bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients
Authors: van der Voorn Stephanie M. , Bourfiss Mimount , te Riele Anneline S. J. M. , Taha Karim , Vos Marc A. , de Brouwer Remco , Verstraelen Tom E. , de Boer Rudolf A. , Remme Carol Ann , van Veen Toon A. B.
Published: January 2022

Background: Pathogenic variants in phospholamban (PLN, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP).

Aim: To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in PLN p.Arg14del variant carriers.

Methods: Serum and EDTA blood samples were collected from 72 PLN p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (n = 12), DCM (n = 14), and preclinical variant carriers (n = 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records.

Results: No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both rs = 0.40, n = 23, p = 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4–V6, II, III, and aVF (p < 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (p = 0.007).

Conclusion: High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in PLN p.Arg14del patients.
Study on Mechanical Problems of Complex Rock Mass by Composite Material Micromechanics Methods: A Literature Review
Authors: He Junzhao , Li Yunan , Jin Yuling , Wang Anming , Zhang Yumin , Jia Jinchao , Song Hei , Liang Dong
Published: January 2022

The mechanical analysis of complex rock mass is a difficult problem, which often occurs in scientific research and practical engineering. Many achievements have been made in the study of rock mass composite problems by composite material micromechanics method, but it has not been well summarized so far. This paper summarizes in detail the research status of complex rock mass problems by composite material micromechanics method at home and abroad, including the application of the Eshelby equivalent inclusion theory and self-consistent model in rock mass composite problems, and the application of the homogenization method in jointed rock mass and other rock mass composite problems such as anchored rock mass, layered rock mass, and salt rock mass with impurities. It is proposed that the structural similarity and mechanical analysis similarity should be satisfied when the composite material micromechanics method is used to study the complex rock mass. Finally, the problems that need to be further studied are put forward. The research results provide a valuable reference for the study of complex rock mass by the composite material micromechanics method.
Outcome of COVID19 in Patients With Osteogenesis Imperfecta: A Retrospective Multicenter Study in Saudi Arabia
Authors: Alshukairi Abeer N. , Doar Hazem , Al-Sagheir Afaf , Bahasan Mona A. , Sultan Anas A. , Al Hroub Mohammad K. , Itani Dina , Khalid Imran , Saeedi Mohammed F. , Bakhamis Sarah , Layqah Laila , Almutairi Afnan A. , Saifullah Mona , Hefni Lama , Al-Omari Awad , Alraddadi Basem M. , Baharoon Salim A.
Published: January 2022

Background

Although genetic diseases are rare, children with such conditions who get infected with COVID-19 tend to have a severe illness requiring hospitalization. Osteogenesis imperfecta (OI) is a rare genetic disorder of collagen resulting in fractures and skeletal deformities. Kyphoscoliosis, restrictive lung disease, and pneumonia worsen the prognosis of patients with OI. The use of bisphosphonate improves bone mineral density (BMD) and reduces fractures in OI. There is no literature describing the impact of COVID-19 in patients with OI.

Methodology

A retrospective multi-center study was performed in three hospitals in Jeddah and Riyadh, Saudi Arabia, from March 1st, 2020, until August 31st, 2021, aiming to evaluate the outcome of COVID-19 in patients with OI. Demographics, vaccination status, underlying kyphoscoliosis, functional status, use of bisphosphonate, BMD, and COVID-19 severity, and course were recorded for all patients.

Results

Twelve cases of confirmed COVID-19 were identified among 146 patients with OI. 9 (75%) of patients were less than 18 years, 6 (50%) were male, 5 (41%) had kyphoscoliosis, and 5 (41%) were wheelchair-bound. 6 (50%) received bisphosphonate, and 7(58%) had normal BMD. All patients had mild disease and did not require hospitalization. None of OI the patients with COVID-19 were fully vaccinated before the infection, and some were ineligible for vaccination.

Conclusion

Patients with OI and COVID-19 in our study recovered without complications, unlike patients with other genetic diseases. Young age and mild illness contributed to the favorable outcome. Half of the patients received bisphosphonate and had normal BMD.
Association Between Pre-Pregnancy Body Mass Index and Maternal and Neonatal Outcomes of Singleton Pregnancies After Assisted Reproductive Technology
Authors: Sun Hanxiang , Liu Yang , Huang Shijia , Liu Xiaosong , Li Guohua , Du Qiaoling
Published: January 2022

Objective

To study the association between pre-pregnancy body mass index (BMI) and adverse maternal and neonatal outcomes of singleton pregnancies after assisted reproductive technology (ART).

Methods

This hospital-based retrospective cohort study of women with live singleton births through ART in China from January 2015 to August 2020 included 3043 Chinese women. According to the latest BMI classification standard of Asian women, the women included in this study were classified as underweight (BMI <18.5 kg/m2), normal (BMI 18.5 to <23 kg/m2), overweight (BMI 23 to <27.5 kg/m2), and obese (BMI ≥27.5 kg/m2). We compared the risk of adverse outcomes of different pre-pregnancy BMI values of women with singleton pregnancies conceived through ART. We used Logistic regression analysis to estimate the associations between pre-pregnancy BMI and adverse perinatal and neonatal outcomes.

Results

Our findings showed that women who were overweight or obese before pregnancy through ART are more likely to have a cesarean section, gestational diabetes mellitus, gestational hypertension, and preeclampsia, regardless of whether confounding factors are adjusted. Moreover, pre-pregnancy obesity was more associated with a higher risk of these adverse outcomes than pre-pregnancy overweight. In addition, neonates from women who had obesity before pregnancy through ART were more likely to have macrosomia; adjusted odds ratios and 95% confidence intervals were 3.004 (1.693-5.330).

Conclusions

Our research showed that women who had pre-pregnancy overweight or obesity with singleton pregnancies through ART were more likely to have a cesarean section, gestational diabetes mellitus, gestational hypertension, and preeclampsia. Moreover, neonates from women who had obesity before pregnancy were more likely to have macrosomia.
A Control Parameters Design Method With Multi-Constrains for an LCL-Filtered Grid-Connected Inverter in a Weak Grid
Authors: Wu Fuyun , Sun Zhuang , Xu Weiji , Li Zhizhou , Lyu Jianguo
Published: January 2022

Under weak grid conditions, the variation of the grid impedance will affect the steady-state and dynamic performance of the LCL-filtered grid-connected inverter and even make the inverter unstable. To ensure the system stability and further improve the dynamic performance in a weak grid, a control parameter design method with multi-constrains considering the system bandwidth for the current controller and active damping is proposed in this paper. First, based on the current controller and active damping with only grid current feedback, the effects of control parameters and grid impedance on the LCL resonant suppression and the performance of the inverter are analyzed. Moreover, the parameter constraints of the controllers are derived considering the grid impedance, including stability, resonance suppression, and margin constraints. Furthermore, as the system bandwidth affects the dynamic performance of the inverter, combined with the obtained multi-constraints, the optimal control parameters are determined by achieving the maximum bandwidth of the system against the impedance variation. Compared with other two methods, when the proposed method is applied, the system can operate with a better dynamic and steady-state performance. Finally, experiments are performed on a 2 kW three-phase grid-connected inverter in the weak grid, which verify the effectiveness of the parameter design method proposed in this paper.
Operation Energy Consumption Study on Reel and Polyethylene Tube of a New Hard Hose Traveler
Authors: Xu Zhengdian , Li Hong , Jiang Yue , Xiang Qingjiang , Tang Pan
Published: January 2022

To solve the problems of higher energy consumption and lower intelligence of traditional hard hose travelers, a new hard hose traveler with the function of electric drive and self-propelled is developed in this paper. The operational energy consumption of a reel and a polyethylene tube is an important part of hard-hose traveler energy consumption. In this paper, based on the JP50-180 hard hose traveler, the required pulling force and energy consumption at the reel and tube operation are theoretically and experimentally obtained. The aforementioned provides support for reducing energy consumption in the future. The influencing factor that affects the energy consumption of the reel rotation is the tube length, and the influencing factors that affect the energy consumption of the tube sliding are the ground slope, soil moisture content, and tube length. A calculation model for the dynamic change of the pulling force and energy consumption of the reel and tube operation is proposed in this study. Through theoretical analysis, maximum pulling tension and cumulative energy consumption requirements for the for reel rotation are 278.6 N and 15120.83 J, respectively. Furthermore, the requirements for the tube sliding are 1372.86 N and 123,456.96 J. Through test analysis, the maximum pulling tension for the tube sliding is between 1258.3 N and 1773.3 N, while the maximum pulling tension for reel rotation is 285.05 N. Under the same influencing factors, the deviation rates between theoretical and testable energy consumption for the reel rotation and tube sliding are 2.3 and 8.3%, respectively. The pulling force and cumulative energy consumption required for the reel rotation and tube sliding both increase with an increase in their influencing factors. The operating costs of the tube one-time unrolled are approximately 0.0185 CNY. Combined with the mobile resistance of the electric tracked vehicle, the power configuration of this new hard hose traveler is provided by two servo motors with a power of 5500 W each.
Selectivity Control of C-O Bond Cleavage for Catalytic Biomass Valorization
Authors: Jian Yumei , Meng Ye , Li Hu
Published: January 2022

Increasing fossil fuels consumption and global warming have driven the global revolution towards renewable energy sources. Lignocellulosic biomass is the main source of renewable carbon-based fuels. The abundant intermolecular linkages and high oxygen content between cellulose, hemicellulose, and lignin limit the use of traditional fuels. Therefore, it is a promising strategy to break the above linkages and remove oxygen by selective catalytic cracking of C–O bond to further transform the main components of biomass into small molecular products. This mini-review discusses the significance of selectivity control in C–O bond cleavage with well-tailored catalytic systems or strategies for furnishing biofuels and value-added chemicals of high efficiency from lignocellulosic biomass. The current challenges and future opportunities of converting lignocellulose biomass into high-value chemicals are also summarized and analyzed.
CO2, Environmental Emergencies, and Industrial Pollution Assessment in China from the Perspective of the Circular Economy
Authors: Zhang Min , Ren Fang-rong , Shi Ying-ying , Chen Hang-sheng , Tian Ze
Published: January 2022

The rise of energy consumption has also increased emissions of the “three wastes” (wastewater, waste gas, and industrial solid waste), and environmental emergencies caused by pollutants, natural disasters, and production safety accidents have aroused social concerns. As few scholars have combined treatment efficiency of the three wastes with environmental emergencies to explore their relationships, this research thus uses a two-stage undesirable Data Envelopment Analysis (DEA) method to explore the situations of 4 regions and 30 provinces in China from 2013 to 2017 based on such interactive perspectives. The study finds that the overall regional environmental efficiency in China is generally low, and in terms of regional differences, the eastern and northeastern regions are better than the central and western regions. The efficiency values of the three wastes in China have also fluctuated greatly from 0.7 down to 0.2 in recent years. The efficiency of environmental emergencies in China is greatly impacted by the efficiency of environmental governance inputs. Based on the results, the study proposes that the eastern provinces can be an example for promoting balanced regional development and offers policy recommendations such as taking precautions against environmental emergencies.
Great Tits Learn Odors and Colors Equally Well, and Show No Predisposition for Herbivore-Induced Plant Volatiles
Authors: Rubene Diana , Urhan Utku , Ninkovic Velemir , Brodin Anders
Published: January 2022

Ability to efficiently localize productive foraging habitat is crucial for nesting success of insectivorous birds. Some bird species can use olfaction to identify caterpillar-infested trees by detection of herbivore induced plant volatiles (HIPVs), but these cues probably need to be learned. So far, we know very little about the process of olfactory learning in birds, whether insectivorous species have a predisposition for detecting and learning HIPVs, due to the high ecological significance of these odors, and how olfaction is integrated with vision in making foraging decisions. In a standardized setup, we tested whether 35 wild-caught great tits (Parus major) show any preference for widely abundant HIPVs compared to neutral (non-induced) plant odors, how fast they learn to associate olfactory, visual and multimodal foraging cues with food, and whether the olfactory preferences and learning speed were influenced by bird sex or habitat (urban or rural). We also tested how fast birds switch to a new cue of the same modality. Great tits showed no initial preference for HIPVs compared to neutral odors, and they learned all olfactory cues at a similar pace, except for methyl salicylate (MeSA), which they learned more slowly. We also found no differences in learning speeds between visual, olfactory and multimodal foraging cues, but birds learned the second cue they were offered faster than the first one. Bird sex or habitat had no effect on learning speed or olfactory preference, but urban birds tended to learn visual cues more slowly. We conclude that insectivorous birds utilize olfactory and visual cues with similar efficiency in foraging, and that they probably don‘t have any special predisposition toward the tested HIPVs. These results confirm that great tits are flexible foragers with good learning abilities.
Functional Responses of Phytoplankton Assemblages to Watershed Land Use and Environmental Gradients
Authors: Du Xue , Song Dan , Ming Kun , Yang Jingshuang , Jin Xing , Wang Huibo , Liu Hui , Wang Le , Zhao Chen , Huo Tangbin
Published: January 2022

Watershed land-use changes have been identified as major threats to lake fauna, subsequently affecting ecosystem functioning. In this study, the functional-based approach was used to examine the effects of land use and environmental changes on phytoplankton communities in four selected lakes in Northeast China. We also identified the sensitive functional traits as indicators of environmental stressors. The integration of RLQ analysis with the fourth-corner approach significantly identified five of 18 functional trait categories, including flagella, filamentous, unicellular, mixotrophic, and chlorophyll c, as potential indicators to changes in watershed land-use intensity and environmental gradients. Significant relationships between traits and land use and water quality highlighted the consequential indirect impact of extensive agricultural and urban development on phytoplankton via allochthonous nutrient inputs and various contaminants. In addition, the functional richness of phytoplankton assemblages generally increased along with surface area and forests, but decreased along with intensive agricultural and urban land use, implying that functional homogenization may cause a reduction in ecosystem productivity and reliability to land-use intensity. Given the superior performance of the functional-based approach, our findings also highlighted the importance of the application of both the biological traits and functional diversity index in monitoring programs for lake ecosystems.
Small Angle Neutron Scattering Reveals Wood Nanostructural Features in Decay Resistant Chemically Modified Wood
Authors: Ibach Rebecca E. , Plaza Nayomi Z. , Pingali Sai Venkatesh
Published: January 2022

While it is known that modifying the hydroxyls in wood can improve the decay resistance; what is often missing in the literature is whether these modifications alter wood nanostructure, and how these changes correlate to the improved decay resistance. Here, we used small angle neutron scattering (SANS) to probe the effects of alkylene oxide modifications on wood nanostructure. Southern pine wood samples were chemically modified to various weight percentage gains (WPG) using four different alkylene oxides: propylene oxide (PO), butylene oxide (BO), epichlorohydrin (EpH), and epoxybutene (EpB). After modification, the samples were water leached for 2 weeks to remove any unreacted reagents or homopolymers and then equilibrium moisture content (EMC) was determined at 90% relative humidity (RH) and 27°C. Laboratory soil block decay evaluations against the brown rot fungus Gloeophyllum trabeum were performed to determine weight loss and biological efficacy of the modifications. To assist in understanding the mechanism, SANS was used to study samples that were fully immersed in deuterium oxide (D2O). These measurements revealed that the modifications altered the water distribution inside the cell wall, and the most effective modifications reduced the microfibril swelling and preserved the microfibril structure even after being subject to 12 weeks of brown rot exposure.
Comprehensive Assessment of Serum hsa_circ_0070354 as a Novel Diagnostic and Predictive Biomarker in Non-small Cell Lung Cancer
Authors: Huang Yuejiao , Qin Shiyi , Gu Xinliang , Zheng Ming , Zhang Qi , Liu Yupeng , Cheng Chun , Huang Kaibin , Peng Chunlei , Ju Shaoqing
Published: January 2022

Background: More and more studies have shown that circular RNAs (circRNAs) play an essential role in the occurrence and development of tumors. Hence, they can be used as biomarkers to assist in diagnosing tumors. This study focuses on exploring the role of circular RNA (hsa_circ_0070354) in the diagnosis and prognosis of non-small cell lung cancer (NSCLC).

Materials and Methods: First of all, high-throughput sequencing was used to find the difference in the expression of circular RNA between NSCLC and adjacent tissues. The circRNAs with higher differences in expression were selected to verify their expressions in tissues, cells, and serum using qRT-PCR. Secondly, the hsa_circ_0070354 with a significant difference was chosen as the research goal, and the molecular properties were verified by agarose gel electrophoresis and Sanger sequencing, etc. Then, actinomycin D and repeated freeze-thaw were used to explore the stability and repeatability of hsa_circ_0070354. Finally, the expression of hsa_circ_0070354 in serum of 133 patients with NSCLC and 97 normal donors was detected, and its sensitivity, specificity, and prognosis as tumor markers were statistically analyzed.

Results: Hsa_circ_0070354 was highly expressed in tissues, cells, and serum of NSCLC, and it has the characteristics of sensitivity, stability, and repeatability. The ROC curve indicates that hsa_circ_0070354 is superior to conventional tumor markers in detecting NSCLC, and the combined diagnosis is of more significance in the diagnosis. The high expression of hsa_circ_0070354 is closely related to the late-stage, poor differentiation of the tumor and the short survival time of the patients, which is an independent indicator of poor prognosis.

Conclusion: Hsa_circ_0070354 is not only a novel sensitive index for the diagnosis of NSCLC but also a crucial marker for bad biological behavior.
The Antibacterial Activity of Erythrocytes From Goose (Anser domesticus) Can Be Associated With Phagocytosis and Respiratory Burst Generation
Authors: Yang Youcheng , Chen Jiajun , Lu Linqing , Xu Zizheng , Li Feng , Yang Minxuan , Li Jun , Lin Li , Qin Zhendong
Published: January 2022

In the lumen of blood vessels, there are large numbers of erythrocytes, which are approximately 95% of the total blood cells. Although the function of erythrocytes is to transport oxygen in the organism, recent studies have shown that mammalian and teleost erythrocytes are involved in the immune response against bacterial infections. However, the immune mechanisms used by avian erythrocytes are not yet clear. Here, we demonstrated that erythrocytes from goose have the ability to phagocytose as well as conduct antimicrobial activity. Firstly, we revealed the phagocytosis or adhesion activity of goose erythrocytes for latex beads 0.1-1.0 μm in diameter by fluorescence microscopy, and scanning and transmission electron microscopy. The low cytometry results also proved that goose erythrocytes had a wide range of phagocytic or adhesion activity for different bacteria. Followed, the low cytometry analysis data further explored that the goose erythrocytes contain the ability to produce reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) in response to bacterial stimulation, and also up-regulated the expression of NOX family includes NOX1 and NOX5. Finally, we also found that goose erythrocytes showed a powerful antibacterial activity against all the three bacteria, meanwhile the stimulation of three kinds of bacteria up-regulated the expression of inflammatory factors, and increased the production of antioxidant enzymes to protect the cells from oxidative damage. Herein, our results demonstrate that goose Erythrocytes possess a certain phagocytic capacity and antioxidant system, and that the antimicrobial activity of erythrocytes can occurred through the production of unique respiratory burst against foreign pathogenic bacteria, which provides new clues to the interaction between bacteria and avian erythrocytes.
Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II
Authors: Tang Lili , Li Ge , Zheng Yang , Hou Chunmei , Gao Yang , Hao Ying , Gao Zhenfang , Mo Rongliang , Li Yuxiang , Shen Beifen , Wang Renxi , Wang Zhiding , Han Gencheng
Published: January 2022

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.
Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration
Authors: Henriques-Pons Andrea , Beghini Daniela Gois , Silva Vanessa dos Santos , Iwao Horita Samuel , Silva Fabrício Alves Barbosa da
Published: January 2022

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the “cytokine storm” observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.
Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia
Authors: Sasahara Yoji , Uchida Takashi , Suzuki Tasuku , Abukawa Daiki
Published: January 2022

Background

Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders.

Aim

This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia.

Methods

A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted.

Results

The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved.

Conclusion

Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.
Combination of Tertiary Lymphoid Structure and Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients With Hepatocellular Carcinoma
Authors: Wen Shaodi , Chen Yuzhong , Hu Chupeng , Du Xiaoyue , Xia Jingwei , Wang Xin , Zhu Wei , Wang Qingbo , Zhu Miaolin , Chen Yun , Shen Bo
Published: January 2022

Background

Hepatocellular carcinoma (HCC) is the most common pathological type of primary liver cancer. The lack of prognosis indicators is one of the challenges in HCC. In this study, we investigated the combination of tertiary lymphoid structure (TLS) and several systemic inflammation parameters as a prognosis indicator for HCC.

Materials and Methods

We retrospectively recruited 126 postoperative patients with primary HCC. The paraffin section was collected for TLS density assessment. In addition, we collected the systemic inflammation parameters from peripheral blood samples. We evaluated the prognostic values of those parameters on overall survival (OS) using Kaplan-Meier curves, univariate and multivariate Cox regression. Last, we plotted a nomogram to predict the survival of HCC patients.

Results

We first found TLS density was positively correlated with HCC patients’ survival (HR=0.16, 95% CI: 0.06 − 0.39, p < 0.0001), but the power of TLS density for survival prediction was found to be limited (AUC=0.776, 95% CI:0.772 − 0.806). Thus, we further introduced several systemic inflammation parameters for survival analysis, we found neutrophil-to-lymphocyte ratio (NLR) was positively associated with OS in univariate Cox regression analysis. However, the combination of TLS density and NLR better predicts patient’s survival (AUC=0.800, 95% CI: 0.698-0.902, p < 0.001) compared with using any single indicator alone. Last, we incorporated TLS density, NLR, and other parameters into the nomogram to provide a reproducible approach for survival prediction in HCC clinical practice.

Conclusion

The combination of TLS density and NLR was shown to be a good predictor of HCC patient survival. It also provides a novel direction for the evaluation of immunotherapies in HCC.
Disease-Modifying Drug Uptake and Health Service Use in the Ageing MS Population
Authors: Ng Huah Shin , Graf Jonas , Zhu Feng , Kingwell Elaine , Aktas Orhan , Albrecht Philipp , Hartung Hans-Peter , Meuth Sven G. , Evans Charity , Fisk John D. , Marrie Ruth Ann , Zhao Yinshan , Tremlett Helen
Published: January 2022

Background

Evidence regarding the efficacy or effectiveness of the disease-modifying drugs (DMDs) in the older multiple sclerosis (MS) population is scarce. This has contributed to a lack of evidence-based treatment recommendations for the ageing MS population in practice guidelines. We examined the relationship between age (<55 and ≥55 years), DMD exposure and health service use in the MS population.

Methods

We conducted a population-based observational study using linked administrative health data from British Columbia, Canada. We selected all persons with MS and followed from the most recent of their first MS or demyelinating event, 18th birthday or 01-January-1996 (index date) until the earliest of emigration, death or 31-December-2017 (study end). We assessed DMD exposure status over time, initially as any versus no DMD, then by generation (first or second) and finally by each individual DMD. Age-specific analyses were conducted with all-cause hospitalizations and number of physician visits assessed using proportional means model and negative binomial regression with generalized estimating equations.

Results

We included 19,360 persons with MS (72% were women); 10,741/19,360 (56%) had ever reached their 55th birthday. Person-years of follow-up whilst aged <55 was 132,283, and 93,594 whilst aged ≥55. Any DMD, versus no DMD in the <55-year-olds was associated with a 23% lower hazard of hospitalization (adjusted hazard ratio, aHR0.77; 95%CI 0.72-0.82), but not in the ≥55-year-olds (aHR0.95; 95%CI 0.87-1.04). Similar patterns were observed for the first and second generation DMDs. Exposure to any (versus no) DMD was not associated with rates of physician visits in either age group (<55 years: adjusted rate ratio, aRR1.02; 95%CI 1.00-1.04 and ≥55 years: aRR1.00; 95%CI 0.96-1.03), but variation in aRR was observed across the individual DMDs.

Conclusion

Our study showed beneficial effects of the DMDs used to treat MS on hospitalizations for those aged <55 at the time of exposure. In contrast, for individuals ≥55 years of age exposed to a DMD, the hazard of hospitalization was not significantly lowered. Our study contributes to the broader understanding of the potential benefits and risks of DMD use in the ageing MS population.
Neutrophils Lose the Capacity to Suppress T Cell Proliferation Upon Migration Towards Inflamed Joints in Juvenile Idiopathic Arthritis
Authors: Arve-Butler Sabine , Mossberg Anki , Schmidt Tobias , Welinder Charlotte , Yan Hong , Berthold Elisabet , Król Petra , Kahn Robin
Published: January 2022

Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4+T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in anin vitrotransmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4+T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.
Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes
Authors: Barcenilla Hugo , Pihl Mikael , Wahlberg Jeanette , Ludvigsson Johnny , Casas Rosaura
Published: January 2022

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.
When a Friend Becomes Your Enemy: Natural Killer Cells in Atherosclerosis and Atherosclerosis-Associated Risk Factors
Authors: Palano Maria Teresa , Cucchiara Martina , Gallazzi Matteo , Riccio Federica , Mortara Lorenzo , Gensini Gian Franco , Spinetti Gaia , Ambrosio Giuseppe , Bruno Antonino
Published: January 2022

Atherosclerosis (ATS), the change in structure and function of arteries with associated lesion formation and altered blood flow, is the leading cause of cardiovascular disease, the number one killer worldwide. Beyond dyslipidemia, chronic inflammation, together with aberrant phenotype and function of cells of both the innate and adaptive immune system, are now recognized as relevant contributors to atherosclerosis onset and progression. While the role of macrophages and T cells in atherosclerosis has been addressed in several studies, Natural Killer cells (NKs) represent a poorly explored immune cell type, that deserves attention, due to NKs’ emerging contribution to vascular homeostasis. Furthermore, the possibility to re-polarize the immune system has emerged as a relevant tool to design new therapies, with some succesfull exmples in the field of cancer immunotherapy. Thus, a deeper knowledge of NK cell pathophysiology in the context of atherosclerosis and atherosclerosis-associated risk factors could help developing new preventive and treatment strategies, and decipher the complex scenario/history from “the risk factors for atherosclerosis” Here, we review the current knowledge about NK cell phenotype and activities in atherosclerosis and selected atherosclerosis risk factors, namely type-2 diabetes and obesity, and discuss the related NK-cell oriented environmental signals.
β2-Adrenoceptor Deficiency Results in Increased Calcified Cartilage Thickness and Subchondral Bone Remodeling in Murine Experimental Osteoarthritis
Authors: Rösch Gundula , Muschter Dominique , Taheri Shahed , El Bagdadi Karima , Dorn Christoph , Meurer Andrea , Zaucke Frank , Schilling Arndt F. , Grässel Susanne , Straub Rainer H. , Jenei-Lanzl Zsuzsa
Published: January 2022

Purpose

Recent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/-) mice after surgical OA induction.

Methods

OA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.

Results

WT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.

Conclusion

We propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.
The Interplay Between Neuroinfections, the Immune System and Neurological Disorders: A Focus on Africa
Authors: Ngarka Leonard , Siewe Fodjo Joseph Nelson , Aly Esraa , Masocha Willias , Njamnshi Alfred K.
Published: January 2022

Neurological disorders related to neuroinfections are highly prevalent in Sub-Saharan Africa (SSA), constituting a major cause of disability and economic burden for patients and society. These include epilepsy, dementia, motor neuron diseases, headache disorders, sleep disorders, and peripheral neuropathy. The highest prevalence of human immunodeficiency virus (HIV) is in SSA. Consequently, there is a high prevalence of neurological disorders associated with HIV infection such as HIV-associated neurocognitive disorders, motor disorders, chronic headaches, and peripheral neuropathy in the region. The pathogenesis of these neurological disorders involves the direct role of the virus, some antiretroviral treatments, and the dysregulated immune system. Furthermore, the high prevalence of epilepsy in SSA (mainly due to perinatal causes) is exacerbated by infections such as toxoplasmosis, neurocysticercosis, onchocerciasis, malaria, bacterial meningitis, tuberculosis, and the immune reactions they elicit. Sleep disorders are another common problem in the region and have been associated with infectious diseases such as human African trypanosomiasis and HIV and involve the activation of the immune system. While most headache disorders are due to benign primary headaches, some secondary headaches are caused by infections (meningitis, encephalitis, brain abscess). HIV and neurosyphilis, both common in SSA, can trigger long-standing immune activation in the central nervous system (CNS) potentially resulting in dementia. Despite the progress achieved in preventing diseases from the poliovirus and retroviruses, these microbes may cause motor neuron diseases in SSA. The immune mechanisms involved in these neurological disorders include increased cytokine levels, immune cells infiltration into the CNS, and autoantibodies. This review focuses on the major neurological disorders relevant to Africa and neuroinfections highly prevalent in SSA, describes the interplay between neuroinfections, immune system, neuroinflammation, and neurological disorders, and how understanding this can be exploited for the development of novel diagnostics and therapeutics for improved patient care.
Corilagin Ameliorates Con A-Induced Hepatic Injury by Restricting M1 Macrophage Polarization
Authors: Yan Fenglian , Cheng Dalei , Wang Haiyan , Gao Min , Zhang Junfeng , Cheng Hongyan , Wang Changying , Zhang Hui , Xiong Huabao
Published: January 2022

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.