bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of a Novel Metabolic-Related Signature Predicting Overall Survival for Pancreatic Cancer
Authors: Huo Junyu , Wu Liqun , Zang Yunjin
Published: May 2021

Recently, growing evidence has revealed the significant effect of reprogrammed metabolism on pancreatic cancer in relation to carcinogenesis, progression, and treatment. However, the prognostic value of metabolism-related genes in pancreatic cancer has not been fully revealed. We identified 379 differentially expressed metabolic-related genes (DEMRGs) by comparing 178 pancreatic cancer tissues with 171 normal pancreatic tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression project (GTEx) databases. Then, we used univariate Cox regression analysis together with Lasso regression for constructing a prognostic model consisting of 15 metabolic genes. The unified risk score formula and cutoff value were taken into account to divide patients into two groups: high risk and low risk, with the former exhibiting a worse prognosis compared with the latter. The external validation results of the International Cancer Genome Consortium (IGCC) cohort and the Gene Expression Omnibus (GEO) cohort further confirm the effectiveness of this prognostic model. As shown in the receiver operating characteristic (ROC) curve, the area under curve (AUC) values of the risk score for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were 0.871, 0.885, and 0.886, respectively. Based on the Gene Set Enrichment Analysis (GSEA), the 15-gene signature can affect some important biological processes and pathways of pancreatic cancer. In addition, the prognostic model was significantly correlated with the tumor immune microenvironment (immune cell infiltration, and immune checkpoint expression, etc.) and clinicopathological features (pathological stage, lymph node, and metastasis, etc.). We also built a nomogram based on three independent prognostic predictors (including individual neoplasm status, lymph node metastasis, and risk score) for the prediction of 1-, 3-, and 5-year OS of pancreatic cancer, which may help to further improve the treatment strategy of pancreatic cancer.
METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma
Authors: Xu Tianbo , Gao Su , Ruan Hailong , Liu Jingchong , Liu Yuenan , Liu Di , Tong Junwei , Shi Jian , Yang Hongmei , Chen Ke , Zhang Xiaoping
Published: May 2021

Clear cell renal cell carcinoma (ccRCC) is characterized by its insensitivity to chemoradiotherapy and lacks effective diagnostic and prognostic biomarkers. In this study, we focused on the role of m6A RNA methylation regulators for tumor immunity. Based on the expression of 20 m6A regulators, consensus clustering was performed to divide patients into cluster1/cluster2 and showed that there was a survival difference between the two clusters. Through cox regression analysis, five hub m6A regulators were screened to construct a risk model. Further analysis showed that the risk score was an independent prognostic factor. GSEA, GSVA, and KEGG analysis revealed that immune cell pathways played a critical role between the high risk group and low risk group. Combined with CIBERSORT and survival analysis, five hub tumor-infiltrating immune cells (TIICs) were identified for further study. Meanwhile, correlation analysis indicated that IGF2BP2 was positively associated with activated memory CD4 T cell and METTL14 was negatively correlated to the regulatory T cell. Therefore, IGF2BP2 and METTL14 were regarded as key genes. Further study verified that only METTL14 possessed good diagnostic and prognostic value. Then, GSEA exhibited that METTL14 was mainly enriched in chemokine related pathways. We also found that CCL5 was negatively correlated to METTL14 and might serve as a potential target of METTL14. In conclusion, these findings suggest that the METTL14/CCL5/Tregs axis is a potential signaling pathway for regulating tumor immunity, and might become novel therapeutic targets for ccRCC.
Knowledge and Attitudes of Future Healthcare Professionals Toward Rare Diseases
Authors: Domaradzki Jan , Walkowiak Dariusz
Published: May 2021

Caring for patients suffering from a rare disease (RD) requires the special and combined efforts of different healthcare professionals, including nurses, physiotherapists and physicians. Nevertheless, Poland still lacks a national plan for RDs and the undergraduate and postgraduate education of future healthcare professionals on RDs is also inadequate. Thus, the aim of this study was to assess the awareness of RDs among nursing, physiotherapy and medical students in Poland. It shows that although 98% of respondents had heard of the term “rare disease,” most students had problems in defining the most common causes of RDs and their prevalence. Students also lacked basic knowledge about the healthcare system for RD patients in the country. While over 95% of future nurses, physiotherapists and physicians assessed their knowledge about RDs as insufficient or very poor, almost 92% of medical students, and 84% of physiotherapy and nursing students, did not feel prepared for caring for RD patients. Furthermore, although the vast majority of respondents declared eagerness to broaden their knowledge on RDs, only 45% of medical students, 76% of nursing students and 88% of physiotherapy students believed that RDs should be included into the medical curricula. Simultaneously, for most students the Internet was the prime source of information on RDs. It is concluded that as caring for RD patients requires a multidisciplinary approach, by identifying the gap in the education of future nurses, physiotherapists and physicians this study shows that there is an urgent need of better education about RDs among future healthcare professionals.
UMIc: A Preprocessing Method for UMI Deduplication and Reads Correction
Authors: Tsagiopoulou Maria , Maniou Maria Christina , Pechlivanis Nikolaos , Togkousidis Anastasis , Kotrová Michaela , Hutzenlaub Tobias , Kappas Ilias , Chatzidimitriou Anastasia , Psomopoulos Fotis
Published: May 2021

A recent refinement in high-throughput sequencing involves the incorporation of unique molecular identifiers (UMIs), which are random oligonucleotide barcodes, on the library preparation steps. A UMI adds a unique identity to different DNA/RNA input molecules through polymerase chain reaction (PCR) amplification, thus reducing bias of this step. Here, we propose an alignment free framework serving as a preprocessing step of fastq files, called UMIc, for deduplication and correction of reads building consensus sequences from each UMI. Our approach takes into account the frequency and the Phred quality of nucleotides and the distances between the UMIs and the actual sequences. We have tested the tool using different scenarios of UMI-tagged library data, having in mind the aspect of a wide application. UMIc is an open-source tool implemented in R and is freely available from https://github.com/BiodataAnalysisGroup/UMIc.
Prognostic Immune-Related Genes of Patients With Ewing’s Sarcoma
Authors: Zhou Yangfan , Xu Bin , Wu Shusheng , Liu Yulian
Published: May 2021

Ewing’s sarcoma (ES) is an extremely aggressive malignant bone tumor with a high incidence among children and adolescents. The immune microenvironment plays an important role in ES development. The aim of the current study was to investigate the immune microenvironment in ES patients to identify immune-related gene signatures. Single-sample gene set enrichment analysis (ssGSEA) was used to cluster the RNA sequences of 117 ES patients, and their immune cell infiltration data were downloaded and evaluated based on the Gene Expression Omnibus (GEO) database. High, medium, and low immune cell infiltration clusters were identified. Based on the comparison of clusters with high and low immune cell infiltration, normal skeletal muscle cells, and ES, we identified 198 common differentially expressed genes. GO and KEGG enrichment analyses indicated the underlying immune mechanism in ES. Cox and LASSO regression analyses were conducted to select immune-related prognostic genes. An external dataset from the International Cancer Genome Consortium (ICGC) was used to validate our results. Ten immune-related, independent prognostic genes (FMO2, GLCE, GPR64, IGFBP4, LOXHD1, PBK, SNAI2, SPP1, TAPT1-AS1, and ZIC2) were selected for analysis. These 10 immune-related genes signature were determined to exhibit independent prognostic significance for ES. The results of this study provide an approach for predicting the prognosis and survival of ES patients, and the elucidated genes may be a promising target for immunotherapy.
Immune Infiltration Subtypes Characterization and Identification of Prognosis-Related lncRNAs in Adenocarcinoma of the Esophagogastric Junction
Authors: Hu Xin , Wu Liuxing , Liu Ben , Chen Kexin
Published: May 2021

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has markedly increased worldwide. However, the precise etiology of AEG is still unclear, and the therapeutic options thus remain limited. Growing evidence has implicated long non-coding RNAs (lncRNAs) in cancer immunomodulation. This study aimed to examine the tumor immune infiltration status and assess the prognostic value of immune-related lncRNAs in AEG. Using the ESTIMATE method and single-sample GSEA, we first evaluated the infiltration level of 28 immune cell types in AEG samples obtained from the TCGA dataset (N=201). Patients were assigned into high- and low-immune infiltration subtypes based on the immune cell infiltration’s enrichment score. GSEA and mutation pattern analysis revealed that these two immune infiltration subtypes had distinct phenotypes. We identified 1470 differentially expressed lncRNAs in two immune infiltration subtypes. From these differentially expressed lncRNAs, six prognosis-related lncRNAs were selected using the Cox regression analysis. Subsequently, an immune risk signature was constructed based on combining the values of the six prognosis-associated lncRNAs expression levels and multiple regression coefficients. To determine the risk model’s prognostic capability, we performed a series of survival analyses with Kaplan–Meier methods, Cox proportional hazards regression models, and the area under receiver operating characteristic (ROC) curve. The results indicated that the immune-related risk signature could be an independent prognostic factor with a significant predictive value in patients with AEG. Furthermore, the immune-related risk signature can effectively predict the response to immunotherapy and chemotherapy in AEG patients. In conclusion, the proposed immune-related lncRNA prognostic signature is reliable and has high survival predictive value for patients with AEG and is a promising potential biomarker for immunotherapy.
Potent and Persistent Antibody Response in COVID-19 Recovered Patients
Authors: Tian Xiaodong , Liu Ling , Jiang Wenguo , Zhang He , Liu Wenjun , Li Jing
Published: May 2021

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Virus-specific antibodies can be detected in infected patients approximately two weeks after symptom onset. In this study, we set up ELISA technology coating with purified SARS-CoV-2 S and N proteins to study the antibody response of 484 serum samples. We established a surrogate viral inhibition assay using SARS-CoV-2 S protein pseudovirus system to determine the neutralization potency of collected serum samples. Here, we report robust antibody responses to SARS-CoV-2 in 484 recovered patients varying from 154 to 193 days, with 92% of recovered patients displaying a positive virus-specific spike glycoprotein IgG (s-IgG) response, while the ratio of positive spike glycoprotein IgM (s-IgM) reached 63%. Furthermore, moderate to potent neutralization activities were also observed in 62% of patients, correlating significantly with s-IgG response. This study strongly supports the long-term presence of antibodies in recovered patients against SARS-CoV-2, although all serum samples were collected from individuals with mild or moderate symptoms.
Transcriptomic Analysis of Ovine Hepatic Lymph Node Following Fasciola hepatica Infection – Inhibition of NK Cell and IgE-Mediated Signaling
Authors: Naranjo-Lucena Amalia , Correia Carolina N. , Molina-Hernández Verónica , Martínez-Moreno Álvaro , Browne John A. , Pérez José , MacHugh David E. , Mulcahy Grace
Published: May 2021

Fasciola hepaticais a trematode parasite responsible for major economic losses in livestock production, and is also a food-borne zoonotic agent in developing rural regions. For years, the immunoregulatory mechanisms employed by the parasite have hampered efforts to develop a successful vaccine candidate. Given that a comprehensive understanding of the immune response to infection is needed, we investigated the gene expression changes in ovine hepatic lymph nodes after experimental infection withF. hepatica. Lymph nodes from uninfected and infected animals were processed for RNA sequencing (RNA-seq) at 16 weeks post-infection. Comparison of groups revealed 5,132 differentially-expressed genes (DEGs). An inhibition of pro-inflammatory pathways, which has previously been described during fasciolosis, was evident in our data. However, other signals previously identified in ruminant peripheral blood mononuclear cells (PBMC) or liver tissue, such as activation of TGF-β or apoptosis-related pathways were not detected. We found inhibition of some key immunological pathways, including natural killer (NK) cell activity and IgE-mediated signaling. These may point to additional some as yet unrecognized mechanisms employed by the parasite to evade the host immune response. Understanding these, and leveraging information from this and other omics studies, will be important for the development of future vaccine prototypes against this parasite.
Dectin-1-Mediated Production of Pro-Inflammatory Cytokines Induced by Yeast β-Glucans in Bovine Monocytes
Authors: Pedro Ana R. V. , Lima Tânia , Fróis-Martins Ricardo , Leal Bárbara , Ramos Isabel C. , Martins Elisabete G. , Cabrita Ana R. J. , Fonseca António J. M. , Maia Margarida R. G. , Vilanova Manuel , Correia Alexandra
Published: May 2021

Yeast-derived products containing β-glucans have long been used as feed supplements in domesticated animals in an attempt to increase immunity. β-glucans are mainly recognized by the cell surface receptor CLEC7A, also designated Dectin-1. Although the immune mechanisms elicited through Dectin-1 activation have been studied in detail in mice and humans, they are poorly understood in other species. Here, we evaluated the response of bovine monocytes to soluble and particulate purified β-glucans, and also to Zymosan. Our results show that particulate, but not soluble β-glucans, can upregulate the surface expression of costimulatory molecules CD80 and CD86 on bovine monocytes. In addition, stimulated cells increased production of IL-8 and of TNF, IL1B, and IL6 mRNA expression, in a dose-dependent manner, which correlated positively with CLEC7A gene expression. Production of IL-8 and TNF expression decreased significantly after CLEC7A knockdown using two different pairs of siRNAs. Overall, we demonstrated here that bovine monocytes respond to particulate β-glucans, through Dectin-1, by increasing the expression of pro-inflammatory cytokines. Our data support further studies in cattle on the induction of trained immunity using dietary β-glucans.
The Importance of Home Cleaning: Sediment Transport by Alpheid Shrimps Provides a Competitive Advantage to Their Host Anemones
Authors: Pérez-Botello Antar Mijail , Mascaró Maite , Simões Nuno
Published: May 2021

Bartholomea annulata is a facultative host of the A. armatus species complex. In the Mexican Caribbean it is commonly found in cracks and crevices located where the vertical walls meet the sandy bottom or on large coral patches away from the sand. To protect themselves from predators, anemones often contract their hydraulic body into a cavernous den and extend the stinging tentacles toward the entrance. The high sediment dynamics of the region, however, result in a permanent risk of animal shelters to be obstructed by sand. By both analysing field data and conducting laboratory experiments with artificial shelters, the present study explored the den cleaning behaviour widely extended amongst alpheid shrimp, and its role in the alpheid-anemone symbiotic interaction. Videorecordings showed that den cleaning was composed of three main behaviours: digging, tossing and tamping. It commenced as soon as 7.2 ± 10.5 min after anemones were recognised by alpheids, and behaviours were displayed systematically amongst all 12 replicates. Despite being completely burrowed in sand, Alpheus spp. were capable of finding the anemone and liberating the entrance of the artificial shelters in less than 2.5 h. In addition, manipulative experiments showed that anemones confronted with shelters that were obstructed with sediment had a 25% probability of fully retracting when Alpheus spp. were absent, compared to a 75% probability when shrimps had cleaned the shelter’s entry and internal passage. The analysis of field data indicated that the presence of alpheid shrimps as symbionts of B. annulata was 30% higher amongst anemones in close contact with sandy bottoms than when inhabiting crevices on the top or lateral walls of hard substrates, away from the sediment. Overall, our study concludes that den cleaning constitutes a quick and effective mechanism to assure the anemone’s full retraction into their den, and by keeping the sediment away, alpheids provide the necessary conditions that serve both the anemone’s and the shrimp’s higher chances of acquiring maximum protection from predators. This advantageous exchange in protection partially explains why alpheids are more frequently present in B. annulata in interface microhabitats where the benefit of the interaction is maximised.
Recent Advancements in Biomimetic 3D Printing Materials With Enhanced Mechanical Properties
Authors: Yan Xinxin , Bethers Brandon , Chen Hengxi , Xiao Siqi , Lin Shuang , Tran Brian , Jiang Laiming , Yang Yang
Published: May 2021

Nature has developed a wide range of functional microstructures with optimized mechanical properties over millions of years of evolution. By learning from nature’s excellent models and principles, biomimicry provides a practicable strategy for designing and fabricating the next smart materials with enhanced properties. Nevertheless, the complicated micro-structural constructions in nature models are beyond the ability of conventional processes, hindering the developments of biomimetic research and its forthputting in engineering systems. Additive manufacturing (AM) or 3D printing processes have revolutionized manufacturing via their ability to manufacture complex micro/mesostructures, increase design freedom, provide mass customization, and waste minimization, as well as rapid prototyping. Here, a review of recent advances in biomimetic 3D printing materials with enhanced mechanical properties is provided. The design and fabrication were inspired by various natural structures, such as balsa wood, honeycomb, nacre, lobster claw, etc., which are presented and discussed. Finally, future challenges and perspectives are given.
4D Printing of Lead Zirconate Titanate Piezoelectric Composites Transducer Based on Direct Ink Writing
Authors: Liu Kai , Zhang Qingqing , Zhou Chenyang , Shi Yusheng , Sun Ce , Sun Huajun , Yin Changxia , Hu Jiaming , Zhou Shuyu , Zhang Yuzhen , Fu Yu
Published: May 2021

Lead zirconate titanate (PZT) piezoelectric composites used in transducers were fabricated via direct ink writing (DIW) combined with furnace sintering and resin impregnation. A ceramic slurry with a volume fraction of 52 vol% and suitable viscoelasticity was prepared. After post-process, the PZT ceramic specimens showed a nanoscale grain size with a density of 7.63 g/cm3, accounting for 97.8% of the theoretical density. The effects of different printing rod spacing on the electrical properties of composites were evaluated and lucubrated. Finally, an underwater acoustic transducer was assembled by using the PZT piezoelectric composites fabricated by the above method. The electrical signal generated by the underwater acoustic transducer changed autonomously with the acoustic stimulation, which indicated the application mode of 4D printing in functional devices in the future.
Correlation Between Microstructure and Fracture Behavior in Thick HARDOX 450 Wear-Resistant Steel With TiN Inclusions
Authors: Wang Zhongyang , Wu Xiang , Liu Denghui , Zuo Xiurong
Published: May 2021

This work investigates the correlation between TiN inclusions and microstructural properties of HARDOX 450 steel using optical microscopy (OM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and electron backscattered diffractometer (EBSD) methods. Some amount of microsized TiN inclusions were formed in the temperature range of the solid–liquid zone; however, they exhibited fracture features of deep dimples rather than a cleavage plane, which is closely related to the ability of the microstructure to arrest cracks. Upon tensile loading, a single microcrack first appeared inside the microsized TiN inclusions, and then, multiple microcracks formed, parts of which widened in the direction of tensile stress. A schematic mechanism map was plotted to reveal the propagation behavior and fracture mechanism of the microcracks in the TiN inclusions.
Epidemiology and Clinical Outcomes of COVID-19 Patients in Northwestern China Who Had a History of Exposure in Wuhan City: Departure Time-Originated Pinpoint Surveillance
Authors: Zhang Qingqing , Zhu Jianfei , Jia Chenghui , Xu Shuonan , Jiang Tao , Wang Shengyu
Published: May 2021

Background: Most COVID-19 patients cannot provide a clear exposure time; therefore, this study was designed to predict the progression of COVID-19 by using the definite departure time from Wuhan.

Methods: In this retrospective study, all cases were selected from Northwestern China, which has the lowest population density. As our study endpoints, the incubation period was defined as the date of departure from Wuhan City to the date of symptom onset; we defined the confirmed time as the interval from symptom onset to positive results (samples from the respiratory tract). Both of them were estimated by fitting a Weibull distribution on the departure date and symptom onset. The differences among the variables were analyzed.

Results: A total of 139 patients were ultimately enrolled, and ~10.1% of patients (14 patients) had no symptoms during their disease course. We estimated the median incubation period to be 4.0 days (interquartile intervals, 2.0–8.0), and the 95th percentile of the distribution was 15.0 days. Moreover, ~5.6% of patients (7 patients) experienced symptoms 2 weeks after leaving. Furthermore, the estimation median interval from symptom onset to final diagnosis was 4.0 days (interquartile intervals, 2.0–6.0), and the 95th percentile of the distribution was 12.0 days. Finally, the median hospitalization time was 16.0 days, ranging from 3.0 to 45.0 days. Univariate analysis showed that age (P = 0.021) and severity status (P = 0.001) were correlated significantly with hospitalization time.

Conclusions: We provide evidence that departure time can be used to estimate the incubation and confirmed times of patients infected with COVID-19 when they leave an epidemic area.
Early Prediction of Sepsis in the ICU Using Machine Learning: A Systematic Review
Authors: Moor Michael , Rieck Bastian , Horn Max , Jutzeler Catherine R. , Borgwardt Karsten
Published: May 2021

Background: Sepsis is among the leading causes of death in intensive care units (ICUs) worldwide and its recognition, particularly in the early stages of the disease, remains a medical challenge. The advent of an affluence of available digital health data has created a setting in which machine learning can be used for digital biomarker discovery, with the ultimate goal to advance the early recognition of sepsis.

Objective: To systematically review and evaluate studies employing machine learning for the prediction of sepsis in the ICU.

Data Sources: Using Embase, Google Scholar, PubMed/Medline, Scopus, and Web of Science, we systematically searched the existing literature for machine learning-driven sepsis onset prediction for patients in the ICU.

Study Eligibility Criteria: All peer-reviewed articles using machine learning for the prediction of sepsis onset in adult ICU patients were included. Studies focusing on patient populations outside the ICU were excluded.

Study Appraisal and Synthesis Methods: A systematic review was performed according to the PRISMA guidelines. Moreover, a quality assessment of all eligible studies was performed.

Results: Out of 974 identified articles, 22 and 21 met the criteria to be included in the systematic review and quality assessment, respectively. A multitude of machine learning algorithms were applied to refine the early prediction of sepsis. The quality of the studies ranged from “poor” (satisfying ≤ 40% of the quality criteria) to “very good” (satisfying ≥ 90% of the quality criteria). The majority of the studies (n = 19, 86.4%) employed an offline training scenario combined with a horizon evaluation, while two studies implemented an online scenario (n = 2, 9.1%). The massive inter-study heterogeneity in terms of model development, sepsis definition, prediction time windows, and outcomes precluded a meta-analysis. Last, only two studies provided publicly accessible source code and data sources fostering reproducibility.

Limitations: Articles were only eligible for inclusion when employing machine learning algorithms for the prediction of sepsis onset in the ICU. This restriction led to the exclusion of studies focusing on the prediction of septic shock, sepsis-related mortality, and patient populations outside the ICU.

Conclusions and Key Findings: A growing number of studies employs machine learning to optimize the early prediction of sepsis through digital biomarker discovery. This review, however, highlights several shortcomings of the current approaches, including low comparability and reproducibility. Finally, we gather recommendations how these challenges can be addressed before deploying these models in prospective analyses.

Systematic Review Registration Number: CRD42020200133.
Longitudinal Clinical Profiles of Hospital vs. Community-Acquired Acute Kidney Injury in COVID-19
Authors: Lu Justin Y. , Babatsikos Ioannis , Fisher Molly C. , Hou Wei , Duong Tim Q.
Published: May 2021

Acute kidney injury (AKI) is associated with high mortality in coronavirus disease 2019 (COVID-19). However, it is unclear whether patients with COVID-19 with hospital-acquired AKI (HA-AKI) and community-acquired AKI (CA-AKI) differ in disease course and outcomes. This study investigated the clinical profiles of HA-AKI, CA-AKI, and no AKI in patients with COVID-19 at a large tertiary care hospital in the New York City area. The incidence of HA-AKI was 23.26%, and CA-AKI was 22.28%. Patients who developed HA-AKI were older and had more comorbidities compared to those with CA-AKI and those with no AKI (p < 0.05). A higher prevalence of coronary artery disease, heart failure, and chronic kidney disease was observed in those with HA-AKI compared to those with CA-AKI (p < 0.05). Patients with CA-AKI received more invasive and non-invasive mechanical ventilation, anticoagulants, and steroids compared to those with HA-AKI (p < 0.05), but patients with HA-AKI had significantly higher mortality compared to those with CA-AKI after adjusting for demographics and clinical comorbidities (adjusted odds ratio = 1.61, 95% confidence interval = 1.1–2.35, p < 0.014). In addition, those with HA-AKI had higher markers of inflammation and more liver injury (p < 0.05) compared to those with CA-AKI. These results suggest that HA-AKI is likely part of systemic multiorgan damage and that kidney injury contributes to worse outcomes. These findings provide insights that could lead to better management of COVID-19 patients in time-sensitive and potentially resource-constrained environments.
Exogenous Biological Renal Support Improves Kidney Function in Mice With Rhabdomyolysis-Induced Acute Kidney Injury
Authors: Liu Chao , Chi Kun , Geng Xiaodong , Hong Quan , Mao Zhi , Huang Qi , Liu Dong , Wang Yiqin , Zhang Ying , Zhou Feihu , Cai Guangyan , Chen Xiangmei , Sun Xuefeng
Published: May 2021

Background:Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia–reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved.

Methods:A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis.

Results:No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation.

Conclusions:Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.
Female Patients With Sleep-Disordered Breathing Display More Frequently Heart Failure With Preserved Ejection Fraction
Authors: Lebek Simon , Hegner Philipp , Tafelmeier Maria , Rupprecht Leopold , Schmid Christof , Maier Lars Siegfried , Arzt Michael , Wagner Stefan
Published: May 2021

Objective: Sleep-disordered breathing (SDB) is a widespread disease that is often associated with heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF is more frequent in women than in men, but detailed pathomechanisms remain unclear. We investigated HFpEF in women and men in a high-risk cohort with SDB monitoring.

Methods and Results: Three hundred twenty-seven patients (84.4% men) undergoing elective coronary artery bypass grafting were prospectively subjected to SDB monitoring, and an apnea–hypopnea index (AHI) ≥15/h defined SDB. HF was classified according to current guidelines. HFpEF was significantly more frequent in SDB patients compared to those without SDB (28 vs. 17%, P = 0.016). This distribution was driven by an increased frequency of HFpEF in female SDB patients (48% vs. only 25% in male, P = 0.022). In accordance, female patients with SDB exhibited significantly more impaired diastolic left ventricular filling compared to men (echocardiographic E/e′). In contrast to men, in women, minimum oxygen saturation (O2min, measured by polygraphy, R2 = 0.470, P < 0.001) and time of oxygen saturation <90% (R2 = 0.165, P = 0.044) were significantly correlated with E/e′. Moreover, the correlation between O2min and E/e′ was significantly different in women compared to men (P < 0.001). Intriguingly, this association remained independent of clinical covariates in women [age, body mass index, systolic contractile dysfunction, diabetes mellitus, and glomerular filtration rate (GFR), R2 = 0.534, P = 0.042, multivariate regression analysis]. Since angiotensin II signaling has been mechanistically linked to HF, we measured protein expression of its cleavage enzyme ACE2 in human right atrial appendage biopsies (Western blot). Intriguingly, we found a significantly decreased ACE2 expression preferentially in women with SDB (2.66 ± 0.42 vs. 4.01 ± 2.47 in men with SDB, P = 0.005). In accordance, left ventricular mass index was significantly increased in women with SDB compared to women without SDB.

Conclusion: In patients with SDB, HFpEF and diastolic dysfunction were more frequent in women compared to men. In contrast to men, the severity of SDB was associated with the degree of diastolic dysfunction in women. These insights might help to find sex-specific therapies for patients with sleep-disordered breathing and heart failure.

Clinical Trial Registration: Unique identifier: NCT02877745, URL: http://www.clinicaltrials.gov.
Outcomes in Juvenile-Onset Spondyloarthritis
Authors: Smith Judith A. , Burgos-Vargas Ruben
Published: May 2021

Some studies have suggested children with juvenile onset spondyloarthritis (JoSpA) have a relatively poor outcome compared to other juvenile idiopathic arthritis (JIA) categories, in regards to functional status and failure to attain remission. Thus, in the interest of earlier recognition and risk stratification, awareness of the unique characteristics of this group is critical. Herein, we review the clinical burden of disease, prognostic indicators and outcomes in JoSpA. Of note, although children exhibit less axial disease at onset compared to adults with spondyloarthritis (SpA), 34–62% have magnetic resonance imaging (MRI) evidence for active inflammation in the absence of reported back pain. Furthermore, some studies have reported that more than half of children with “enthesitis related arthritis” (ERA) develop axial disease within 5 years of diagnosis. Axial disease, and more specifically sacroiliitis, portends continued active disease. The advent of TNF inhibitors has promised to be a “game changer,” given their relatively high efficacy for enthesitis and axial disease. However, the real world experience in various cohorts since the introduction of more widespread TNF inhibitor usage, in which greater than a third still have persistently active disease, suggests there is still work to be done in developing new therapies and improving the outlook for JoSpA.
Variation of Metagenome From Feedstock to Digestate in Full-Scale Biogas Plants
Authors: Jiang Fan , Wang Sen , Zhang Yan , Ma Shichun , Huang Yan , Fan Hui , Li Qiang , Wang Hengchao , Wang Anqi , Liu Hangwei , Cheng Lei , Deng Yu , Fan Wei
Published: May 2021

Anaerobic digestion (AD) has been widely used to resolve the problem of organic wastes worldwide. Previous studies showed that the types of feedstock have a great influence on the AD microbiome, and a huge number of AD populations are migrated from upstream feedstocks. However, the changes of microbial compositions from feedstock to AD digestate are still less understood. We collected feedstock samples from 56 full-scale biogas plants, generated 1,716 Gb feedstock metagenomic data in total, and constructed the first comprehensive microbial gene catalog of feedstock containing 25.2 million genes. Our result indicated that the predominant phyla in feedstock areFirmicutes,Bacteroidetes, andProteobacteria, which is similar to that in AD digestate, and the microbial diversity of feedstock samples is higher than that of AD digestate samples. In addition, the relative abundance of most genes involved in methanogenesis increase from feedstock to AD digestate. Besides, the amount of antibiotic resistance genes (ARGs) and pathogenic bacteria in AD are effectively reduced compared to feedstocks. This study provides a comprehensive microbial gene catalog of feedstock, and deepens the understanding of variation of microbial communities from feedstock to AD digestate of full-scale AD. The results also suggest the potential of AD to reduce the level of ARGs and pathogens in animal manure.
Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Outcomes in Patients With Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Plus Sorafenib
Authors: Zhang Lei , Yan Zhi-Ping , Hou Zhong-Heng , Huang Peng , Yang Min-Jie , Zhang Shuai , Zhang Shen , Zhang Shao-Hua , Zhu Xiao-Li , Ni Cai-Fang , Li Qiang
Published: May 2021

Objectives: To investigate the predictive value of inflammatory biomarkers in patients with unresectable hepatocellular carcinoma (HCC) for outcomes following the combination treatment of transarterial chemoembolization (TACE) plus sorafenib.

Materials and Methods: A total of 314 (270 male and 44 female) treatment-naïve patients with unresectable HCC treated by TACE plus sorafenib between January 2011 and December 2018 were enrolled in the retrospective study. The primary outcome was overall survival (OS). The secondary outcome was progression-free survival (PFS). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were obtained within 3–7 days before the initial TACE and the median value of the NLR and PLR was considered as the cut-off value.

Results: The median value of NLR and PLR was 2.42 and 100, respectively. The median OS and PFS of the entire cohort were 18.7 months (95% CI: 16.8–20.6) and 9.1 months (95% CI: 8.5–9.8), respectively. The low NLR and PLR group showed improved OS and PFS compared with the high NLR and PLR group [21.8 months (95% CI: 15.2–28.5) vs. 15.4 months (95% CI: 12.4–18.3), p < 0.0001; 21.6 months (95% CI: 15.8–27.5) vs. 14.9 months (95% CI: 11.9–17.8), p = 0.00027, respectively]. In addition, the low NLR and PLR group also provided a longer PFS than the high NLR and PLR group [10.4 months (95% CI: 8.9–12.0) vs. 8.1 months (95% CI: 7.1–9.2), p = 0.00022; 10.3 months (95% CI: 8.6–11.9) vs. 8.2 months (95% CI: 7.2–9.2), p < 0.0001, respectively]. High NLR and PLR at baseline were predictive factors of poor OS (p = 0.02 and p = 0.004) and PFS (p = 0.045 and p = 0.005).

Conclusion: This study showed the prognostic value of quantitative inflammatory biomarkers in correlation with OS and PFS in unresectable HCC patients undergoing TACE plus sorafenib treatment.
Yeast Cell-Based Transport Assay for the Functional Characterization of Human 4F2hc-LAT1 and ‐LAT2, and LAT1 and LAT2 Substrates and Inhibitors
Authors: Kantipudi Satish , Fotiadis Dimitrios
Published: May 2021

In mammalian cells, the L-type amino acid transporters (LATs) LAT1 (SLC7A5) and LAT2 (SLC7A8) form heterodimeric amino acid transporters (HATs) with the ancillary protein 4F2hc and are involved in the cellular uptake of specific amino acids. The HAT 4F2hc-LAT1 is found upregulated in various cancer cell types, while 4F2hc-LAT2 is a transporter for non-cancer cells. Preclinical studies have highlighted that 4F2hc-LAT1 plays an important role in tumor progression representing a valid anticancer target. Consequently, current research is focusing on the development of potent and specific human 4F2hc-LAT1 inhibitors. On the other hand, 4F2hc-LAT2 is emerging as target of other diseases, thus also gaining clinical interest. To determine affinity and specificity of substrates and inhibitors for 4F2hc-LAT1 or 4F2hc-LAT2, robust transport cell assays are indispensable. We have optimized and validated a transport assay using cells of the methylotrophic yeast Pichia pastoris stably overexpressing the human HATs 4F2hc-LAT1 or -LAT2, and the LATs LAT1 or LAT2 alone. The radioligand [3H]L-leucine was used as reporter and the substrates L-leucine, triiodothyronine (T3) and thyroxine (T4) as well as the inhibitors BCH and JPH203 (KYT-0353) for assay validation. Obtained half-maximal inhibitory concentrations also provided new insights, e.g., into the LAT specificity of the potent inhibitor JPH203 and on the potency of the thyroid hormones T3 and T4 to inhibit transport through human 4F2hc-LAT2. The LAT1 and LAT2 assays are of particular interest to determine possible implications and influences of 4F2hc in ligand binding and transport. In summary, the presented assays are valuable for characterization of ligands, e.g., towards 4F2hc-LAT1 specificity, and can also be applied for compound screening. Finally, our established approach and assay would also be applicable to other HATs and LATs of interest.
Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease
Authors: Wu Shaochang , Liu Xia , Jiang Ruilai , Yan Xiumei , Ling Zongxin
Published: May 2021

Alzheimer’s disease (AD) is the most common age-related progressive neurodegenerative disease, characterized by a decline in cognitive function and neuronal loss, and is caused by several factors. Numerous clinical and experimental studies have suggested the involvement of gut microbiota dysbiosis in patients with AD. The altered gut microbiota can influence brain function and behavior through the microbiota–gut–brain axis via various pathways such as increased amyloid-β deposits and tau phosphorylation, neuroinflammation, metabolic dysfunctions, and chronic oxidative stress. With no current effective therapy to cure AD, gut microbiota modulation may be a promising therapeutic option to prevent or delay the onset of AD or counteract its progression. Our present review summarizes the alterations in the gut microbiota in patients with AD, the pathogenetic roles and mechanisms of gut microbiota in AD, and gut microbiota–targeted therapies for AD. Understanding the roles and mechanisms between gut microbiota and AD will help decipher the pathogenesis of AD from novel perspectives and shed light on novel therapeutic strategies for AD.
Can Exergames Be Improved to Better Enhance Behavioral Adaptability in Older Adults? An Ecological Dynamics Perspective
Authors: Temprado Jean-Jacques
Published: May 2021

Finding effective training solutions to attenuate the alterations of behavior and cognition in the growing number of older adults is an important challenge for Science and Society. By offering 3D computer-simulated environments to combine perceptual-motor and cognitive exercise, exergames are promising in this respect. However, a careful analysis of meta-analytic reviews suggests that they failed to be more effective than conventional motor-cognitive training. We analyzed the reasons for this situation, and we proposed new directions to design new, conceptually grounded, exergames. Consistent with the evolutionary neuroscience approach, we contend that new solutions should better combine high level of metabolic activity with (neuro)muscular, physical, perceptual-motor, and cognitive stimulations. According to the Ecological Dynamics rationale, we assume that new exergames should act at the agent–environment scale to allow individuals to explore, discover, and adapt to immersive and informationally rich environments that should include cognitively challenging tasks, while being representative of daily living situations.
Right Frontoinsular Cortex: A Potential Imaging Biomarker to Evaluate T2DM-Induced Cognitive Impairment
Authors: Zhang Dongsheng , Lei Yumeng , Gao Jie , Qi Fei , Yan Xuejiao , Ai Kai , Zhe Xia , Cheng Miao , Wang Man , Su Yu , Tang Min , Zhang Xiaoling
Published: May 2021

Cognitive impairment in type 2 diabetes mellitus (T2DM) is associated with functional and structural abnormalities in the intrinsic brain network. The salience network (SN) is a neurocognitive network that maintains normal cognitive function, but it has received little attention in T2DM. We explored SN changes in patients with T2DM with normal cognitive function (DMCN) and in patients with T2DM with mild cognitive impairment (DMCI). Sixty-five T2DM patients and 31 healthy controls (HCs) underwent a neuropsychological assessment, independent component analysis (ICA), and voxel-based morphometry (VBM) analysis. The ICA extracted the SN for VBM to compare SN functional connectivity (FC) and gray matter (GM) volume (GMV) between groups. A correlation analysis examined the relationship between abnormal FC and GMV and clinical/cognitive variables. Compared with HCs, DMCN patients demonstrated increased FC in the left frontoinsular cortex (FIC), right anterior insula, and putamen, while DMCI patients demonstrated decreased right middle/inferior frontal gyrus FC. Compared with DMCN patients, DMCI patients showed decreased right FIC FC. There was no significant difference in SN GMV in DMCN and DMCI patients compared with HCs. FIC GMV was decreased in the DMCI patients compared with DMCN patients. In addition, right FIC FC and SN GMV positively correlated with Montreal Cognitive Assessment and Mini-Mental State Examination (MMSE) scores. These findings indicate that changes in SN FC, and GMV are complex non-linear processes accompanied by increased cognitive dysfunction in patients with T2DM. The right FIC may be a useful imaging biomarker for supplementary assessment of early cognitive dysfunction in patients with T2DM.
Total Cerebral Small Vessel Score Association With Hoehn and Yahr Stage in Parkinson’s Disease
Authors: Ma Xinxin , Li Shuhua , Li Chunmei , Wang Rui , Chen Min , Chen Haibo , Su Wen
Published: May 2021

Background: This study aimed to evaluate the total cerebral small vessel disease (CSVD) score in patients with Parkinson’s disease (PD) at different stages and related factors.

Methods: A 100 and seven patients with idiopathic PD and 62 normal controls (NCs) who underwent brain magnetic resonance imaging (MRI) were enrolled. PD patients were divided into two groups: early PD [(Hoehn and Yahr (H&Y) 1–1.5, n = 36)] and advanced PD (H&Y 2–4, n = 71) groups. We calculated the total CSVD score for each participant based on lacunes, high-grade white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), and cerebral microbleeds (CMBs). Differences in total CSVD score between the PD and NCs and between the two subgroups were compared. In addition, a multivariate logistic regression analysis was conducted to investigate the association between CSVD markers and clinical variables in PD.

Results: Lacunes were found in 9.3% of patients with PD, periventricular WMH (PVWMH) in 89.7%, deep WMH (DWMH) in 81.3%, EPVS in 85%, and CMBs in 2.8%. Compared with NCs, patients with PD showed higher PVWMH and DWMH scores. Advanced PD patients exhibited greater PVWMH (P = 0.041), DWMH (P = 0.046), and total CSVD score (P = 0.044) than the early PD group. After adjusting for multiple variables, higher H&Y stage was independently correlated with increased total CSVD score (OR = 2.667, 95% CI 1.154–2.266) and PVWMH score (OR = 2.237, 95% CI 1.084–1.696).

Conclusions: CSVD may play a critical role in patients with PD. The total CSVD score is a potential neuroimaging marker for monitoring the progression of PD.