bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating Choline and Specific Intestinal Microbiota to Classify Type 2 Diabetes in Adults: A Machine Learning Based Metagenomics Study
Authors: Zeng Qiang , Zhao Mingming , Wang Fei , Li Yanping , Li Huimin , Zheng Jianqiong , Chen Xianyang , Zhao Xiaolan , Ji Liang , Gao Xiangyang , Liu Changjie , Wang Yu , Cheng Si , Xu Jie , Pan Bing , Sun Jing , Li Yongli , Li Dongfang , He Yuan , Zheng Lemin
Published: June 2022

Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris, Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes.
Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme
Authors: Pablos Marta , Casanueva-Álvarez Elena , González-Casimiro Carlos M. , Merino Beatriz , Perdomo Germán , Cózar-Castellano Irene
Published: June 2022

The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.
Negative Emission Power Plants: Thermodynamic Modeling and Evaluation of a Biomass-Based Integrated Gasification Solid Oxide Fuel Cell/Gas Turbine System for Power, Heat, and Biochar Co-Production—Part 1
Authors: Jaiganesh N. , Kuo Po-Chih , Woudstra Theo , Ajith Kumar R. , Aravind P. V.
Published: June 2022

This article is the first of a two-part series presenting the thermodynamic evaluation and techno-economics of developing negative-emission power plants. The aim of this research is to evaluate the potential of biochar co-production in negative-emission power plants based on biomass-fed integrated gasification solid oxide fuel cell systems with carbon capture and storage (BIGFC/CCS) units. The influence of two gasification agents, namely, air and steam-oxygen, on the proposed system is investigated. In Part I, we present the thermodynamic models. A sensitivity analysis is carried out to investigate the system response to stepwise increase in biochar co-production (up to 10% by weight). Providing a secondary oxy-combustor in the steam-oxygen gasification case has been shown to be a solution to meet the heat requirements of the allothermal gasification process. A comprehensive exergy analysis indicated significant efficiency improvement for the steam-oxygen gasification case. The results show that the biomass steam-oxygen gasification yields the higher electrical exergy efficiency (48.3%) and combined heat and power (CHP) exergy efficiency (54.6%) for the similar rates of biochar co-production. The specific power output per unit of CO2 stored is 2.65 MW/(kg/s) and 3.58 MW/(kg/s) for the air and steam-oxygen gasification cases, respectively, when the biochar is co-produced at 10% by weight for the given biomass flow of 20 kg/s. Moreover, the total CO2 stored due to the proposed system is calculated as 133.9 t/h, and it is estimated to remove 1.17 Mt of CO2 from the atmosphere annually (when the biochar-based carbon storage is also considered). The models are used for the techno-economic analysis presented in Part II of the series.
Inverse Design of Local Solar Flux Distribution for a Solar Methanol Reforming Reactor Based on Shape Optimization
Authors: Tang Xinyuan , Yang Weiwei , Dai Zhouqiao , Yang Yongjian
Published: June 2022

In this work, an inverse design method that couples the multi-physics model for a solar trough thermochemical reactor (SPTR) and shape optimization model is proposed to find out optimal solar flux distribution for maximizing overall reactor performance. The gradient-based segmentation method is applied to convert the continuous solar flux into step-like flux to guide the concentrator system design. Performance comparisons among uniform flux, linear decreasing flux, and the optimized non-linear flux are also conducted to discuss the reliability of SPTR performance improvement. The results show that the optimized non-linear solar flux can improve the methanol conversion, solar thermochemical conversion, and hydrogen yield of SPTR by 2.5, 3.3, and 2.4%, respectively, compared with the uniform flux. This is attributed to the fact that the optimized non-uniform flux distribution enhances the synergy between temperature and reaction fields, and achieves a better match between spatial solar flux supply and local energy demand by reactions. Also, it is shown that the optimized step-like flux, achieved by regressing the optimized non-linear flux, can perfectly maintain SPTR performance and is effective in boosting SPTR performance under different operating conditions.
Enhanced Efficiency of the Sieve Tray in a Desulfurization Spray Scrubber
Authors: Qirong Wu , Mengli Wu , Yungui Du , Cunfang Lu , Jianhong Chen
Published: June 2022

The wet flue gas desulfurization (WFGD) system is widely used in coal-fired power plants worldwide. Improving its efficiency is very important for economical running. In this study, SO2 removal by the spray scrubber by adding a new sieve tray was studied and compared to that by the traditional spray scrubber without a sieve tray (the WFGD system). The effects of gas flow rate, liquid flow rate, inlet SO2 concentration, and pH value on both types of scrubbers were evaluated. Pore diameter and porosity of the sieve tray in the sieve-tray spray scrubber were determined, and its enhanced efficiency under different experimental conditions was calculated. The results showed that the enhanced efficiency increased with the increasing liquid flow rate, gas flow rate under the same liquid/gas ratio (L/G), and pH value. Compared to the spray scrubber without a sieve tray, the sieve-tray spray scrubber had significantly higher efficiency. The enhanced efficiencies were mostly between 20% and 60% in the experimental range.
Intelligent Decoupling Control Study of PMSM Based on the Neural Network Inverse System
Authors: Da-Wei Gong , Zhi-Qiang Qiu , Wei Zheng , Zhi-Wu Ke , Yang Liu
Published: June 2022

This study obtains the analytical inverse system of a permanent magnet synchronous motor (PMSM) model based on the traditional magnetic field orientation decoupling control mode by analyzing the inverse quality of the PMSM. Using the neural network’s excellent approximation ability and well learning functions, a neural network inverse system (NNIS) of the decoupling control system was established by identifying and offline training the back propagation neural network (BPNN) and radial basis function neural network (RBFNN). The data collected from the analytical inverse system of the PMSM model are used to analyze and compare the prediction accuracy and running time of the neural network, so as to optimize the structure and parameters of the neural network. The simulation results of three PMSM decoupling control systems show that the PMSM decoupling control system based on RBF NNIS has good dynamic and static decoupling performance, and robustness.
Influence Analysis of Convective Heat Transfer of Circular Tubes and Flat Plates in a Polar Environment
Authors: Dongwei Yu , Zhibing Liu , Gang Wu , Xueyang Han , Guojun Wang , Dayong Zhang
Published: June 2022

Electric heating serves as a major cold-proof measure because engineering equipment often loses efficacy in harsh weather conditions in a polar environment. Because Convective heat transfer is the key issue to solve the cold-proof design, this paper analyzes convective heat transfer of tube and plate in the constant heat flow heating mode. According to fluent numerical simulation analysis with a wind speed of 0–40 m/s and a temperature of −40°C–0°C, both an increase in wind speed and a decrease in temperature would cause the growth of the convective heat transfer coefficient of circular tubes and flat plates, Wind speed displayed a more significant impact on convective heat transfer. In a low-temperature laboratory, a model experiment of convective heat transfer was carried out to validate the reliability of the numerical simulation. Last, a prediction model for convective heat transfer coefficient of circular tubes and flat plates in polar environment was developed using numerical and experimental data.
Variations in Litterfall Dynamics, C:N:P Stoichiometry and Associated Nutrient Return in Pure and Mixed Stands of Camphor Tree and Masson Pine Forests
Authors: Farooq Taimoor Hassan , Li Zhongwen , Yan Wende , Shakoor Awais , Kumar Uttam , Shabbir Rubab , Peng Yuanying , Gayathiri Ekambaram , Alotaibi Saqer S. , Wróbel Jacek , kalaji Hazem M. , Chen Xiaoyong
Published: June 2022

Litterfall, directly and indirectly, affects the soil physicochemical properties, microbial activity, and diversity of soil fauna and flora by adding organic matter and nutrients to the soil. This study explores litterfall dynamics such as litterfall production, litter decomposition rate, and associated nutrient return in three forest types, that is, camphor tree forest (CTF), Masson pine forest (MPF), and camphor tree and Masson pine mixed forest (CMF), in subtropical China. Results showed that CMF had the highest mean annual litterfall production (4.30 ± 0.22 t ha−1), which was significantly higher than that of MPF (3.41 ± 0.25 t ha−1) and CTF (3.26 ± 0.17 t ha−1). Leaf represented the major fraction of litterfall, constituting over 71% of the total litterfall mass in the three forest types. The contribution of branch litter was 16.3, 8.9, and 16.9%, and miscellaneous litter was 12.6, 18.9, and 11.1% in CTF, MPF, and CMF, respectively. The concentration of macronutrients ranked as N > Ca > K > Mg > P in all litter fractions. The total annual macronutrient return to the soil from the litterfall was in order as CTF (74.2 kg ha−1‧yr−1) > CMF (70.7 kg ha−1‧yr−1) > MPF (33.6 kg ha−1‧yr−1). The decomposition rate was higher in leaf litter than in branch litter throughout the three forests. Among the forest types, the leaf and branch decomposition rates were in a pattern: CTF > CMF > MPF. The ratio of C/N in both leaf and branch litters was significantly higher in MPF than in CTF and CMF, while no significant differences in N/P ratio were found in these litters among the three forests. The high N:P ratios in leaf litter (23/30) and the branch (24/32) litter indicated the high N returning and low nutrient returning to the soil. Our results suggested that the broadleaved forests have faster litter decomposition and higher macronutrient returns than conifer forests. Moreover, the litter decomposition rate was mainly associated with litterfall quality and chemical composition. The introduction of broadleaved trees into monoculture coniferous stands could increase litter production nutrients return, and thus, it had advantages in soil nutrients restoration and sustainable forest management.
Modeling Biogenic Volatile Organic Compounds Emissions and Subsequent Impacts on Ozone Air Quality in the Sichuan Basin, Southwestern China
Authors: Zhang Shaobo , Lyu Yaqiong , Yang Xianyu , Yuan Liang , Wang Yurun , Wang Lei , Liang Yuxin , Qiao Yuhong , Wang Shigong
Published: June 2022

Biogenic volatile organic compounds (BVOCs) impact atmospheric oxidation capacity and regional air quality through various biogeochemistry processes. Accurate estimation of BVOC emissions is crucial for modeling the fate and transport of air pollutants in chemical transport models. Previous modeling characterizes the spatial variability of BVOCs while estimated BVOC emissions show large uncertainties, and the impacts of BVOC emissions on ozone (O3) air quality are not well understood. In this study, we estimate the BVOC emissions by model of emissions of gases and aerosols from nature (MEGAN) v2.1 and MEGAN v3.1 over the Sichuan Basin (SCB) situated in southwestern China for 2017. Further, the critical role of BVOC emissions on regional O3 pollution is illustrated with a CMAQ modeled O3 episode in summer 2017. Annual BVOC emissions over the SCB in 2017 are estimated to be 1.8 × 106 tons with isoprene emissions as high as 7.3 × 105 tons. Abundant BVOC emissions are depicted over the southern and southeastern SCB, in contrast to the relatively low emissions of BVOC over the Chengdu Plain and northeastern SCB. CMAQ simulations depict a strong influence of BVOC on ambient O3 formation over densely forested regions including southern SCB and Chongqing city, accounting for 10% of daily maximum hourly O3 concentration (DM1h O3) and 6% of daily maximum 8-h average O3 (MDA8h O3) concentrations in July 2017. Over the severe O3 episode in summer 2017, sensitivity experiments indicate that enhanced BVOC emissions contribute substantially to basin-wide O3 concentrations and elevate peak O3 levels by 36.5 and 31.2 μg/m3 for the southern SCB and Chengdu Plain, respectively. This work identifies robustly important effects of BVOC emissions on O3 exceedance events over the SCB and contributes insight into pursuing an O3 abatement strategy with full consideration of potential contributions from BVOC emissions.
Association Between GSDMB Gene Polymorphism and Cervical Cancer in the Northeast Chinese Han Population
Authors: Li Songxue , Li Xiaoying , Zhang Shuang , Feng Yanan , Jia Tianshuang , Zhu Manning , Fang Lei , Gong Liping , Dong Shuang , Kong Xianchao , Wang Zhenzhen , Sun Litao
Published: June 2022

Objective: The purpose of this study was to investigate the relationship between GSDMB gene polymorphism and genetic susceptibility to cervical cancer in the Han population in Northeast China.

Methods: In this case–control study, the genotypes and alleles of rs8067378 in the GSDMB gene were analyzed by multiplex polymerase chain reaction (PCR) and next-generation sequencing methods in 482 cervical cancer (CC) patients, 775 cervical squamous intraepithelial lesion (SIL) patients, and 495 healthy women. The potential relationships between the SNP of the GSDMB gene with SIL and CC were analyzed by multivariate logistic regression analysis combined with 10,000 permutation tests.

Results: In the comparison between the SIL group and the control group, the genotype and allele distribution frequencies of rs8067378 SNP of the GSDMB gene were statistically significant (p = 0.0493 and p = 0.0202, respectively). The allele distribution frequencies of rs8067378 were also statistically significant in the comparison between high-grade cervical squamous intraepithelial lesion (HSIL) and low-grade cervical squamous intraepithelial lesion (LSIL) groups with control group ( p = 0.0483 and p = 0.0330, respectively). Logistic regression analysis showed that after adjusting for age, the rs8067378 SNP of the GSDMB gene was significantly associated with the reduced risk of SIL under the dominant model (p = 0.0213, OR = 0.764, CI = 0.607–0.961) and the additive model (p = 0.0199, OR = 0.814, and CI = 0.684–0.968), and its mutant gene G may play a role in the progression of healthy people to LSIL and even HSIL as a protective factor. However, there was no significant association between cervical cancer and its subtypes with the control group (p > 0.05). After 10,000 permutations, there was still no correlation that has provided evidence for the accuracy of our study.

Conclusion: The results of this study showed that rs8067378 single nucleotide polymorphism of the GSDMB gene may reduce the risk of SIL and protect the susceptibility to cervical precancerous lesions in the Northeast Chinese Han population, but it has no significant correlation with the progression of cervical cancer.
L1 Retrotransposons: A Potential Endogenous Regulator for Schizophrenia
Authors: Jahangir Muhammad , Li Li , Zhou Jian-Song , Lang Bing , Wang Xiao-Ping
Published: June 2022

The long interspersed nuclear elements 1 (LINE-1/L1s) are the only active autonomous retrotransposons found in humans which can integrate anywhere in the human genome. They can expand the genome and thus bring good or bad effects to the host cells which really depends on their integration site and associated polymorphism. LINE-1 retrotransposition has been found participating in various neurological disorders such as autism spectrum disorder, Alzheimer’s disease, major depression disorder, post-traumatic stress disorder and schizophrenia. Despite the recent progress, the roles and pathological mechanism of LINE-1 retrotransposition in schizophrenia and its heritable risks, particularly, contribution to “missing heritability” are yet to be determined. Therefore, this review focuses on the potentially etiological roles of L1s in the development of schizophrenia, possible therapeutic choices and unaddressed questions in order to shed lights on the future research.
Concordant and Heterogeneity of Single-Cell Transcriptome in Cardiac Development of Human and Mouse
Authors: Shang Mengyue , Hu Yi , Cao Huaming , Lin Qin , Yi Na , Zhang Junfang , Gu Yanqiong , Yang Yujie , He Siyu , Lu Min , Peng Luying , Li Li
Published: June 2022

Normal heart development is vital for maintaining its function, and the development process is involved in complex interactions between different cell lineages. How mammalian hearts develop differently is still not fully understood. In this study, we identified several major types of cardiac cells, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), ECs/FBs, epicardial cells (EPs), and immune cells (macrophage/monocyte cluster, MACs/MONOs), based on single-cell transcriptome data from embryonic hearts of both human and mouse. Then, species-shared and species-specific marker genes were determined in the same cell type between the two species, and the genes with consistent and different expression patterns were also selected by constructing the developmental trajectories. Through a comparison of the development stage similarity of CMs, FBs, and ECs/FBs between humans and mice, it is revealed that CMs at e9.5 and e10.5 of mice are most similar to those of humans at 7 W and 9 W, respectively. Mouse FBs at e10.5, e13.5, and e14.5 are correspondingly more like the same human cells at 6, 7, and 9 W. Moreover, the e9.5-ECs/FBs of mice are most similar to that of humans at 10W. These results provide a resource for understudying cardiac cell types and the crucial markers able to trace developmental trajectories among the species, which is beneficial for finding suitable mouse models to detect human cardiac physiology and related diseases.
It’s Just a Phase: Exploring the Relationship Between mRNA, Biomolecular Condensates, and Translational Control
Authors: Parker Dylan M. , Winkenbach Lindsay P. , Osborne Nishimura Erin
Published: June 2022

Cells spatially organize their molecular components to carry out fundamental biological processes and guide proper development. The spatial organization of RNA within the cell can both promote and result from gene expression regulatory control. Recent studies have demonstrated diverse associations between RNA spatial patterning and translation regulatory control. One form of patterning, compartmentalization in biomolecular condensates, has been of particular interest. Generally, transcripts associated with cytoplasmic biomolecular condensates—such as germ granules, stress granules, and P-bodies—are linked with low translational status. However, recent studies have identified new biomolecular condensates with diverse roles associated with active translation. This review outlines RNA compartmentalization in various condensates that occur in association with repressed or active translational states, highlights recent findings in well-studied condensates, and explores novel condensate behaviors.
Markers of Immune Cell Exhaustion as Predictor of Survival in Surgically-Treated Early-Stage NSCLC
Authors: Sellmer Laura , Kovács Julia , Walter Julia , Kumbrink Jörg , Neumann Jens , Kauffmann-Guerrero Diego , Kiefl Rosemarie , Schneider Christian , Jung Andreas , Behr Jürgen , Tufman Amanda
Published: June 2022

Background

Tumor tissue as well as regional lymph nodes are removed during curative surgery for early-stage non-small cell lung cancer (NSCLC). These tissues provide a unique snapshot of the immune cell composition at the time of surgery. We investigated the immune landscape in matched tumor tissue, tumor bearing (tb) and non-tumor bearing (ntb) N1 as well as N2 lymph nodes (LNs) in patients with NSCLC and its relation to survival.

Methods

Internal hospital databases were screened for surgically treated NSCLC patients for whom tumor tissue, tbLNs as well as N1 and N2 ntbLNs were available. Clinical as well as demographic data were extracted from hospital records. Expression profiling of 770 immune-related genes was performed using the PanCancer IO 360 panel by NanoString Technologies.

Results

We identified 190 surgically treated patients of whom 16 fulfilled inclusion criteria and had sufficient archived tissue. The Tumor Immune Dysfunction and Exclusion (TIDE) score in N1 tumor-free lymph nodes was associated with OS. TIM-3 expression was inversely correlated with TIDE scores in affected LNs, N1 and N2 ntbLNs. Levels of CD8 expression were significantly higher in TIDE High compared to TIDE Low patients. TIM-3 and PD-L1 were selected for the final model for OS in multivariate regression in more than one tissue.

Conclusion

Levels of immune cell exhaustion markers may indicate a dysfunctional immune status and are associated with survival after curative surgery in NSCLC.
Clinical Significance of MPO-ANCA in Eosinophilic Granulomatosis With Polyangiitis: Experience From a Longitudinal Chinese Cohort
Authors: Liu Suying , Han Linna , Liu Yanhui , Yang Jun , Zhang Yu , Li Mengtao , Tian Xinping , Zeng Xiaofeng , Wang Li , Zhang Fengchun
Published: June 2022

Objectives

The aim of this study is to investigate the clinical significance of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) on eosinophilic granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.

Methods

A total of 120 patients with EGPA were consecutively enrolled and followed up. Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations, treatment, and outcomes were analyzed. Logistic regression analysis was performed to analyze the independently associated factors for renal involvement.

Results

ANCA positivity was observed in 24.2% of patients with EGPA. Patients with MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven vasculitis. Heart manifestations and asthma were more common in patients with negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil count, and BVAS and were higher in patients with methylprednisolone pulse. Among patients with renal involvement, patients with positive MPO-ANCA had higher proportions of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear involvement were the independent factors associated with renal involvement. Intravenous cyclophosphamide and immunoglobulins were prescribed more frequently in patients with positive MPO-ANCA.

Conclusion

In this cohort, patients with positive MPO-ANCA and negative ANCA displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with disease activity of EGPA. MPO-ANCA was a significant independent factor associated with renal involvement.
Construction and Application of Polygenic Risk Scores in Autoimmune Diseases
Authors: Khunsriraksakul Chachrit , Markus Havell , Olsen Nancy J. , Carrel Laura , Jiang Bibo , Liu Dajiang J.
Published: June 2022

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with autoimmune diseases and provided unique mechanistic insights and informed novel treatments. These individual genetic variants on their own typically confer a small effect of disease risk with limited predictive power; however, when aggregated (e.g., via polygenic risk score method), they could provide meaningful risk predictions for a myriad of diseases. In this review, we describe the recent advances in GWAS for autoimmune diseases and the practical application of this knowledge to predict an individual’s susceptibility/severity for autoimmune diseases such as systemic lupus erythematosus (SLE) via the polygenic risk score method. We provide an overview of methods for deriving different polygenic risk scores and discuss the strategies to integrate additional information from correlated traits and diverse ancestries. We further advocate for the need to integrate clinical features (e.g., anti-nuclear antibody status) with genetic profiling to better identify patients at high risk of disease susceptibility/severity even before clinical signs or symptoms develop. We conclude by discussing future challenges and opportunities of applying polygenic risk score methods in clinical care.
Development of Immunotherapy Strategies Targeting Tumor Microenvironment Is Fiercely Ongoing
Authors: Bai Rilan , Cui Jiuwei
Published: June 2022

Tumor immune microenvironment is a very complex system that is influenced by a wide range of factors; in this microenvironment, various immune cells, stromal cells, and cytokines can interact with tumor cells and jointly regulate this complex ecosystem. During tumor development, the tumor microenvironment (TME) shows the upregulation of inhibitory signals and downregulation of activating signals, which result in an immunosuppressive microenvironment and lead to tumor immune escape. In recent years, a variety of precision immunotherapy strategies have been developed to remodel the TME into a positive immune microenvironment by stimulating or restoring the inherent tumor inhibition ability of the immune system so as to improve anti-tumor therapeutic efficacy. This review focuses on immunotherapy strategies targeting the TME, including those that target the microenvironment to inhibit signaling, activate signaling, and specifically involve many new targets such as physical barriers, immune cells and their surface molecular receptors, cytokines, and metabolic factors. Furthermore, it summarizes the challenges faced while conducting research on the tumor immune microenvironment and the corresponding solutions.
NF-κB Inducing Kinase Regulates Intestinal Immunity and Homeostasis
Authors: Wang Bingran , Shen Jun
Published: June 2022

Intestinal immunity and homeostasis are maintained through the regulation of cytokine trafficking, microbiota, necrosis and apoptosis. Intestinal immunity and homeostasis participate in host defenses and inflammatory responses locally or systemically through the gut-organ axis. NF-κB functions as a crucial transcription factor mediating the expression of proteins related to the immune responses. The activation of NF-κB involves two major pathways: canonical and non-canonical. The canonical pathway has been extensively studied and reviewed. Here, we present the current knowledge of NIK, a pivotal mediator of the non-canonical NF-κB pathway and its role in intestinal immunity and homeostasis. This review also discusses the novel role of NIK signaling in the pathogenesis and treatment of inflammatory bowel disease.
Type 1 Innate Lymphoid Cells Are Proinflammatory Effector Cells in Ischemia-Reperfusion Injury of Steatotic Livers
Authors: Kang Jiman , Liggett Jedson R. , Patil Digvijay , Ranjit Suman , Loh Katrina , Duttargi Anju , Cui Yuki , Oza Kesha , Frank Brett S. , Kwon DongHyang , Kallakury Bhaskar , Robson Simon C. , Fishbein Thomas M. , Cui Wanxing , Khan Khalid , Kroemer Alexander
Published: June 2022

Innate lymphoid cells (ILCs), the most recently described family of lymphoid cells, play fundamental roles in tissue homeostasis through the production of key cytokine. Group 1 ILCs, comprised of conventional natural killer cells (cNKs) and type 1 ILCs (ILC1s), have been implicated in regulating immune-mediated inflammatory diseases. However, the role of ILC1s in nonalcoholic fatty liver disease (NAFLD) and ischemia-reperfusion injury (IRI) is unclear. Here, we investigated the role of ILC1 and cNK cells in a high-fat diet (HFD) murine model of partial warm IRI. We demonstrated that hepatic steatosis results in more severe IRI compared to non-steatotic livers. We further elicited that HFD-IRI mice show a significant increase in the ILC1 population, whereas the cNK population was unchanged. Since ILC1 and cNK are major sources of IFN-γ and TNF-α, we measured the level of ex vivo cytokine expression in normal diet (ND)-IRI and HFD-IRI conditions. We found that ILC1s in HFD-IRI mice produce significantly more IFN-γ and TNF-α when compared to ND-IRI. To further assess whether ILC1s are key proinflammatory effector cells in hepatic IRI of fatty livers, we studied both Rag1−/− mice, which possess cNK cells, and a substantial population of ILC1s versus the newly generated Rag1−/−Tbx21−/− double knockout (Rag1-Tbet DKO) mice, which lack type 1 ILCs, under HFD IRI conditions. Importantly, HFD Rag1-Tbet DKO mice showed significant protection from hepatic injury upon IRI when compared to Rag1−/− mice, suggesting that T-bet-expressing ILC1s play a role, at least in part, as proinflammatory effector cells in hepatic IRI under steatotic conditions.
The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection
Authors: Moga Esther , Lynton-Pons Elionor , Domingo Pere
Published: June 2022

Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ T follicular helper (Tfh), which play a critical role in infection control as well as long-term protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes interrupt viral replication by secreting antiviral cytokines (IFN-γ and TNF-α) and directly killing infected cells, negatively correlating with stages of disease progression. In addition, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 cases a dysregulated CD4+ T cell signature may contribute to the greater production of pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components revolve, since it orchestrates and leads antiviral response by regulating the inflammatory cascade and, as a consequence, the innate immune system, as well as promoting a correct humoral response through CD4+ Tfh cells. This review also analyses the critical role of cellular immunity in modulating the development of high-affinity neutralizing antibodies and germinal center B cell differentiation in memory and long-lived antibody secreting cells. Finally, since there is currently a high percentage of vaccinated population and, in some cases, vaccine booster doses are even being administered in certain countries, we have also summarized newer approaches to long-lasting protective immunity and the cross-protection of cellular immune response against SARS-CoV-2.
A Machine Learning Approach to Predict Remission in Patients With Psoriatic Arthritis on Treatment With Secukinumab
Authors: Venerito Vincenzo , Lopalco Giuseppe , Abbruzzese Anna , Colella Sergio , Morrone Maria , Tangaro Sabina , Iannone Florenzo
Published: June 2022

Background

Psoriatic Arthritis (PsA) is a multifactorial disease, and predicting remission is challenging. Machine learning (ML) is a promising tool for building multi-parametric models to predict clinical outcomes. We aimed at developing a ML algorithm to predict the probability of remission in PsA patients on treatment with Secukinumab (SEC).

Methods

PsA patients undergoing SEC treatment between September 2017 and September 2020 were retrospectively analyzed. At baseline and 12-month follow-up, we retrieved demographic and clinical characteristics, including Body Mass Index (BMI), disease phenotypes, Disease Activity in PsA (DAPSA), Leeds Enthesitis Index (LEI) and presence/absence of comorbidities, including fibromyalgia and metabolic syndrome. Two random feature elimination wrappers, based on an eXtreme Gradient Boosting (XGBoost) and Logistic Regression (LR), were trained and validated with 10-fold cross-validation for predicting 12-month DAPSA remission with an attribute core set with the least number of predictors. The performance of each algorithm was assessed in terms of accuracy, precision, recall and area under receiver operating characteristic curve (AUROC).

Results

One-hundred-nineteen patients were selected. At 12 months, 20 out of 119 patients (25.21%) achieved DAPSA remission. Accuracy and AUROC of XGBoost was of 0.97 ± 0.06 and 0.97 ± 0.07, overtaking LR (accuracy 0.73 ± 0.09, AUROC 0.78 ± 0.14). Baseline DAPSA, fibromyalgia and axial disease were the most important attributes for the algorithm and were negatively associated with 12-month DAPSA remission.

Conclusions

A ML approach may identify SEC good responders. Patients with a high disease burden and axial disease with comorbid fibromyalgia seem challenging to treat.
Role of NLRP3 Inflammasome in Rheumatoid Arthritis
Authors: Yin Hui , Liu Na , Sigdel Keshav Raj , Duan Lihua
Published: June 2022

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by multi-articular, symmetrical and invasive arthritis resulting from immune system abnormalities involving T and B lymphocytes. Although significant progress has been made in the understanding of RA pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest that NLRP3 inflammasome, a regulator of inflammation, might play an important role in the development of RA. There have been increasing clinical and pre-clinical evidence showing the treatment of NLRP3/IL-1β in inflammatory diseases. To provide a foundation for the development of therapeutic strategies, we will briefly summarize the roles of NLRP3 inflammasome in RA and explore its potential clinical treatment.
Colloidal Stability of Magnetite Nanoparticles Coated by Oleic Acid and 3-(N,N-Dimethylmyristylammonio)propanesulfonate in Solvents
Authors: Li Liu , Li Decai , Zhang Zhili
Published: June 2022

In order to understand the factors affecting the colloidal stability in the carrier liquids of different ferrofluids, magnetite nanoparticles coated by surfactants 3-(N,N-dimethylmyristylammonio)propanesulfonate (DP) and oleic acid (OA) were fabricated as dispersions in diverse colloidal systems. The OA-coated magnetite could only be dispersed in the apolar carrier liquid (εr < 5), while DP-coated magnetite particles could establish a stable colloidal system in the polar base liquid (εr > 5) such as water and ethanol. The colloidal stability of OA-coated particles in the apolar solvents was mainly attributed to the steric repulsion of its outer thick liquid shell (∼3 nm). Due to the absence of steric repulsion on the solid thin shell (∼1 nm) on DP-coated magnetite, DP-coated particles could not be dispersed in the apolar liquid. In the polar liquid-based ferrofluids, DP-coated magnetite could form an electric double layer (EDL). The total Gibbs interfacial energy was analyzed based on Van Oss-Chaudhry-Good and DLVO theory to describe the behaviors of coated particles in solvents. In the case of neutral (pH = 7) water-based colloidal, DP-coated magnetite could establish an energy barrier of ∼2.2 kBT to prevent the particles from precipitation. Bare magnetite particles could form a relatively fragile colloid in a water system with an energy repulsion of ∼1.2 kBT. In contrast, OA-coated magnetite exhibited a severe phase separation in a water-based colloidal system due to its net attraction ∼ −1.3 kBT.
Long-Term Organic–Inorganic Fertilization Regimes Alter Bacterial and Fungal Communities and Rice Yields in Paddy Soil
Authors: Ma Tengfei , He Xiaohui , Chen Shanguo , Li Yujia , Huang Qiwei , Xue Chao , Shen Qirong
Published: June 2022

Microorganisms are the most abundant and diverse organisms in soils and have important effects on soil fertility. In this study, effects of the long-term fertilization treatments no fertilizer (CK), chemical fertilizer (nitrogen–phosphorus–potassium (NPK)), and organic–inorganic fertilizer (NPK and organic fertilizer (NPKM)) on rice yield and soil bacterial and fungal community diversity, structure, composition, and interaction networks were evaluated. Of the three treatments, the highest rice yield was in NPKM. Bacterial richness was significantly higher in NPKM than in NPK. Fertilization treatment significantly altered β diversity of communities, species composition of bacterial and fungal communities, and structure of soil microbial networks. The most complex bacterial and fungal interaction co-occurrence network with the highest average degree and numbers of edges and nodes was in NPKM. Relative abundance of the plant growth-promoting fungus Trichoderma increased significantly in NPKM compared with CK and NPK. The results of the study indicate that bacterial richness and microbial community member interactions (network complexity) might be suitable indicators of soil biological fertility. This research provides new insights on the effects of different fertilization regimes on responses of soil bacterial and fungal communities and their contributions to crop yield. New indicators such as bacterial richness and complexity of microbial interaction networks are also identified that can be used to evaluate soil biological fertility.
The Role of Gut Microbiota-Bile Acids Axis in the Progression of Non-alcoholic Fatty Liver Disease
Authors: Ni Yiming , Lu Mengna , Xu Yuan , Wang Qixue , Gu Xinyi , Li Ying , Zhuang Tongxi , Xia Chenyi , Zhang Ting , Gou Xiao-jun , Zhou Mingmei
Published: June 2022

Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25–30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake. The increasing prevalence of NAFLD will lead to an increasing number of cirrhosis patients, as well as hepatocellular carcinoma (HCC) requiring liver transplantation, while the current treatments for NAFLD and its advanced diseases are suboptimal. Accordingly, it is necessary to find signaling pathways and targets related to the pathogenesis of NAFLD for the development of novel drugs. A large number of studies and reviews have described the critical roles of bile acids (BAs) and their receptors in the pathogenesis of NAFLD. The gut microbiota (GM), whose composition varies between healthy and NAFLD patients, promotes the transformation of more than 50 secondary bile acids and is involved in the pathophysiology of NAFLD through the GM-BAs axis. Correspondingly, BAs inhibit the overgrowth of GM and maintain a healthy gut through their antibacterial effects. Here we review the biosynthesis, enterohepatic circulation, and major receptors of BAs, as well as the relationship of GM, BAs, and the pathogenesis of NAFLD in different disease progression. This article also reviews several therapeutic approaches for the management and prevention of NAFLD targeting the GM-BAs axis.
Atypical Serogroup IVb-v1 of Listeria monocytogenes Assigned to New ST2801, Widely Spread and Persistent in the Environment of a Pork-Meat Producing Plant of Central Italy
Authors: Guidi Fabrizia , Lorenzetti Cinzia , Centorotola Gabriella , Torresi Marina , Cammà Cesare , Chiaverini Alexandra , Pomilio Francesco , Blasi Giuliana
Published: June 2022

In this study, we characterized 84 Listeria monocytogenes (Lm) strains having an atypical IVb-v1 profile and isolated in a meat producing plant of Central Italy. They were assigned to the new MLST type ST2801 (CC218). The new ST was widespread in the food-producing environment where it was able to persist for over a year even after cleaning and sanitation. Cluster analysis identified three main clusters genetically close to each other (0–22 allelic differences and 0–28 SNPs) from two different cgMLST types, suggesting a common source. The coexistence of closely related clusters over time could be the result of a different evolution path starting from a common ancestor first introduced in the plant and/or the consequence of the repetitive reintroduction of closely related clones probably by raw materials. All the strains presented several determinants for heavy metals resistance, stress response, biofilm production, and multidrug efflux pumps with no significant differences among the clusters. A total of 53 strains carried pLI100 and the j1776 plasmids, while in one strain, the pLM33 was found in addition to pLI100. Only the strains carrying plasmids presented cadA and cadC for cadmium resistance and the mco gene encoding a multicopper oxidase and gerN for an additional Na+/H+-K+ antiporter. All the strains presented a virulence profile including a full-length inlA gene and the additional LIPI-3. The isolation of a new ST with a large pattern of stress-adaptation genes and able to persist is an important contribution to deepening the current knowledge on the uncommon IVb-v1 and in general on the genomic diversity of Lm.
A Method for Assessing the Robustness of Protein Structures by Randomizing Packing Interactions
Authors: Yadahalli Shilpa , Jayanthi Lakshmi P. , Gosavi Shachi
Published: June 2022

Many single-domain proteins are not only stable and water-soluble, but they also populate few to no intermediates during folding. This reduces interactions between partially folded proteins, misfolding, and aggregation, and makes the proteins tractable in biotechnological applications. Natural proteins fold thus, not necessarily only because their structures are well-suited for folding, but because their sequences optimize packing and fit their structures well. In contrast, folding experiments on the de novo designed Top7 suggest that it populates several intermediates. Additionally, in de novo protein design, where sequences are designed for natural and new non-natural structures, tens of sequences still need to be tested before success is achieved. Both these issues may be caused by the specific scaffolds used in design, i.e., some protein scaffolds may be more tolerant to packing perturbations and varied sequences. Here, we report a computational method for assessing the response of protein structures to packing perturbations. We then benchmark this method using designed proteins and find that it can identify scaffolds whose folding gets disrupted upon perturbing packing, leading to the population of intermediates. The method can also isolate regions of both natural and designed scaffolds that are sensitive to such perturbations and identify contacts which when present can rescue folding. Overall, this method can be used to identify protein scaffolds that are more amenable to whole protein design as well as to identify protein regions which are sensitive to perturbations and where further mutations should be avoided during protein engineering.
Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
Authors: Roth Aileen , Sander Annabelle , Oswald Marleen Silke , Gärtner Fabian , Knippschild Uwe , Bischof Joachim
Published: June 2022

A main pathological event in Alzheimer’s disease is the generation of neurofibrillary tangles originating from hyperphosphorylated and subsequently aggregated tau proteins. Previous reports demonstrated the critical involvement of members of the protein kinase family CK1 in the pathogenesis of Alzheimer’s disease by hyperphosphorylation of tau. However, precise mechanisms and effects of CK1-mediated tau phosphorylation are still not fully understood. In this study, we analyzed recombinant tau441 phosphorylated by CK1δ in vitro via mass spectrometry and identified ten potential phosphorylation sites, five of them are associated to Alzheimer’s disease. To confirm these results, in vitro kinase assays and two-dimensional phosphopeptide analyses were performed with tau441 phosphomutants confirming Alzheimer’s disease-associated residues Ser68/Thr71 and Ser289 as CK1δ-specific phosphorylation sites. Treatment of differentiated human neural progenitor cells with PF-670462 and Western blot analysis identified Ser214 as CK1δ-targeted phosphorylation site. The use of an in vitro tau aggregation assay demonstrated a possible role of CK1δ in tau aggregation. Results obtained in this study highlight the potential of CK1δ to be a promising target in the treatment of Alzheimer’s disease.