bluuebunny/crossref_metadata_2025 huggingface dataset:
StAR-Related Lipid Transfer (START) Domains Across the Rice Pangenome Reveal How Ontogeny Recapitulated Selection Pressures During Rice Domestication
Authors: Mahtha Sanjeet Kumar , Purama Ravi Kiran , Yadav Gitanjali
Published: September 2021

The StAR-related lipid transfer (START) domain containing proteins or START proteins, encoded by a plant amplified family of evolutionary conserved genes, play important roles in lipid binding, transport, signaling, and modulation of transcriptional activity in the plant kingdom, but there is limited information on their evolution, duplication, and associated sub- or neo-functionalization. Here we perform a comprehensive investigation of this family across the rice pangenome, using 10 wild and cultivated varieties. Conservation of START domains across all 10 rice genomes suggests low dispensability and critical functional roles for this family, further supported by chromosomal mapping, duplication and domain structure patterns. Analysis of synteny highlights a preponderance of segmental and dispersed duplication among STARTs, while transcriptomic investigation of the main cultivated variety Oryza sativa var. japonica reveals sub-functionalization amongst genes family members in terms of preferential expression across various developmental stages and anatomical parts, such as flowering. Ka/Ks ratios confirmed strong negative/purifying selection on START family evolution, implying that ontogeny recapitulated selection pressures during rice domestication. Our findings provide evidence for high conservation of START genes across rice varieties in numbers, as well as in their stringent regulation of Ka/Ks ratio, and showed strong functional dependency of plants on START proteins for their growth and reproductive development. We believe that our findings advance the limited knowledge about plant START domain diversity and evolution, and pave the way for more detailed assessment of individual structural classes of START proteins among plants and their domain specific substrate preferences, to complement existing studies in animals and yeast.
Single-Cell RNA Sequencing Identifies New Inflammation-Promoting Cell Subsets in Asian Patients With Chronic Periodontitis
Authors: Qian Shu-jiao , Huang Qian-ru , Chen Rui-ying , Mo Jia-ji , Zhou Lin-yi , Zhao Yi , Li Bin , Lai Hong-chang
Published: September 2021

Periodontitis is a highly prevalent chronic inflammatory disease leading to periodontal tissue breakdown and subsequent tooth loss, in which excessive host immune response accounts for most of the tissue damage and disease progression. Despite of the imperative need to develop host modulation therapy, the inflammatory responses and cell population dynamics which are finely tuned by the pathological microenvironment in periodontitis remained unclear. To investigate the local microenvironment of the inflammatory response in periodontitis, 10 periodontitis patients and 10 healthy volunteers were involved in this study. Single-cell transcriptomic profilings of gingival tissues from two patients and two healthy donors were performed. Histology, immunohistochemistry, and flow cytometry analysis were performed to further validate the identified cell subtypes and their involvement in periodontitis. Based on our single-cell resolution analysis, we identified HLA-DR-expressing endothelial cells and CXCL13+ fibroblasts which are highly associated with immune regulation. We also revealed the involvement of the proinflammatory NLRP3+ macrophages in periodontitis. We further showed the increased cell-cell communication between macrophage and T/B cells in the inflammatory periodontal tissues. Our data generated an intriguing catalog of cell types and interaction networks in the human gingiva and identified new inflammation-promoting cell subtypes involved in chronic periodontitis, which will be helpful in advancing host modulation therapy.
Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation
Authors: Liu Jin , Liu Yang , Panda Snigdha , Liu Anguo , Lei Jun , Burd Irina
Published: September 2021

CD8+ T cells recognize non-self antigen by MHC class I molecules and kill the target cells by the release of proinflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Our group previously reported an increase of CD8+ T‐cell trafficking in the placenta with exposure to Lipopolysaccharides (LPS). CD8+ cytotoxic T cells have been classified into distinct subsets based upon cytokine production: Tc1 cells produce IFN-γ, Tc2 cells produce interleukin 4 (IL-4). Accordingly, the purpose of this research is to analyze the subsets of placenta CD8+ T cells. We hypothesized that LPS injection would induce a change of properties of CD8+ T cell and Tc1/Tc2 ratio. We investigated the subsets of CD8+ T cell infiltration to placenta and their specific function in response to LPS-induced inflammation in a mouse model. At embryonic (E) day 17, pregnant CD-1 dams received an intrauterine injection of 25 µg LPS in100 μl PBS or 100 μl of PBS only. Flow cytometry was used to quantify CD8+ T cells, evaluate the phenotype and subtypes, and detect markers of Tc1 and Tc2 cells in placenta, at 6 hours and 24 hours post injection (hpi). Intracellular staining and flow cytometry were performed to characterize cytokines produced by CD8+ T cells. Standard statistical analysis were employed. After 6 and 24 hours of LPS injection, total CD8 T cells increased (P<0.05). Tc1 cells expanded (P<0.05) in LPS-treated dams compared with the PBS group. The Tc1/Tc2 ratio was significantly higher in the LPS group than the PBS group (P<0.05). The expression of TNF-α and IFN-γ were increased in LPS group both at 6hpi and 24 hpi (P<0.05). We identified functional placental CD8+ T cell subtypes and found a significant increase ratio of Tc1/Tc2. Following IUI, CD8+ T cells induced inflammatory response in the placenta primarily via the production of Type 1 cytokines such as IFN-γ and TNF-α. We have provided evidence of a Tc1-bias response and cytokines in the mouse model of IUI.
Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm
Authors: Boni Carolina , Cavazzini Davide , Bolchi Angelo , Rossi Marzia , Vecchi Andrea , Tiezzi Camilla , Barili Valeria , Fisicaro Paola , Ferrari Carlo , Ottonello Simone
Published: September 2021

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these “hot” concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.
Assessing the Risk of Contaminant Dispersion From Fibrous Sediments of Industrial Origin
Authors: Göransson Gunnel , Apler Anna , Dahlberg Anna-Karin , Löfroth Hjördis , Josefsson Sarah , Wiberg Karin , Frogner-Kockum Paul , Nylander Per , Hedfors Jim , Snowball Ian
Published: September 2021

Unregulated discharges of wastewater from pulp and paper factories resulted in the formation of relatively thick organic (cellulose) rich sediments in shallow waters along the Swedish coast. These deposits are known as fiberbanks and are contaminated by persistent organic pollutants (POPs), metals and methylmercury, which can be dispersed by diffusion and advective processes coupled to propeller wash, high river discharges, strong wind waves and submarine landslides. Based on a case study of polychlorinated biphenyls (PCBs), one group of prevalent POPs in the fiberbanks, we present a probabilistic approach to estimate the potential risk of dispersion of fiberbank contaminants. The approach allows for estimation of the dispersal pathways that dominates the risk within a given time and provides more insight about the significance of various dispersion processes. We show that it is highly likely that chemical diffusion and advection triggered by ship-induced resuspension will disperse PCBs (sum of seven congeners; Σ7PCB) above a threshold level for environmental impact, while the likelihood of river and wind-wave generated resuspension dispersion pathways are lower (∼20%, respectively). We further show that there is approximately 5% likelihood that a submarine landslide will disperse Σ7PCB above the threshold level. The study implies that the governing parameters for risk assessment specifically should include reliable data on contaminant concentration, water depth above the fiberbank, estimation of concerned fiberbank areas, time duration of erosive fluid flows and measured diffusion. The approach provides insight into the importance of various dispersion processes. We suggest that it can be applied to support risk assessment, especially when there are limited available data and/or knowledge about the system under study.
A Five-Gene-Based Prognostic Signature for Hepatocellular Carcinoma
Authors: Tian Dazhi , Yu Yang , Zhang Li , Sun Jisan , Jiang Wentao
Published: September 2021

Objective: This study intends to identify potential prognostic marker genes associated with the prognosis of patients suffering from hepatocellular carcinoma (HCC) based on TCGA and GEO analysis.

Methods: TCGA-LIHC cohort was downloaded and the data related to HCC were extracted from The Cancer Genome Atlas (TCGA) database and subjected to differential analysis. HCC-related gene expression datasets were retrieved from the GEO database, followed by differential analysis. After intersection of the results of TCGA and GEO databases, gene interaction analysis was performed to obtain the core genes. To identify the genes related to the prognosis of HCC patients, we conducted univariate and multivariate Cox analyses.

Results: Based on differential analysis of TCGA database, 854 genes were differentially expressed in HCC, any of which might link to the occurrence and progression of HCC. Meanwhile, joint analysis of HCC-related gene expression datasets in the GEO database screened 214 genes. Five core genes CDC20, TOP2A, RRM2, UBE2C and AOX1 were significantly associated with the prognosis of HCC patients and the risk model based on these five genes effectively predicted the prognosis of HCC patients.

Conclusion: Collectively, our data suggest that CDC20, TOP2A, RRM2, UBE2C and AOX1 may be the key genes affecting the prognosis of patients with HCC. The five-gene signature could accurately predict the prognosis of HCC patients.
Predicting Severe/Critical Outcomes in Patients With SARS-CoV2 Pneumonia: Development of the prediCtion seveRe/crItical ouTcome in COVID-19 (CRITIC) Model
Authors: Salaffi Fausto , Carotti Marina , Di Carlo Marco , Ceccarelli Luca , Galli Massimo , Sarzi-Puttini Piercarlo , Giovagnoni Andrea
Published: September 2021

Objective: To create a prediction model of the risk of severe/critical disease in patients with Coronavirus disease (COVID-19).

Methods: Clinical, laboratory, and lung computed tomography (CT) severity score were collected from patients admitted for COVID-19 pneumonia and considered as independent variables for the risk of severe/critical disease in a logistic regression analysis. The discriminative properties of the variables were analyzed through the area under the receiver operating characteristic curve analysis and included in a prediction model based on Fagan's nomogram to calculate the post-test probability of severe/critical disease. All analyses were conducted using Medcalc (version 19.0, MedCalc Software, Ostend, Belgium).

Results: One hundred seventy-one patients with COVID-19 pneumonia, including 37 severe/critical cases (21.6%) and 134 mild/moderate cases were evaluated. Among all the analyzed variables, Charlson Comorbidity Index (CCI) was that with the highest relative importance (p = 0.0001), followed by CT severity score (p = 0.0002), and age (p = 0.0009). The optimal cut-off points for the predictive variables resulted: 3 for CCI [sensitivity 83.8%, specificity 69.6%, positive likelihood ratio (+LR) 2.76], 69.9 for age (sensitivity 94.6%, specificity 68.1, +LR 2.97), and 53 for CT severity score (sensitivity 64.9%, specificity 84.4%, +LR 4.17).

Conclusion: The nomogram including CCI, age, and CT severity score, may be used to stratify patients with COVID-19 pneumonia.
Case Series: The Coexistence of Thrombocytopenia and Thromboembolism in COVID-19 Patients on ECMO: A Case Series and Literature Review
Authors: Jones Can , Chen Kai , Narendran Vijay
Published: September 2021

Thrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients. The fact that COVID-19 patients develop both thrombocytopenia and thromboembolism has been observed, and multiple studies have investigated the underlying pathophysiology. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure and not respond to conventional mechanical ventilation. ECMO induces thromboembolism and raises the incidence of developing thromboembolic events in COVID-19 patients. Here, we report the hospital courses and outcomes of three COVID-19 patients who were treated with ECMO, then developed both thrombocytopenia and thromboembolism. The coexistence of thrombocytopenia and thromboembolism challenges the clinical treatment strategy, including the decision of initiating anticoagulation. Based on current data, anticoagulation is recommended to all hospitalized COVID-19 patients unless there is active bleeding, previous bleeding history within 3 days, or platelet count is lower than 30,000 cells/μl. Further investigation into the mechanisms and implications of thrombocytopenia and thromboembolism in patients with COVID-19 pneumonia will lead to significantly improved outcomes and prognosis for the patients.
Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development
Authors: Reynolds Lauren M. , Flores Cecilia
Published: September 2021

Mesocorticolimbic dopamine circuity undergoes a protracted maturation during adolescent life. Stable adult levels of behavioral functioning in reward, motivational, and cognitive domains are established as these pathways are refined, however, their extended developmental window also leaves them vulnerable to perturbation by environmental factors. In this review, we highlight recent advances in understanding the mechanisms underlying dopamine pathway development in the adolescent brain, and how the environment influences these processes to establish or disrupt neurocircuit diversity. We further integrate these recent studies into the larger historical framework of anatomical and neurochemical changes occurring during adolescence in the mesocorticolimbic dopamine system. While dopamine neuron heterogeneity is increasingly appreciated at molecular, physiological, and anatomical levels, we suggest that a developmental facet may play a key role in establishing vulnerability or resilience to environmental stimuli and experience in distinct dopamine circuits, shifting the balance between healthy brain development and susceptibility to psychiatric disease.
Non-Coding RNAs: Emerging Therapeutic Targets in Spinal Cord Ischemia–Reperfusion Injury
Authors: Ling Xiao , Lu Jun , Yang Jun , Qin Hanjun , Zhao Xingqi , Zhou Pengyu , Zheng Shaoyi , Zhu Peng
Published: September 2021

Paralysis or paraplegia caused by transient or permanent spinal cord ischemia–reperfusion injury (SCIRI) remains one of the most devastating post-operative complications after thoracoabdominal aortic surgery, even though perioperative strategies and surgical techniques continue to improve. Uncovering the molecular and cellular pathophysiological processes in SCIRI has become a top priority. Recently, the expression, function, and mechanism of non-coding RNAs (ncRNAs) in various diseases have drawn wide attention. Non-coding RNAs contain a variety of biological functions but do not code for proteins. Previous studies have shown that ncRNAs play a critical role in SCIRI. However, the character of ncRNAs in attenuating SCIRI has not been systematically summarized. This review article will be the first time to assemble the knowledge of ncRNAs regulating apoptosis, inflammation, autophagy, and oxidative stress to attenuate SCIRI. A better understanding of the functional significance of ncRNAs following SCIRI could help us to identify novel therapeutic targets and develop potential therapeutic strategies. All the current research about the function of nRNAs in SCIRI will be summarized one by one in this review.
Admission and Readmission/Death Patterns in Hospitalized and Non-hospitalized First-Ever-in-a-Lifetime Stroke Patients During the First Year: A Population-Based Incidence Study
Authors: Abreu Pedro , Magalhães Rui , Baptista Diana , Azevedo Elsa , Correia Manuel
Published: September 2021

Background: Hospitalization and readmission rates after a first-ever-in-a-lifetime stroke (FELS) are considered measures of quality of care and, importantly, may give valuable information to better allocate health-related resources. We aimed to investigate the hospitalization pattern and the unplanned readmissions or death of hospitalized (HospS) and non-hospitalized stroke (NHospS) patients 1 year after a FELS, based on a community register.

Methods: Data about hospitalization and unplanned readmissions and case fatality 1 year after a FELS were retrieved from the population-based register undertaken in Northern Portugal (ACIN2), comprising all FELS in 2009–2011. We used the Kaplan–Meier method to estimate 1-year readmission/death-free survival and Cox proportional hazard models to identify independent factors for readmission/death.

Results: Of the 720 FELS, 35.7% were not hospitalized. Unplanned readmission/death within 1 year occurred in 33.0 and 24.9% of HospS and NHospS patients, respectively. The leading causes of readmission were infections, recurrent stroke, and cardiovascular events. Stroke-related readmissions were observed in more than half of the patients in both groups. Male sex, age, pre- and post-stroke functional status, and diabetes were independent factors of readmission/death within 1 year.

Conclusion: About one-third of stroke patients were not hospitalized, and the readmission/death rate was higher in HospS patients. Still, that readmission/death rate difference was likely due to other factors than hospitalization itself. Our research provides novel information that may help implement targeted health-related policies to reduce the burden of stroke and its complications.
Quantifying the Changes of Mechanical and Electrical Properties of Paralyzed Muscle in Survivors With Cervical Spinal Cord Injury
Authors: Hu Huijing , Chen Yingyue , Wang Xiaoyun , Lo Wai Leung Ambrose , Li Le
Published: September 2021

Background: Survivors with spinal cord injury (SCI) have neuromuscular deficits such as muscle atrophy that lead to functional impairments. This study utilized myotonometry and electrical impedance myography (EIM) to quantitatively evaluate the changes in muscle mechanical properties and compositions after SCI.

Methods: This study adopted a cross-sectional design. Eighteen SCI patients and 18 healthy individuals were recruited. The outcome measures were: (1) The myotonometer measured muscle mechanical parameters of oscillation frequency (freq), dynamic stiffness, logarithmic decrement (decr), mechanical stress relaxation time, and indication of creep. (2) The electrical impedance myography measured parameters of resistance (R), reactance (X), and phase angle (θ). (3) muscle strength (maxForce); (4) clinical scales of Manual Muscle Testing (MMT) and modified Ashworth scale (MAS). All outcome measures were compared between the bicep brachii muscle of the weaker side of the SCI group and the non-dominate side of the healthy group. Correlation analysis was performed at quantitative data and clinical scales.

Results: Freq, stiffness, and maxForce of the SCI group were significantly lower (p < 0.01) than those of the healthy control. The relaxation time and creep were significantly higher in the SCI group than in the control group. Significant differences of R and Xc were observed between the two groups. Significant correlation was observed between freq, stiffness, and months past injury, and between Xc, creep, and relaxation time.

Conclusions: Reduced muscle tone and stiffness might relate to muscle atrophy, and higher relax time and creep may be caused by poor contractile ability. The changes in EIM parameters could indirectly reflect the muscle cell size, and fatty and connective tissue alterations. These findings support the feasibility of myotonometer and EIM to quantify muscle mechanical and intrinsic properties in patients with SCI. The results could facilitate the understanding of neuromuscular changes that are related to functional impairments.
Physical, Emotional, Medical, and Socioeconomic Status of Patients With NMOSD: A Cross-Sectional Survey of 123 Cases From a Single Center in North China
Authors: Jia Zhen , Dong XiuYu , Song Shuang , Guo Ruoyi , Zhang Lu , Liu Jia , Li Bin
Published: September 2021

Objective: This study aimed to assess the physical, emotional, medical, and socioeconomic conditions of patients with neuromyelitis optica spectrum disorder (NMOSD) in North China.

Methods: A cross-sectional survey of patients with NMOSD was performed, based on an established questionnaire from the Multiple Sclerosis Patient Survival Report 2018. Logistic regression analysis was conducted to define the significant determinants of certain physical or emotional characteristics of patients. A total of 123 patients were included.

Results: A total of 63.4% of participants were initially diagnosed with conditions other than NMOSD, with a median delay of 6 months for accurate diagnosis. An aggregate of 72.2% of patients had one or more relapses, corresponding to an annual relapse rate of 0.8. Paresthesia was the most frequent physical symptom among patients both at disease onset (53.7%) and throughout the duration of the disease (86.2%). Onset in elderly (>50 years) patients was associated with an annual Expanded Disability Status Scale increase ≥1, compared with onset in younger (<30 years) patients (P = 0.001, OR = 7.83). A total of 76.4% of patients had received attack-prevention treatments in the remission phase, and 31.7 and 10.6% of patients had ever been administered rituximab and traditional Chinese medicine, respectively. Additionally, 63.4 and 43.1% of patients reported participating in few or no social activities and being out of work because of the disease. To be noted, 76.4% of patients reported suffering from negative emotions, with the most frequent being worry (60.2%), with 20.3% of patients experiencing suicidal thoughts. The inability to work and participating in few or no social activities due to NMOSD were two determinants of experiencing negative emotions (Pwork = 0.03, ORwork = 3.34; Psocialactivities = 0.02, ORsocialactivities = 3.19).

Conclusion: This study reported patient perspectives on NMOSD in North China, whereby demonstrating that the inability to work and participating in few or no social activities due to NMOSD rather than the physical impairment caused by the disease, was directly associated with patients experiencing negative emotions. This insight offers potential ways to manage patients' negative emotions by enhancing family and social support and facilitating active employment.
Role of 3D Volumetric and Perfusion Imaging for Detecting Early Changes in Pancreatic Adenocarcinoma
Authors: Rahmanuddin Syed , Korn Ronald , Cridebring Derek , Borazanci Erkut , Brase Jordyn , Boswell William , Jamil Asma , Cai Wenli , Sabir Aqsa , Motarjem Pejman , Koay Eugene , Mitra Anirban , Goel Ajay , Ho Joyce , Chung Vincent , Von Hoff Daniel D.
Published: September 2021

Purpose

There is a major shortage of reliable early detection methods for pancreatic cancer in high-risk groups. The focus of this preliminary study was to use Time Intensity-Density Curve (TIDC) and Marley Equation analyses, in conjunction with 3D volumetric and perfusion imaging to demonstrate their potential as imaging biomarkers to assist in the early detection of Pancreatic Ductal Adenocarcinoma (PDAC).

Experimental Designs

A quantitative retrospective and prospective study was done by analyzing multi-phase Computed Tomography (CT) images of 28 patients undergoing treatment at different stages of pancreatic adenocarcinoma using advanced 3D imaging software to identify the perfusion and radio density of tumors.

Results

TIDC and the Marley Equation proved useful in quantifying tumor aggressiveness. Perfusion delays in the venous phase can be linked to Vascular Endothelial Growth Factor (VEGF)-related activity which represents the active part of the tumor. 3D volume analysis of the multiphase CT scan of the patient showed clear changes in arterial and venous perfusion indicating the aggressive state of the tumor.

Conclusion

TIDC and 3D volumetric analysis can play a significant role in defining the response of the tumor to treatment and identifying early-stage aggressiveness.
Exploration of Lipid Metabolism in Gastric Cancer: A Novel Prognostic Genes Expression Profile
Authors: Xiong Zhen , Lin Yao , Yu Yan , Zhou Xianghui , Fan Jun , Rog Colin J. , Cai Kailin , Wang Zheng , Chang Zhijie , Wang Guobin , Tao Kaixiong , Cai Ming
Published: September 2021

Background

Alterations in lipid metabolism are increasingly being recognized. However, the application of lipid metabolism in the prognosis of gastric cancer (GC) has not yet been explored.

Methods

A total of 204 lipid metabolism relative genes were analyzed in the GC cohort from The Cancer Genome Atlas (TCGA), and four independent cohorts from Gene Expression Omnibus (GEO) and one cohort from Wuhan Union Hospital were applied for external validation. Differential expression and enrichment analyses were performed between GC and normal tissue. The LASSO-Cox proportional hazard regression model was applied to select prognostic genes and to construct a gene expression profile.

Results

Our research indicated that higher expression level of AKR1B1, PLD1, and UGT8 were correlated with worse prognosis of GC patients, while AGPAT3 was correlated with better prognosis. Furthermore, we developed a gene profile composed of AGPAT3, AKR1B1, PLD1, and UGT8 suggested three groups with a significant difference in overall survival (OS). The profile was successfully validated in an independent cohort and performed well in the immunohistochemical cohort. Furthermore, we found that ether lipid metabolism, glycerophospholipid metabolism, and glycerolipid metabolism were upregulated, and fatty acid β-oxidation and other lipid peroxidation processes were reduced in GC.

Conclusion

Collectively, we found lipid metabolism is reliable and clinically applicable in predicting the prognosis of GC based on a novel gene profile.
Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma
Authors: Qi Feng , Du Xiaojing , Zhao Zhiying , Zhang Ding , Huang Mengli , Bai Yuezong , Yang Biwei , Qin Wenxing , Xia Jinglin
Published: September 2021

Tumor mutation burden (TMB) is associated with immune infiltration, while its underlying mechanism in hepatocellular carcinoma (HCC) remains unclear. A long noncoding RNA (lncRNA)-related competitive endogenous RNA (ceRNA) network can regulate various tumor behaviors, and research about its correlation with TMB and immune infiltration is warranted. Data were downloaded from TCGA and ArrayExpress databases. Cox analysis and machine learning algorithms were employed to establish a lncRNA-based prognostic model for HCC. We then developed a nomogram model to predict overall survival and odds of death for HCC patients. The association of this prognostic model with TMB and immune infiltration was also analyzed. In addition, a ceRNA network was constructed by using DIANA-LncBasev2 and the starBase database and verified by luciferase reporter and colocalization analysis. Multiplex immunofluorescence was applied to determine the correlation between ULBP1 and PD-L1. An eight-lncRNA (SLC25A30-AS1, HPN-AS1, LINC00607, USP2-AS1, HCG20, LINC00638, MKLN1-AS and LINC00652) prognostic score model was constructed for HCC, which was highly associated with TMB and immune infiltration. Next, we constructed a ceRNA network, LINC00638/miR-4732-3p/ULBP1, that may be responsible for NK cell infiltration in HCC with high TMB. However, patients with high ULBP1 possessed a poorer prognosis. Using multiplex immunofluorescence, we found a significant correlation between ULBP1 and PD-L1 in HCC, and patients with high ULBP1 and PD-L1 had the worst prognosis. In brief, the eight-lncRNA model is a reliable tool to predict the prognosis of HCC patients. The LINC00638/miR-4732-3p/ULBP1 axis may regulate immune escape via PD-L1 in HCC with high TMB.
MYBL2 Gene Polymorphism Is Associated With Acute Lymphoblastic Leukemia Susceptibility in Children
Authors: Guo Haixia , Li Na , Sun Yaping , Wu Cuiling , Deng Huixia , Xu Ling , Yang Xu
Published: September 2021

Purpose

Although MYBL2 had been validated to participate in multiple cancers including leukemia, the role of MYBL2 polymorphisms in acute lymphoblastic leukemia (ALL) was still not clear. In this study, we aimed to evaluate the association between MYBL2 single nucleotide polymorphisms (SNPs) and ALL risk in children.

Methods

A total of 687 pediatric ALL cases and 971 cancer-free controls from two hospitals in South China were recruited. A case-control study by genotyping three SNPs in the MYBL2 gene (rs285162 C>T, rs285207 A>C, and rs2070235 A>G) was conducted. The associations were assessed by odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup and stratification analyses were conducted to explore the association of rs285207 with ALL risk in terms of age, sex, immunophenotype, risk level, and other clinical characteristics. The false-positive report probability (FPRP) analysis was performed to verify each significant finding. Functional analysis in silico was used to evaluate the probability that rs285207 might influence the regulation of MYBL2.

Results

Our study demonstrated that rs285207 was related to a decreased ALL risk (adjusted OR = 0.78; 95% CI = 0.63-0.97, P = 0.022) in the dominant model. The associations of rs285207 with ALL risk appeared stronger in patients with pre B ALL (adjusted OR=0.56; 95% CI=0.38-0.84, P=0.004), with normal diploid (adjusted OR=0.73; 95% CI=0.57-0.95, P=0.017), with low risk (adjusted OR=0.68; 95% CI=0.49-0.94, P=0.021), with lower WBC (adjusted OR=0.62; 95% CI=0.43-0.87, P=0.007) or lower platelet level (adjusted OR=0.76; 95% CI=0.59-0.96, P=0.023). With FPRP analysis, the significant association between the rs285207 polymorphism and decreased ALL risk was still noteworthy (FPRP=0.128). Functional analysis showed that IKZF1 bound to DNA motif overlapping rs285207 and had a higher preference for the risk allele A. As for rs285162 C>T and rs2070235 A>G, no significant was found between them and ALL risk.

Conclusion

In this study, we revealed that rs285207 polymorphism decreased the ALL risk in children, and rs285207 might alter the binding to IKZF1, which indicated that the MYBL2 gene polymorphism might be a potential biomarker of childhood ALL.
Type-4 Phosphodiesterase (PDE4) Blockade Reduces NETosis in Cystic Fibrosis
Authors: Totani Licia , Amore Concetta , Piccoli Antonio , Dell’Elba Giuseppe , Di Santo Angelo , Plebani Roberto , Pecce Romina , Martelli Nicola , Rossi Alice , Ranucci Serena , De Fino Ida , Moretti Paolo , Bragonzi Alessandra , Romano Mario , Evangelista Virgilio
Published: September 2021

Neutrophilic inflammation is a key determinant of cystic fibrosis (CF) lung disease. Neutrophil-derived free DNA, released in the form of extracellular traps (NETs), significantly correlates with impaired lung function in patients with CF, underlying their pathogenetic role in CF lung disease. Thus, specific approaches to control NETosis of neutrophils migrated into the lungs may be clinically relevant in CF. We investigated the efficacy of phosphodiesterase (PDE) type-4 inhibitors, in vitro, on NET release by neutrophils from healthy volunteers and individuals with CF, and in vivo, on NET accumulation and lung inflammation in mice infected with Pseudomonas aeruginosa. PDE4 blockade curbed endotoxin-induced NET production and preserved cellular integrity and apoptosis in neutrophils, from healthy subjects and patients with CF, challenged with endotoxin, in vitro. The pharmacological effects of PDE4 inhibitors were significantly more evident on CF neutrophils. In a mouse model of Pseudomonas aeruginosa chronic infection, aerosol treatment with roflumilast, a selective PDE4 inhibitor, gave a significant reduction in free DNA in the BALF. This was accompanied by reduced citrullination of histone H3 in neutrophils migrated into the airways. Roflumilast-treated mice showed a significant improvement in weight recovery. Our study provides the first evidence that PDE4 blockade controls NETosis in vitro and in vivo, in CF-relevant models. Since selective PDE4 inhibitors have been recently approved for the treatment of COPD and psoriasis, our present results encourage clinical trials to test the efficacy of this class of drugs in CF.
LncRNA Nqo1-AS1 Attenuates Cigarette Smoke-Induced Oxidative Stress by Upregulating its Natural Antisense Transcript Nqo1
Authors: Zhang Haiyun , Guan Ruijuan , Zhang Zili , Li Defu , Xu Jingyi , Gong Yuxin , Chen Xin , Lu Wenju
Published: September 2021

Evidence of the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of chronic obstructive pulmonary disease (COPD) is growing but still largely unknown. This study aims to explore the expression, functions and molecular mechanisms of Fantom3_F830212L20, a lncRNA that transcribes in an antisense orientation to Nqo1.We name this lncRNA as Nqo1 antisense transcript 1 (Nqo1-AS1). The distribution, expression level and protein coding potential of Nqo1-AS1 were determined. The effects of Nqo1-AS1 on cigarette smoke (CS)-induced oxidative stress were also evaluated. The results showed that Nqo1-AS1 were mainly located in the cytoplasm of mouse alveolar epithelium and had a very low protein coding potential. Nqo1-AS1 (or its human homologue) was increased with the increase of CS exposure. Nqo1-AS1 overexpression enhanced the mRNA and protein levels of Nqo1 and Serpina1 mRNA expression, and attenuated CS-induced oxidative stress, whereas knockdown of Nqo1-AS1 significantly decreased Nqo1 and Serpina1 mRNA expressions, and aggravated CS-induced oxidative stress. Nqo1-AS1 increased Nqo1 mRNA stability and upregulated Nqo1 expression through antisense pairing with Nqo1 3′UTR. In conclusion, these results suggest that Nqo1-AS1 attenuates CS-induced oxidative stress by increasing Nqo1 mRNA stability and upregulating Nqo1 expression, which might serve as a novel approach for the treatment of COPD.
Comparison of Complex k-Space Data and Magnitude-Only for Training of Deep Learning–Based Artifact Suppression for Real-Time Cine MRI
Authors: Haji-Valizadeh Hassan , Guo Rui , Kucukseymen Selcuk , Tuyen Yankama , Rodriguez Jennifer , Paskavitz Amanda , Pierce Patrick , Goddu Beth , Ngo Long H. , Nezafat Reza
Published: September 2021

Propose: The purpose of this study was to compare the performance of deep learning networks trained with complex-valued and magnitude images in suppressing the aliasing artifact for highly accelerated real-time cine MRI.

Methods: Two 3D U-net models (Complex-Valued-Net and Magnitude-Net) were implemented to suppress aliasing artifacts in real-time cine images. ECG-segmented cine images (n = 503) generated from both complex k-space data and magnitude-only DICOM were used to synthetize radial real-time cine MRI. Complex-Valued-Net and Magnitude-Net were trained with fully sampled and synthetized radial real-time cine pairs generated from highly undersampled (12-fold) complex k-space and DICOM images, respectively. Real-time cine was prospectively acquired in 29 patients with 12-fold accelerated free-breathing tiny golden-angle radial sequence and reconstructed with both Complex-Valued-Net and Magnitude-Net. Cardiac function, left-ventricular (LV) structure, and subjective image quality [1(non-diagnostic)-5(excellent)] were calculated from Complex-Valued-Net– and Magnitude-Net–reconstructed real-time cine datasets and compared to those of ECG-segmented cine (reference).

Results: Free-breathing real-time cine reconstructed by both networks had high correlation (all R2 > 0.7) and good agreement (all p > 0.05) with standard clinical ECG-segmented cine with respect to LV function and structural parameters. Real-time cine reconstructed by Complex-Valued-Net had superior image quality compared to images from Magnitude-Net in terms of myocardial edge sharpness (Complex-Valued-Net = 3.5 ± 0.5; Magnitude-Net = 2.6 ± 0.5), temporal fidelity (Complex-Valued-Net = 3.1 ± 0.4; Magnitude-Net = 2.1 ± 0.4), and artifact suppression (Complex-Valued-Net = 3.1 ± 0.5; Magnitude-Net = 2.0 ± 0.0), which were all inferior to those of ECG-segmented cine (4.1 ± 1.4, 3.9 ± 1.0, and 4.0 ± 1.1).

Conclusion: Compared to Magnitude-Net, Complex-Valued-Net produced improved subjective image quality for reconstructed real-time cine images and did not show any difference in quantitative measures of LV function and structure.
Ca2+ and Membrane Potential Transitions During Action Potentials Are Self-Similar to Each Other and to Variability of AP Firing Intervals Across the Broad Physiologic Range of AP Intervals During Autonomic Receptor Stimulation
Authors: Yang Dongmei , Morrell Christopher H. , Lyashkov Alexey E. , Tagirova Sirenko Syevda , Zahanich Ihor , Yaniv Yael , Vinogradova Tatiana M. , Ziman Bruce D. , Maltsev Victor A. , Lakatta Edward G.
Published: September 2021

Ca2+ and Vm transitions occurring throughout action potential (AP) cycles in sinoatrial nodal (SAN) cells are cues that (1) not only regulate activation states of molecules operating within criticality (Ca2+ domain) and limit-cycle (Vm domain) mechanisms of a coupled-clock system that underlies SAN cell automaticity, (2) but are also regulated by the activation states of the clock molecules they regulate. In other terms, these cues are both causes and effects of clock molecular activation (recursion). Recently, we demonstrated that Ca2+ and Vm transitions during AP cycles in single SAN cells isolated from mice, guinea pigs, rabbits, and humans are self-similar (obey a power law) and are also self-similar to trans-species AP firing intervals (APFIs) of these cells in vitro, to heart rate in vivo, and to body mass. Neurotransmitter stimulation of β-adrenergic receptor or cholinergic receptor–initiated signaling in SAN cells modulates their AP firing rate and rhythm by impacting on the degree to which SAN clocks couple to each other, creating the broad physiologic range of SAN cell mean APFIs and firing interval variabilities. Here we show that Ca2+ and Vm domain kinetic transitions (time to AP ignition in diastole and 90% AP recovery) occurring within given AP, the mean APFIs, and APFI variabilities within the time series of APs in 230 individual SAN cells are self-similar (obey power laws). In other terms, these long-range correlations inform on self-similar distributions of order among SAN cells across the entire broad physiologic range of SAN APFIs, regardless of whether autonomic receptors of these cells are stimulated or not and regardless of the type (adrenergic or cholinergic) of autonomic receptor stimulation. These long-range correlations among distributions of Ca2+ and Vm kinetic functions that regulate SAN cell clock coupling during each AP cycle in different individual, isolated SAN cells not in contact with each other. Our numerical model simulations further extended our perspectives to the molecular scale and demonstrated that many ion currents also behave self-similar across autonomic states. Thus, to ensure rapid flexibility of AP firing rates in response to different types and degrees of autonomic input, nature “did not reinvent molecular wheels within the coupled-clock system of pacemaker cells,” but differentially engaged or scaled the kinetics of gears that regulate the rate and rhythm at which the “wheels spin” in a given autonomic input context.
Long-Term Desynchronization by Coordinated Reset Stimulation in a Neural Network Model With Synaptic and Structural Plasticity
Authors: Manos Thanos , Diaz-Pier Sandra , Tass Peter A.
Published: September 2021

Several brain disorders are characterized by abnormal neuronal synchronization. To specifically counteract abnormal neuronal synchrony and, hence, related symptoms, coordinated reset (CR) stimulation was computationally developed. In principle, successive epochs of synchronizing and desynchronizing stimulation may reversibly move neural networks with plastic synapses back and forth between stable regimes with synchronized and desynchronized firing. Computationally derived predictions have been verified in pre-clinical and clinical studies, paving the way for novel therapies. However, as yet, computational models were not able to reproduce the clinically observed increase of desynchronizing effects of regularly administered CR stimulation intermingled by long stimulation-free epochs. We show that this clinically important phenomenon can be computationally reproduced by taking into account structural plasticity (SP), a mechanism that deletes or generates synapses in order to homeostatically adapt the firing rates of neurons to a set point-like target firing rate in the course of days to months. If we assume that CR stimulation favorably reduces the target firing rate of SP, the desynchronizing effects of CR stimulation increase after long stimulation-free epochs, in accordance with clinically observed phenomena. Our study highlights the pivotal role of stimulation- and dosing-induced modulation of homeostatic set points in therapeutic processes.
Genetic Variation in Host-Specific Competitiveness of the Symbiont Rhizobium leguminosarum Symbiovar viciae
Authors: Boivin Stéphane , Mahé Frederic , Debellé Frédéric , Pervent Marjorie , Tancelin Mathilde , Tauzin Marc , Wielbo Jerzy , Mazurier Sylvie , Young Peter , Lepetit Marc
Published: September 2021

Legumes of the Fabeae tribe form nitrogen-fixing root nodules resulting from symbiotic interaction with the soil bacteria Rhizobium leguminosarum symbiovar viciae (Rlv). These bacteria are all potential symbionts of the Fabeae hosts but display variable partner choice when co-inoculated in mixture. Because partner choice and symbiotic nitrogen fixation mostly behave as genetically independent traits, the efficiency of symbiosis is often suboptimal when Fabeae legumes are exposed to natural Rlv populations present in soil. A core collection of 32 Rlv bacteria was constituted based on the genomic comparison of a collection of 121 genome sequences, representative of known worldwide diversity of Rlv. A variable part of the nodD gene sequence was used as a DNA barcode to discriminate and quantify each of the 32 bacteria in mixture. This core collection was co-inoculated on a panel of nine genetically diverse Pisum sativum, Vicia faba, and Lens culinaris genotypes. We estimated the relative Early Partner Choice (EPC) of the bacteria with the Fabeae hosts by DNA metabarcoding on the nodulated root systems. Comparative genomic analyses within the bacterial core collection identified molecular markers associated with host-dependent symbiotic partner choice. The results revealed emergent properties of rhizobial populations. They pave the way to identify genes related to important symbiotic traits operating at this level.
Sex Differences in Psychological Status and Fatigue of Frontline Staff After the COVID-19 Outbreak in China: A Cross-Sectional Study
Authors: Teng Ziwei , Su Yuhan , Chen Jindong , Wu Renrong , Tang Hui , Wu Haishan , Liu Xuming , Ling Heqiao , Yuan Hui , Huang Jing
Published: September 2021

Background: The coronavirus disease 2019 (COVID-19) is spreading globally, and it is significant to pay attention to the mental health of frontline staff in this pandemic. This study is aimed to explore the sex difference among the frontline staff in demographics, characteristics of mental state, and the potential relationship between them.

Method: A total of 2,614 Chinese frontline staff were recruited. The Self-Rating Anxiety Scale (SAS) and the Patient Health Questionnaire-9 (PHQ-9) were used for assessing the mental status of frontline staff, and the Fatigue Self-Assessment Scale (FSAS) was used for detecting fatigue.

Result: The prevalence rate of anxiety for female frontline staff is higher than that of male (P = 0.003), and the prevalence rate of depression is similar between them (P = 0.091). After comparing the risk factors of unhealthy mental state between different sexes, it is found that family income below 100,000 [depression: odds ratio (OR) 1.37; 95% CI, 1.08–1.73; anxiety: OR 1.99; 95% CI, 1.44–2.75], unsupported of family (depression: OR 10.94; 95% CI, 1.39–85.79; anxiety: OR 11.92; 95% CI, 3.80–37.36), and marriage (depression: OR 1.67; 95% CI, 1.15–2.43) are risk factors for male, and total fatigue (depression: OR 2.96; 95% CI, 1.46–6.02) is risk factor for female.

Conclusions: This study found that depression and anxiety are widespread among the frontline staff of COVID-19, and anxiety showed a higher prevalence rate among female frontline staff. From the sex difference in risk factors, the focus of psychological interventions may differ between genders. Men with low family income, unsupported by family or marriage, and women with a high score of total fatigue required particular attention to their psychological status.
Leadership Styles and Organizational Citizenship Behavior for the Environment: The Mediating Role of Self-Efficacy and Psychological Ownership
Authors: Ullah Irfan , Wisetsri Worakamol , Wu Hao , Shah Syed Mehmood Ali , Abbas Ali , Manzoor Shahid
Published: September 2021

Graphical Abstract

Graphical abstract shows the visual representation of direct and indirect relationships.