relative to the other water elements on the TP. Results indicated remarkable depth differences in the DOC of ground ice, suggestive of diverse sources of DOC and different sequestration processes of DOC into ice during permafrost evolution. Combined with DOC and carbon isotopes (δ13CDOC), we clarified that decomposition of soil organic matter and leaching of DOC from organic layers and surrounding permafrost sediments are the important carbon sources of ground ice. The DOC sequestration of ground ice in the upper layers was related to the active layer hydrology and freeze–thaw cycle. However, the permafrost evolution controlled the decomposition of organic carbon and sequestration of DOC in the deep layers. A conceptual model clearly illustrated the dynamics of DOC in ground ice and suggested a significant impact on the carbon cycle on the NETP. The first attempt to explore the DOC in ground ice on the NETP is important and effective for further understanding of carbon cycle under permafrost degradation on the Tibetan Plateau.
The Virtual Element Method for the Dam Foundation With Joint
Authors: Sun Yinghao , Sun Guanhua , Yi Qi , Wang Jiao
Published: March 2022

The contact is a typical non-linear problem that exists in various projects. For traditional three-node triangular mesh and four-node quadrilateral mesh, the accuracy and convergence of the calculation results are affected by the quality of the mesh. The test space and trial space in the virtual element method (VEM) do not need to be accurately calculated, avoiding mesh dependence. In this paper, the formulation of linear elasticity and the formulation of the frictionless node-to-segment (NTS) contact model via VEM are shown. There are four numerical simulations. The sensitivity of the virtual element method to mesh distortion is studied in the first numerical simulation. The exactness and convergence of the algorithm are investigated by the second numerical example. The second numerical example simultaneously explores the penalty factor’s effect on the results. The third example investigated the impact of mesh shape and number of Voronoi mesh elements on the results by comparing normal contact stresses. The fourth numerical example studies the application of the method to engineering. Those numerical examples show that the virtual element method is insensitive to mesh distortion and could solve the joint contact in engineering.
Boundary-Crossing Movements: A Resource for Student Learning
Authors: Cattaruzza Elisa , Kloetzer Laure , Iannaccone Antonio
Published: March 2022

This paper focuses on the learning processes of students involved in a pedagogical design bridging in-class and out-of-class activities. As academic teachers–researchers, we designed a semester-long course in which academic and out-of-university activities interact and overlap. The data were collected at the end of the course from student reports (diaries) and audio-recorded semi-structured interviews inspired by the elicitation interview technique. This technique involves a fine-grained description of the lived experience. We present selected excerpts in which students described their boundary-crossing movements between academic and out-of-university activities. Data were evaluated using a purpose-built analysis approach comprising two macro-categories and three sub-categories of students’ boundary-crossing movements. The results showed that specific learning processes emerged and developed through these movements. Implications for teaching and learning are highlighted.
The Role of Physical Activity Behavior in the Mental Wellbeing of Vocational Education and Training Students: The PHIT2LEARN Study
Authors: Kirschner Mara , Golsteijn Rianne H. J. , van der Wurff Inge S. M. , Savelberg Hans H. C. M. , de Groot Renate H. M.
Published: March 2022

A positive association has been found between physical activity (PA) and student mental wellbeing (SMW). This association has been mainly explored in secondary school and university students. Studies in vocational education and training (VET) are lacking, while VET students could especially benefit from exploring this association since research shows that VET students, who often come from low socioeconomic status (SES) households, are prone to low SMW. Low SMW can result in higher school dropout rates and long-term negative effects, such as unemployment, social exclusion, and impoverishment. The aim of the current study was to explore the association between total PA and different physical activity behaviors {PABs, i.e., moderate to vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SB)}, and SMW in the VET setting. In this cross-sectional observational study, students wore an ActivPAL3™ accelerometer for 7 consecutive days to measure PAB. SMW was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Rosenberg self-esteem questionnaire (RSE). Complete data for the analyses were obtained from 85 students. Multiple regression analyses showed a significant positive association between total PA and self-esteem and a significant negative association between total PA and depressive symptoms. Taking different PA intensities into account, there was a significant positive association between LPA and self-esteem and a significant negative association between LPA and depressive symptoms. No significant associations were found between MVPA and the outcome measures, although the associations were aligned with the findings for LPA. High levels of SB were significantly associated with low self-esteem; however, the association between SB and depressive symptoms was not significant. The significant positive associations between LPA and SMW and the negative association between SB and self-esteem indicate that decreasing SB and increasing LPA could contribute to improve SMW. Future research should determine if these are causal relationships.
Multiplexing Error and Noise Reduction in Electrical Impedance Tomography Imaging
Authors: Barreiro Martina , Sánchez Pablo , Vera Julián , Viera Matías , Morales Isabel , Dell´Osa Antonio Hector , Bertemes-Filho Pedro , Simini Franco
Published: March 2022

Electrical Impedance Tomography design can be simplified to obtain a low cost 16 electrodes edema monitoring clinical instrument by using voltage measurement multiplexing. Multiplexers introduce errors, which we have estimated by consecutive phantom measurements both using voltage multiplexers and by selecting the electrodes by hand, all other things being the same. Noise is taken care of by averaging. The EIDORS reconstruction of the phantom with multiplexed measurements is compared to the hand-selected electrode measurements reconstruction. The difference image obtained is considered an estimation of the multiplexer induced error. This measurement error is subtracted from the multiplexed object measurement matrix, giving a modified reconstruction which is closer to the hand-selected electrodes measurement based reconstruction than the multiplexed reconstruction. The quality factor of the uncorrected multiplexer obtained image of 57% is increased to 83% which is the best increase of three methods described. This suggests the benefit of a “calibration” phase for all 16 electrodes, prior to EIT reconstruction, using a set-up-specific “error matrix” to correct the data matrix before submission to the reconstruction method.
Mogroside V Improves Follicular Development and Ovulation in Young-Adult PCOS Rats Induced by Letrozole and High-Fat Diet Through Promoting Glycolysis
Authors: Huang Lan’e , Liang Aihong , Li Tianlong , Lei Xiaocan , Chen Xi , Liao Biyun , Tang Jinru , Cao Xiting , Chen Gang , Chen Fengyu , Wang Yiyao , Hu Linlin , He Weiguo , Li Meixiang
Published: March 2022

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. In this study, we induced a young-adult PCOS rat model by oral administration of letrozole combined with a high-fat diet and then treated with mogroside V (MV) to evaluate the protective effects of MV on endocrine and follicle development in young-adult PCOS rats. MV (600 mg/kg/day) administration not only significantly reduced the body weight and ovary weight, but also attenuated the disrupted estrous cycle and decreased the level of testosterone. MV restored the follicular development, especially by increasing the number of corpus luteum and the thickness of the granular layer in young-adult POCS rats. Moreover, metabolomics showed that MV markedly increased the levels of D-Glucose 6-phosphate, lactate and GTP, while decreased the level of pyruvate. Bioinformatic analysis revealed that MV recovered multiple metabolism-related processes including gluconeogenesis, glycolysis and glucose metabolic process. Further real-time quantitative PCR analysis showed that MV upregulated the expression of lactate dehydrogenase A (Ldha), hexokinase 2 (Hk2) and pyruvate kinase M2 (Pkm2). Western blotting and immunohistochemistry analysis showed that MV restored the expression of lactate dehydrogenase A (Ldha), hexokinase 2 (Hk2) and pyruvate kinase M2 (Pkm2). Collectively, these findings indicated that MV could effectively improve the ovarian microenvironment by upregulating the expression of LDHA, HK2 and PKM2 in granulosa cells and enhancing lactate and energy production, which may contribute to follicle development and ovulation of young-adult PCOS rats.
Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma
Authors: Gilchrist Annette , Echeverria Stephanie L.
Published: March 2022

Multiple myeloma is an incurable plasma B-cell malignancy with 5-year survival rates approximately 10-30% lower than other hematologic cancers. Treatment options include combination chemotherapy followed by autologous stem cell transplantation. However, not all patients are eligible for autologous stem cell transplantation, and current pharmacological agents are limited in their ability to reduce tumor burden and extend multiple myeloma remission times. The “chemokine network” is comprised of chemokines and their cognate receptors, and is a critical component of the normal bone microenvironment as well as the tumor microenvironment of multiple myeloma. Antagonists targeting chemokine-receptor 1 (CCR1) may provide a novel approach for treating multiple myeloma. In vitro CCR1 antagonists display a high degree of specificity, and in some cases signaling bias. In vivo studies have shown they can reduce tumor burden, minimize osteolytic bone damage, deter metastasis, and limit disease progression in multiple myeloma models. While multiple CCR1 antagonists have entered the drug pipeline, none have entered clinical trials for treatment of multiple myeloma. This review will discuss whether current CCR1 antagonists are a viable treatment option for multiple myeloma, and studies aimed at identifying which CCR1 antagonist(s) are most appropriate for this disease.
The Mediating Role of Endocrine Factors in the Positive Relationship Between Fat Mass and Bone Mineral Content in Children Aged 9–11 Years: The Physical Activity and Nutrition in Children Study
Authors: Constable Annie M. , Vlachopoulos Dimitris , Barker Alan R. , Moore Sarah A. , Soininen Sonja , Haapala Eero A. , Väistö Juuso , Jääskeläinen Jarmo , Voutilainen Raimo , Auriola Seppo , Häkkinen Merja R. , Laitinen Tomi , Lakka Timo A.
Published: March 2022

Introduction

We aimed to investigate whether the relationship between fat mass and bone mineral content (BMC) is mediated by insulin, leptin, adiponectin, dehydroepiandrosterone sulphate, testosterone and estradiol in children aged 9-11 years.

Materials and Methods

We utilised cross-sectional data from the Physical Activity and Nutrition in Children study (n = 230 to 396; 112 to 203 girls). Fat mass and BMC were assessed with dual-energy X-ray absorptiometry. Endocrine factors were assessed from fasted blood samples. We applied the novel 4-way decomposition method to analyse associations between fat mass, endocrine factors, and BMC.

Results

Fat mass was positively associated with BMC in girls (ß = 0.007 to 0.015, 95% confidence interval (CI) 0.005 to 0.020) and boys (ß = 0.009 to 0.015, 95% CI 0.005 to 0.019). The relationship between fat mass and BMC was mediated by free leptin index in girls (ß = -0.025, 95% CI -0.039 to -0.010) and boys (ß = -0.014, 95% CI -0.027 to -0.001). The relationship between fat mass and BMC was partially explained by mediated interaction between fat mass and free leptin index in boys (ß = -0.009, 95% CI -0.013 to -0.004) and by interaction between fat mass and adiponectin in girls (ß = -0.003, 95% CI -0.006 to -0.000).

Conclusion

At greater levels of adiponectin and free leptin index, the fat mass and BMC relationship becomes less positive in girls and boys respectively. The positive association between fat mass with BMC was largely not explained by the endocrine factors we assessed.

Clinical Trial Registration

[https://clinicaltrials.gov/ct2/show/NCT01803776], identifier NCT01803776.
Normal Weight Obesity and Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis
Authors: Mohammadian Khonsari Nami , Khashayar Patricia , Shahrestanaki Ehsan , Kelishadi Roya , Mohammadpoor Nami Sahar , Heidari-Beni Motahar , Esmaeili Abdar Zahra , Tabatabaei-Malazy Ozra , Qorbani Mostafa
Published: March 2022

Background

Obesity is one of the most significant causes of morbidity and mortality worldwide. Current studies suggest a new type of obesity, normal weight obesity (NWO), which is defined as having a normal body mass index (BMI), but a high-fat percentage increases the risk of cardiometabolic risk factors (CMRFs). This systematic review and meta-analysis aimed to pool the association between NWO with CMRFs.

Methods

A systematic search of the literature in all available electronic databases, including Scopus, Web of Science, EMBASE, and PubMed, was performed until October 2021. All English studies that assessed the association of NWOs [compared to normal weight non-obese (NWNO)] and the CMRFs were included. Two investigators extracted data and performed a quality assessment. The heterogeneity between studies was assessed with I-squared and Cochran’s Q tests. Odds ratio (OR) was used as an effect size to pool the association of NWO with CMRFs.

Results

Twenty-five articles that met the inclusion criteria entered the study. The total number of participants was 177,792, with an age range of 13 to 75 years. Most studies were conducted on the general population (adults) and were from China. The result of fixed-effect model meta-analysis indicated an increased odds of hyperglycemia (OR:1.50, 95%:1.23, 1.76), high TG (OR:1.90, 95% CH:1.44, 2.35), low HDL (OR: 1.28, 95% CI:1.06, 1.49) and diabetes (OR:1.39, 95% CI:1.30, 1.49). Moreover, the random effect meta-analysis showed that NWO increased the odds of dyslipidemia (OR:1.83, 95% CI:1.61, 20.4), HTN (OR:1.40, 95% CI:1.28, 1.51) and metabolic syndrome (OR:1.92, 95% CI:1.58, 2.26). Moreover, the mean of all CMRFs except plasma glucose in NWO subjects was statistically higher than NWNO subjects (p-value<0.05).

Conclusion

The present study showed that NWO increased the odds of CMRFs. These findings indicate the inadequacy of the BMI measurement and the need for body fat assessment for a better obesity risk assessment.
Platelet-Vesicles-Encapsulated RSL-3 Enable Anti-Angiogenesis and Induce Ferroptosis to Inhibit Pancreatic Cancer Progress
Authors: Zhang Yiyin , Huang Zhengze , Cheng Jiaxi , Pan Haoqi , Lin Tianyu , Shen Xuqiu , Chen Wenchao , Chen Qi , Gu Chenhui , Mao Qijiang , Liang Yuelong
Published: March 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by stromal richness, lack of blood supply and special metabolic reprogramming in the tumor microenvironment, which is difficult to treat and easy to metastase. Great efforts have been made to develop new drugs which can pass through the stroma and are more effective than traditional chemotherapeutics, such as ferroptosis inducers–Erastin and RSL-3. As current anti-angiogenic therapy drugs alone are suboptimal for PDAC, novel vascular disruption agents in combination with ferroptosis inducers might provide a possible solution. Here, we designed human platelet vesicles (PVs) to camouflage RSL-3 to enhance drug uptake rate by tumor cells and circulation time in vivo, deteriorating the tumor vessels and resulting in tumor embolism to cut the nutrient supply as well as causing cell death due to excessive lipid peroxidation. The RSL-3@PVs can also cause the classic ferroptosis-related change of mitochondrial morphology, with changes in cellular redox levels. Besides that, RSL-3@PVs has been proved to have great biological safety profile in vitro and in vivo. This study demonstrates the promising potential of integrating PVs and RSL-3 as a combination therapy for improving the outcome of PDAC.
Sustainable Energy Transition for Renewable and Low Carbon Grid Electricity Generation and Supply
Authors: Kabeyi Moses Jeremiah Barasa , Olanrewaju Oludolapo Akanni
Published: March 2022

The greatest sustainability challenge facing humanity today is the greenhouse gas emissions and the global climate change with fossil fuels led by coal, natural gas and oil contributing 61.3% of global electricity generation in the year 2020. The cumulative effect of the Stockholm, Rio, and Johannesburg conferences identified sustainable energy development (SED) as a very important factor in the sustainable global development. This study reviews energy transition strategies and proposes a roadmap for sustainable energy transition for sustainable electricity generation and supply in line with commitments of the Paris Agreement aimed at reducing greenhouse gas emissions and limiting the rise in global average temperature to 1.5°C above the preindustrial level. The sustainable transition strategies typically consist of three major technological changes namely, energy savings on the demand side, generation efficiency at production level and fossil fuel substitution by various renewable energy sources and low carbon nuclear. For the transition remain technically and economically feasible and beneficial, policy initiatives are necessary to steer the global electricity transition towards a sustainable energy and electricity system. Large-scale renewable energy adoption should include measures to improve efficiency of existing nonrenewable sources which still have an important cost reduction and stabilization role. A resilient grid with advanced energy storage for storage and absorption of variable renewables should also be part of the transition strategies. From this study, it was noted that whereas sustainable development has social, economic, and environmental pillars, energy sustainability is best analysed by five-dimensional approach consisting of environmental, economic, social, technical, and institutional/political sustainability to determine resource sustainability. The energy transition requires new technology for maximum use of the abundant but intermittent renewable sources a sustainable mix with limited nonrenewable sources optimized to minimize cost and environmental impact but maintained quality, stability, and flexibility of an electricity supply system. Technologies needed for the transition are those that use conventional mitigation, negative emissions technologies which capture and sequester carbon emissions and finally technologies which alter the global atmospheric radiative energy budget to stabilize and reduce global average temperature. A sustainable electricity system needs facilitating technology, policy, strategies and infrastructure like smart grids, and models with an appropriate mix of both renewable and low carbon energy sources.
Soil Bacterial Community Along an Altitudinal Gradient in the Sumaco, a Stratovolcano in the Amazon Region
Authors: Díaz Magdalena , Quiroz-Moreno Cristian , Jarrín-V Pablo , Piquer-Esteban Samuel , Monfort-Lanzas Pablo , Rivadeneira Erika , Castillejo Pablo , Arnau Vicente , Díaz Wladimiro , Sangari Félix J. , Molina C. Alfonso
Published: March 2022

Our study is a pioneering exploration of the microbiome in the soil of the Sumaco stratovolcano and an assessment of the effects of an elevational gradient and related physicochemical soil parameters on richness and community structure. The Sumaco, as an isolated Amazonian stratovolcano, may be among one of the least studied ecosystems in Ecuador and perhaps the Amazon region. Universal patterns remain unresolved or available information inconclusive to establish a supported consensus on general governing processes by which elevation and its associated environmental gradients may determine the microbial richness and community structure. We tested a recent proposal on how microbial diversity responds to montane gradients, placing a central role in soils as potentially independent of altitude along an elevational gradient. Correlations and effects among soil physicochemical parameters and altitude were contrasted against richness and community structure through quantitative ecology. The most informative physicochemical parameter in our assessment of bacterial community structure was neither pH nor altitude, but sulfur, which was mostly independent of the other tested parameters. We established a positive effect of richness by parameters associated with metallic cations such as Mn2+, and CEC, which were negatively correlated to altitude and pH. The possible relation between the significant role of sulfur on bacterial community structure with the unique geological origin of the Sumaco stratovolcano should be examined in the context of specialized sulfur metabolisms and additional information on community structure and environmental constraints. Our study establishes an initial baseline for further explorations of microbial diversity in this unexplored tropical stratovolcano.
IPRS: Leveraging Gene-Environment Interaction to Reconstruct Polygenic Risk Score
Authors: Tang Yingdan , You Dongfang , Yi Honggang , Yang Sheng , Zhao Yang
Published: March 2022

Background: Polygenic risk score (PRS) is widely regarded as a predictor of genetic susceptibility to disease, applied to individuals to predict the risk of disease occurrence. When the gene-environment (G×E) interaction is considered, the traditional PRS prediction model directly uses PRS to interact with the environment without considering the interactions between each variant and environment, which may lead to prediction performance and risk stratification of complex diseases are not promising.

Methods: We developed a method called interaction PRS (iPRS), reconstructing PRS by leveraging G×E interactions. Two extensive simulations evaluated prediction performance, risk stratification, and calibration performance of the iPRS prediction model, and compared it with the traditional PRS prediction model. Real data analysis was performed using existing data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial study to predict genetic susceptibility, pack-years of smoking history, and G×E interactions in patients with lung cancer.

Results: Two extensive simulations indicated iPRS prediction model could improve the prediction performance of disease risk, the accuracy of risk stratification, and clinical calibration performance compared with the traditional PRS prediction model, especially when antagonism accounted for the majority of the interaction. PLCO real data analysis also suggested that the iPRS prediction model was superior to the PRS prediction model in predictive effect (p = 0.0205).

Conclusion: IPRS prediction model could have a good application prospect in predicting disease risk, optimizing the screening of high-risk populations, and improving the clinical benefits of preventive interventions among populations.
TMEM199-Congenital Disorder of Glycosylation With Novel Phenotype and Genotype in a Chinese Boy
Authors: Fang Yuan , Abuduxikuer Kuerbanjiang , Wang Yi-Zhen , Li Shao-Mei , Chen Lian , Wang Jian-She
Published: March 2022

Background: TMEM199-congenital disorder of glycosylation (TMEM199-CDG) is a rare autosomal recessive inherited disease characterized by chronically elevated serum transaminase, decreased serum ceruloplasmin, steatosis and/or fibrosis, TMEM199 mutation, reduced level of TMEM199 protein, and abnormal protein glycosylation.

Methods: The information of a Chinese patient with TMEM199-CDG in the Children’s Hospital of Fudan University was reviewed. The patient’s clinical, pathological, and molecular features were obtained by clinical data study, liver biopsy, immunohistochemistry, and molecular genetic analysis.

Results: A 4-year-old Chinese boy presented with hypertransaminasemia, hypercholesterolemia, elevated alkaline phosphatase, decreased serum ceruloplasmin and serum copper level, and coagulopathy since birth. To the best of our knowledge, novel findings included strabismus, cirrhosis by liver biopsy, reduced expression of TMEM199 by immunohistochemistry, and a frameshift variant of c.128delA/p.Lys43Argfs*25 in the TMEM199 gene.

Conclusion: This case added to the phenotypic and genotypic spectrum of TMEM199-CDG.
Identification of Hub Genes With Differential Correlations in Sepsis
Authors: Sheng Lulu , Tong Yiqing , Zhang Yi , Feng Qiming
Published: March 2022

As a multifaceted syndrome, sepsis leads to high risk of death worldwide. It is difficult to be intervened due to insufficient biomarkers and potential targets. The reason is that regulatory mechanisms during sepsis are poorly understood. In this study, expression profiles of sepsis from GSE134347 were integrated to construct gene interaction network through weighted gene co-expression network analysis (WGCNA). R package DiffCorr was utilized to evaluate differential correlations and identify significant differences between sepsis and healthy tissues. As a result, twenty-six modules were detected in the network, among which blue and darkred modules exhibited the most significant associations with sepsis. Finally, we identified some novel genes with opposite correlations including ZNF366, ZMYND11, SVIP and UBE2H. Further biological analysis revealed their promising roles in sepsis management. Hence, differential correlations-based algorithm was firstly established for the discovery of appealing regulators in sepsis.
“Some They Need Male, Some They Need Female”: A Gendered Approach for Breast Cancer Detection in Uganda
Authors: Ikhile Deborah , Omodara Damilola , Seymour-Smith Sarah , Musoke David , Gibson Linda
Published: March 2022

Introduction

There are several challenges associated with breast cancer detection in Uganda and other low-and-middle-income countries. One of the identified challenges is attributed to the health workers' gender, which facilitates gender disparities in access to breast cancer detection services. Although this challenge is well acknowledged in existing literature, there are hardly any studies on how it can be addressed. Therefore, drawing on an intersectionality lens, our study examined how to address gender disparities facilitated by health workers' gender in accessing breast cancer detection services in Uganda.

Materials and Methods

We collected qualitative data through semi-structured interviews with twenty participants comprising community health workers, primary health care practitioners, non-governmental organizations, district health team, and the Ministry of Health. For the data analysis, thematic analysis was conducted on NVivo using Braun and Clarke's non-linear 6-step process to identify the themes presented in the results section.

Results

Four themes emerged from the data analysis: understanding a woman's gender constructions; health workers' approachability; focus on professionalism, not sex; and change in organizational culture. These themes revealed participants' perceptions regarding how to address gender disparities relating to the role health workers' gender play in breast cancer detection. Through the intersectionality lens, our findings showed how gender intersects with other social stratifiers such as religious beliefs, familial control, health worker's approachability, and professionalism within the health workforce.

Conclusion

Our findings show that the solutions to address gender disparities in breast cancer detection are individually and socially constructed. As such, we recommend a gendered approach to understand and redress the underlying power relations perpetuating such constructions. We conclude that taking a gendered approach will ensure that breast cancer detection programs are context-appropriate, cognizant of the prevailing cultural norms, and do not restrict women's access to breast cancer detection services.
A Novel m1A-Score Model Correlated With the Immune Microenvironment Predicts Prognosis in Hepatocellular Carcinoma
Authors: Zhao Mingxing , Shen Shen , Xue Chen
Published: March 2022

RNA methylation plays crucial roles in gene expression and has been indicated to be involved in tumorigenesis, while it is still unclear whether m1A modifications have potential roles in the prognosis of hepatocellular carcinoma (HCC). In this study, we comprehensively analyzed RNA sequencing (RNA-seq) data and clinical information using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We collected 10 m1A regulators and performed consensus clustering to determine m1A modification patterns in HCC. The CIBERSORT method was utilized to evaluate the level of immune cell infiltration. Principal component analysis was used to construct the m1A-score model. In the TCGA-LIHC cohort, the expression of all 10 m1A regulators was higher in tumor tissues than in normal control tissues, and 8 of 10 genes were closely related to the prognosis of HCC patients. Two distinct m1A methylation modification patterns (Clusters C1 and C2) were identified by the 10 regulators and were associated with different overall survival, TNM stage and tumor microenvironment (TME) characteristics. Based on the differentially expressed genes (DEGs) between C1 and C2, we identified three gene clusters (Clusters A, B and C). C1 with a better prognosis was mainly distributed in Cluster C, while Cluster A contained the fewest samples of C1. An m1A-score model was constructed using five m1A regulators related to prognosis. Patients with higher m1A scores showed a poorer prognosis than those with lower scores in the TCGA-LIHC and GSE14520 datasets. In conclusions, our study showed the vital role of m1A modification in the TME and progression of HCC. Quantitative evaluation of the m1A modification patterns of individual patients facilitates the development of more effective biomarkers for predicting the prognosis of patients with HCC.
Janus Kinase Inhibitors in the Treatment of Type I Interferonopathies: A Case Series From a Single Center in China
Authors: Li Wendao , Wang Wei , Wang Wei , Zhong Linqing , Gou Lijuan , Wang Changyan , Ma Jingran , Quan Meiying , Jian Shan , Tang Xiaoyan , Zhang Yu , Wang Lin , Ma Mingsheng , Song Hongmei
Published: March 2022

Objective

This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD).

Methods

A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR.

Results

Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25–4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections.

Conclusion

The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.
The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies
Authors: Brom Victoria C. , Burger Christof , Wirtz Dieter C. , Schildberg Frank A.
Published: March 2022

Immune checkpoint inhibitors have revolutionized immunotherapy against various cancers over the last decade. The use of checkpoint inhibitors results in remarkable re-activation of patients’ immune system, but is also associated with significant adverse events. In this review, we emphasize the importance of cell-type specificity in the context of immune checkpoint-based interventions and particularly focus on the relevance of macrophages. Immune checkpoint blockade alters the dynamic macrophage phenotypes and thereby substantially manipulates therapeutical outcome. Considering the macrophage-specific immune checkpoint biology, it seems feasible to ameliorate the situation of patients with severe side effects and even increase the probability of survival for non-responders to checkpoint inhibition. Apart from malignancies, investigating immune checkpoint molecules on macrophages has stimulated their fundamental characterization and use in other diseases as well, such as acute and chronic infections and autoimmune pathologies. Although the macrophage-specific effect of checkpoint molecules has been less studied so far, the current literature shows that a macrophage-centered blockade of immune checkpoints as well as a stimulation of their expression represents promising therapeutic avenues. Ultimately, the therapeutic potential of a macrophage-focused checkpoint therapy might be maximized by diagnostically assessing individual checkpoint expression levels on macrophages, thereby personalizing an effective treatment approach for each patient having cancer, infection, or autoimmune diseases.
Core Fucosylation Regulates the Function of Pre-BCR, BCR and IgG in Humoral Immunity
Authors: Sun Yuhan , Li Xueying , Wang Tiantong , Li Wenzhe
Published: March 2022

Most of the membrane molecules involved in immune response are glycosylated. N-glycans linked to asparagine (Asn) of immune molecules contribute to the protein conformation, surface expression, stability, and antigenicity. Core fucosylation catalyzed by core fucosyltransferase (FUT8) is the most common post-translational modification. Core fucosylation is essential for evoking a proper immune response, which this review aims to communicate. First, FUT8 deficiency suppressed the interaction between μHC and λ5 during pre-BCR assembly is given. Second, we described the effects of core fucosylation in B cell signal transductionviaBCR. Third, we investigated the role of core fucosylation in the interaction between helper T (TH) cells and B cells. Finally, we showed the role of FUT8 on the biological function of IgG. In this review, we discussed recent insights into the sites where core fucosylation is critical for humoral immune responses.
Persistent Overactive Cytotoxic Immune Response in a Spanish Cohort of Individuals With Long-COVID: Identification of Diagnostic Biomarkers
Authors: Galán Miguel , Vigón Lorena , Fuertes Daniel , Murciano-Antón María Aránzazu , Casado-Fernández Guiomar , Domínguez-Mateos Susana , Mateos Elena , Ramos-Martín Fernando , Planelles Vicente , Torres Montserrat , Rodríguez-Mora Sara , López-Huertas María Rosa , Coiras Mayte
Published: March 2022

Long-COVID is a new emerging syndrome worldwide that is characterized by the persistence of unresolved signs and symptoms of COVID-19 more than 4 weeks after the infection and even after more than 12 weeks. The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.
Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants
Authors: Hu Ye-Fan , Hu Jing-Chu , Gong Hua-Rui , Danchin Antoine , Sun Ren , Chu Hin , Hung Ivan Fan-Ngai , Yuen Kwok Yung , To Kelvin Kai-Wang , Zhang Bao-Zhong , Yau Thomas , Huang Jian-Dong
Published: March 2022

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus–antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus–antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.
Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders
Authors: Tastan Bora , Arioz Burak I. , Genc Sermin
Published: March 2022

The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.