bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune System and Neuroinflammation in Idiopathic Parkinson’s Disease: Association Analysis of Genetic Variants and miRNAs Interactions
Authors: Strafella Claudia , Caputo Valerio , Termine Andrea , Assogna Francesca , Pellicano Clelia , Pontieri Francesco E. , Macchiusi Lucia , Minozzi Giulietta , Gambardella Stefano , Centonze Diego , Bossù Paola , Spalletta Gianfranco , Caltagirone Carlo , Giardina Emiliano , Cascella Raffaella
Published: June 2021

The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of idiopathic Parkinson’s Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated with PD susceptibility. Of them, 12 SNPs were described as significant expression Quantitative Loci (eQTL) variants in different brain regions associated with motor and non-motor PD phenomenology. Moreover, the study highlighted 11 novel susceptibility genes for PD, which may alter multiple signaling pathways critically involved in peripheral immune response, neuroinflammation, neurodegeneration and dopaminergic neurons wiring. The study of miRNA-target genes highlighted a possible role of miR-499a, miR-196a2, and miR-29a in the modulation of multiple neuroinflammatory and neurodegenerative mechanisms underlying PD physiopathology. The study described a network of interconnected genes (APOE, CLU, IL6, IL7R, IL12B, INPP5D, MAPK1, MEF2C, MIF, and TNFSF14), which may act as upstream regulators in the modulation of biological pathways relevant to PD. Intriguingly, IL6 stands out as a master gene regulator since it may indirectly regulate the network of interconnected genes. The study highlighted different genes and miRNAs interactions potentially involved in PD physiopathology, which are worth to be further explored to improve the knowledge of disease and the research of novel treatments strategies.
Identification of a Competing Endogenous RNA Network Related to Immune Signature in Lung Adenocarcinoma
Authors: Zhu Ting , Yu Yong , Liu Jun , Ren Kaiming
Published: June 2021

Background

The establishment of immunotherapy has led to a new era in oncotherapy. But the signature of immune-related genes (IRGs) in LUAD remains to be elucidated. Here we use integrated analysis to identify IRGs roles in immune signature and detect their relationship with competing endogenous RNA (ceRNA) networks in LUAD progression.

Methods

By analyzing the RNA-seq data from different platforms, we recognized the differentially expressed genes (DEGs) of each platform and screened out the top 20 hub IRGs related to immune responses. Then, we applied the CIBERSORT algorithm to explore the landscape of tumor-infiltrating immune cells (TILs) in LUAD and their connection with hub genes. Next, we predicted and validated the upstream miRNAs and lncRNAs according to their expression and prognostic roles. Finally, we constructed and validated an immune-related ceRNA network by co-expression analysis.

Results

A total of 71 IRGs were identified among 248 DEGs, which play key roles in immune responses. CIBERSORT analysis showed that six hub genes were closely related to TILs, such as SPP1 and naive B cells (R = −0.17), TEK and resting mast cells (R = 0.37). Stepwise prediction and validation from mRNA to lncRNA, including 6 hub genes, 5 miRNAs, and 9 lncRNAs, were applied to construct a ceRNA network. Ultimately, we confirmed the TMPO-AS1/miR-126-5p/SPP1 and CARD8-AS1/miR-21-5p/TEK as immune-related ceRNA networks in LUAD progression.

Conclusion

We elucidated two immune-related ceRNA networks in LUAD progression, which can be considered as immunotherapy targets for this disease.
Thymosin Alpha-1 Has no Beneficial Effect on Restoring CD4+ and CD8+ T Lymphocyte Counts in COVID-19 Patients
Authors: Wang Zhenyan , Chen Jun , Zhu Cuiyun , Liu Li , Qi Tangkai , Shen Yinzhong , Zhang Yuyi , Xu Lie , Li Tao , Qian Zhiping , Steinhart Corklin R. , Lu Hongzhou
Published: June 2021

Dysregulation of immune response was observed in COVID-19 patients. Thymosin alpha 1 (Tα1) is used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancers. We aim to observe the longitudinal changes in T lymphocyte subsets and to evaluate the efficacy of Tα1 for COVID-19. A retrospective study was conducted in 275 COVID-19 patients admitted to Shanghai public health clinical center. The clinical and laboratory characteristics between patients with different T lymphocyte phenotypes and those who were and were not treated with Tα1 were compared. Among the 275 patients, 137 (49.8%) were males, and the median age was 51 years [interquartile range (IQR): 37-64]. A total of 126 patients received Tα1 therapy and 149 patients did not. There were 158 (57.5%) patients with normal baseline CD4 counts (median:631/μL, IQR: 501~762) and 117 patients (42.5%) with decreased baseline CD4 counts (median:271/μL, IQR: 201~335). In those with decreased baseline CD4 counts, more patients were older (p<0.001), presented as critically ill (p=0.032) and had hypertension (p=0.008) compared with those with normal CD4 counts. There was no statistical difference in the duration of virus shedding in the upper respiratory tract between the two groups (p=0.214). In both the normal (14 vs 11, p=0.028) and the decreased baseline CD4 counts group (15 vs 11, p=0.008), duration of virus clearance in the patients with Tα1 therapy was significantly longer than that in those without Tα1 therapy. There was no significant difference in the increase of CD4+ (286 vs 326, p=0.851) and CD8+ T cell (154 vs 170, p=0.842) counts in the recovery period between the two groups with or without Tα1 therapy. Multivariate linear regression analysis showed that severity of illness (p<0.001) and Tα1 therapy (p=0.001) were associated with virus clearance. In conclusion, reduction of CD4+ T and CD8+ T cell counts were observed in COVID-19 patients. Tα1 may have no benefit on restoring CD4+ and CD8+ T cell counts or on the virus clearance. The use of Tα1 for COVID-19 need to be more fully investigated.
Recent Advances in Immunosafety and Nanoinformatics of Two-Dimensional Materials Applied to Nano-imaging
Authors: Da Silva Gabriela H. , Franqui Lidiane S. , Petry Romana , Maia Marcella T. , Fonseca Leandro C. , Fazzio Adalberto , Alves Oswaldo L. , Martinez Diego Stéfani T.
Published: June 2021

Two-dimensional (2D) materials have emerged as an important class of nanomaterials for technological innovation due to their remarkable physicochemical properties, including sheet-like morphology and minimal thickness, high surface area, tuneable chemical composition, and surface functionalization. These materials are being proposed for new applications in energy, health, and the environment; these are all strategic society sectors toward sustainable development. Specifically, 2D materials for nano-imaging have shown exciting opportunities in in vitro and in vivo models, providing novel molecular imaging techniques such as computed tomography, magnetic resonance imaging, fluorescence and luminescence optical imaging and others. Therefore, given the growing interest in 2D materials, it is mandatory to evaluate their impact on the immune system in a broader sense, because it is responsible for detecting and eliminating foreign agents in living organisms. This mini-review presents an overview on the frontier of research involving 2D materials applications, nano-imaging and their immunosafety aspects. Finally, we highlight the importance of nanoinformatics approaches and computational modeling for a deeper understanding of the links between nanomaterial physicochemical properties and biological responses (immunotoxicity/biocompatibility) towards enabling immunosafety-by-design 2D materials.
Rate of Freeze Impacts the Survival and Immune Responses Post Cryoablation of Melanoma
Authors: Yakkala Chakradhar , Dagher Julien , Sempoux Christine , Chiang Cheryl Lai-Lai , Denys Alban , Kandalaft Lana E. , Koppolu Bhanu , Duran Rafael
Published: June 2021

The emergence of ablative therapies has revolutionized the treatment of inoperable solid tumors. Cryoablation stands out for its uniqueness of operation based on hypothermia, and for its ability to unleash the native tumor antigens, resulting in the generation of anti-tumor immune responses. It is not clearly understood how alterations in the rate of freeze impact the immune response outcomes. In this study, we tested fast freeze and slow freeze rates for their locoregional effectiveness and their ability to elicit immune responses in a B16F10 mouse model of melanoma. Tumor bearing mice treated with fast freeze protocol survived better than the ones treated with slow freeze protocol. Fast freeze resulted in a higher magnitude of CD4+ and CD8+ T-cell responses, and a significantly extended survival post re-challenge. Thus, fast freeze rate should be applied in any future studies employing cryoablation as an in vivo vaccination tool in conjunction with targeted immunotherapies.
Influence of FKBP5 Variants and Childhood Trauma on Brain Volume in Non-clinical Individuals
Authors: Kwon Aeran , Kim Sungkean , Jeon Hyeonjin , Lee Hyun Seo , Lee Seung-Hwan
Published: June 2021

The present study aimed to investigate the possible influence of childhood trauma and its interaction effect with 10 single-nucleotide polymorphisms (SNPs) of the FK506-binding protein 51 (FKBP5) gene on brain volume in non-clinical individuals. One hundred forty-four non-clinical volunteers (44 men and 100 women) were genotyped with respect to 10 variants (rs9296158, rs3800373, rs1360780, rs9470080, rs4713916, rs4713919, rs6902321, rs56311918, rs3798345, and rs9380528) of FKBP5. Participants underwent magnetic resonance imaging (MRI) scan and psychological assessments such as the childhood Trauma Questionnaire (CTQ), Hospital Anxiety and Depression Scale, rumination response scale, and quality of life assessment instrument. Individuals with the high CTQ score showed enlarged volume of the left orbitofrontal cortex (OFC) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, rs4713919, rs6902321, and rs3798345 and enlarged volume of the left middle temporal gyrus (MTG) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, and rs3798345. Among those with the childhood trauma-susceptible genotype, the left OFC and left MTG showed significant negative correlations with positive feelings about life, and the left OFC showed significant positive correlations with negative cognition. This is one of the few studies to identify the volume alteration of the left OFC and the left MTG for the FKBP5 gene–childhood trauma interaction in non-clinical individuals.
Rare Opportunities for Insights Into Serotonergic Contributions to Brain and Bowel Disorders: Studies of the SERT Ala56 Mouse
Authors: Stilley Samantha E. , Blakely Randy D.
Published: June 2021

Altered structure, expression, and regulation of the presynaptic serotonin (5-HT) transporter (SERT) have been associated with multiple neurobehavioral disorders, including mood disorders, obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). Opportunities to investigate mechanistic links supporting these associations were spurred with the identification of multiple, rare human SERT coding variants in a study that established a male-specific linkage of ASD to a linkage marker on chromosome 17 which encompassed the location of the SERT gene (SLC6A4). We have explored the most common of these variants, SERT Ala56, in vitro and in vivo. Results support a tonic elevation of 5-HT transport activity in transfected cells and human lymphoblasts by the variant in vitro that leads to an increased 5-HT clearance rate in vivo when studied in the SERT Ala56 mouse model, along with altered sensitivity to SERT regulatory signaling pathways. Importantly, hyperserotonemia, or an elevated whole blood 5-HT, level, was found in SERT Ala56 mice, reproducing a well-replicated trait observed in a significant fraction of ASD subjects. Additionally, we found multiple biochemical, physiological, and behavioral alterations in the SERT Ala56 mice that can be analogized to those observed in ASD and its medical comorbidities. The similarity of the functional impact of the SERT Ala56 variant to the consequences of p38α MAPK activation, ascribed to the induction of a biased conformation of the transporter toward an outward-facing conformation, has resulted in successful efforts to restore normal behavioral and bowel function via pharmacological and genetic p38α MAPK targeting. Moreover, the ability of the inflammatory cytokine IL-1β to enhance SERT activity via a p38α MAPK-dependent pathway suggests that the SERT Ala56 conformation mimics that of a chronic inflammatory state, supporting findings in ASD of elevated inflammatory cytokine levels. In this report, we review studies of the SERT Ala56 variant, discussing opportunities for continued insight into how chronically altered synaptic 5-HT homeostasis can drive reversible, functional perturbations in 5-HT sensitive pathways in the brain and periphery, and how targeting the SERT regulome, particularly through activating pathways such as those involving IL-1β/p38α MAPK, may be of benefit for neurobehavioral disorders, including ASD.
The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage
Authors: Cai Lingxin , Zeng Hanhai , Tan Xiaoxiao , Wu Xinyan , Qian Cong , Chen Gao
Published: June 2021

Aneurysmal subarachnoid hemorrhage (aSAH) is an important type of stroke with the highest rates of mortality and disability. Recent evidence indicates that neuroinflammation plays a critical role in both early brain injury and delayed neural deterioration after aSAH, contributing to unfavorable outcomes. The neutrophil-to-lymphocyte ratio (NLR) is a peripheral biomarker that conveys information about the inflammatory burden in terms of both innate and adaptive immunity. This review summarizes relevant studies that associate the NLR with aSAH to evaluate whether the NLR can predict outcomes and serve as an effective biomarker for clinical management. We found that increased NLR is valuable in predicting the clinical outcome of aSAH patients and is related to the risk of complications such as delayed cerebral ischemia (DCI) or rebleeding. Combined with other indicators, the NLR provides improved accuracy for predicting prognosis to stratify patients into different risk categories. The underlying pathophysiology is highlighted to identify new potential targets for neuroprotection and to develop novel therapeutic strategies.
Temporal Fluctuation of Mood in Gaming Task Modulates Feedback Negativity: EEG Study With Virtual Reality
Authors: Yokota Yusuke , Naruse Yasushi
Published: June 2021

Feedback outcomes are generally classified into positive and negative feedback. People often predict a feedback outcome with information that is based on both objective facts and uncertain subjective information, such as a mood. For example, if an action leads to good results consecutively, people performing the action overestimate the behavioral result of the next action. In electroencephalogram measurements, negative feedback evokes negative potential, called feedback negativity, and positive feedback evokes positive potential, called reward positivity. The present study investigated the relationship between the degree of the mood caused by the feedback outcome and the error-related brain potentials. We measured the electroencephalogram activity while the participants played a virtual reality shooting game. The experimental task was to shoot down a cannonball flying toward the player using a handgun. The task difficulty was determined from the size and curve of the flying cannonball. These gaming parameters affected the outcome probability of shooting the target in the game. We also implemented configurations in the game, such as the player’s life points and play times. These configurations affected the outcome magnitude of shooting the target in the game. Moreover, we used the temporal accuracy of shooting in the game as the parameter of the mood. We investigated the relationship between these experimental features and the event-related potentials using the single-trial-based linear mixed-effects model analysis. The feedback negativity was observed at an error trial, and its amplitude was modulated with the outcome probability and the mood. Conversely, reward positivity was observed at hit trials, but its amplitude was modulated with the outcome probability and outcome magnitude. This result suggests that feedback negativity is enhanced according to not only the feedback probability but also the mood that was changed depending on the temporal gaming outcome.
Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels
Authors: Dwivedi Deepanjali , Bhalla Upinder S.
Published: June 2021

SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.
Oncological Outcomes of Patients With Different Pathological Features of pT3a Renal Tumor: A Systematic Review and Quantitative Synthesis
Authors: Guo Pengju , Wang Yongxing , Han Yili , Wei Dechao , Zhao Jiahui , Li Mingchuan , Jiang Yongguang , Luo Yong
Published: June 2021

Purpose

To identify the differences in oncological outcomes for patients with different pT3a renal tumor invasion patterns and pathological features.

Methods

The protocol of this study was registered on PROSPERO (CRD42021234475). Relevant studies were identified by searching the PubMed, Cochrane library, Embase, and Web of Science databases. Cancer-specific survival (CSS) was selected as the endpoint. Pooled hazard ratio (HR) and 95% confidence interval (CI) extracted from multivariate Cox models were evaluated to identify the hazard association.

Results

A total of 22 studies, which enrolled 12384 patients were included for quantitative synthesis. Sinus fat invasion (SFI) + perinephric fat invasion (PFI) was associated with inferior CSS compared to SFI only (p = 0.02). Comparable CSS was observed between SFI and PFI (p = 0.57). SFI ± PFI showed inferior CSS compared to PFI only (p = 0.0002). The presence of pelvicalyceal system invasion significantly increased the risk of cancer-specific mortality (p = 0.0005). Renal vein invasion (RVI) indicated poor oncological outcomes in terms of CSS (p = 0.002). The concomitant RVI and fat invasion (FI) significantly increased the risk of deterioration of CSS compared to RVI or FI (p < 0.0001). Multiple invasion patterns translated into a significantly decreased CSS (p < 0.0001). Aggressive tumor behavior, including lymph node involvement (p = 0.006), distant metastases (p < 0.00001), sarcomatoid differentiation (p < 0.0001), necrosis (p < 0.0001), Fuhrman grade III or IV (p < 0.0001), positive margin (p < 0.0001), and tumor size >7cm (p < 0.0001) were the predictors of inferior CSS. The lymphovascular invasion (p = 0.67) was indolent in terms of CSS.

Conclusion

This study confirmed the heterogenicity of pT3a renal tumors. Multiple invasion patterns could translate into a significantly decreased CSS, and SFI should not be merged in the SFI + PFI group. The presence of PSI or RVI could significantly increase the risk of cancer-specific mortality. Lymph node involvement, distant metastases, sarcomatoid differentiation, necrosis, high Fuhrman grade, positive margin, and size >7cm were the predictors of inferior CSS. A precise-risk grade of CSS for different invasion patterns including comprehensive combinations may be useful for the further refinements of the TNM system.

Systematic Review Registration

The current study was registered on PROSPERO, and the registration numbers is CRD42021234475.
Major Differences in Lymphocyte Subpopulations Between Cerebrospinal Fluid and Peripheral Blood in Non-Hodgkin Lymphoma Without Leptomeningeal Involvement: Flow Cytometry Evidence of a Cerebral Lymphatic System
Authors: Cordone Iole , Masi Serena , Giannarelli Diana , Pasquale Alessia , Conti Laura , Telera Stefano , Pace Andrea , Papa Elena , Marino Mirella , de Fabritiis Paolo , Mengarelli Andrea
Published: June 2021

Cerebrospinal fluid (CSF) flow cytometry has a crucial role in the diagnosis of leptomeningeal disease in onco-hematology. This report describes the flow cytometry characterization of 138 CSF samples from patients affected by non-Hodgkin lymphoma, negative for disease infiltration. The aim was to focus on the CSF non-neoplastic population, to compare the cellular composition of the CSF with paired peripheral blood samples and to document the feasibility of flow cytometry in hypocellular samples. Despite the extremely low cell count (1 cell/µl, range 1.0–35) the study was successfully conducted in 95% of the samples. T lymphocytes were the most abundant subset in CSF (77%; range 20–100%) with a predominance of CD4-positive over CD8-positive T cells (CD4/CD8 ratio = 2) together with a minority of monocytes (15%; range 0–70%). No B cells were identified in 90% of samples. Of relevance, a normal, non-clonal B-cell population was documented in 5/7 (71%) patients with primary central nervous system lymphoma at diagnosis (p<0.0001), suggesting a possible involvement of blood-brain barrier cell permeability in the pathogenesis of cerebral B-cell lymphomas. The highly significant differences between CSF and paired peripheral blood lymphoid phenotype (p<0.0001) confirms the existence of an active mechanism of lymphoid migration through the meninges.
The PREgnancy and FERtility (PREFER) Study Investigating the Need for Ovarian Function and/or Fertility Preservation Strategies in Premenopausal Women With Early Breast Cancer
Authors: Blondeaux Eva , Massarotti Claudia , Fontana Valeria , Poggio Francesca , Arecco Luca , Fregatti Piero , Bighin Claudia , Giannubilo Irene , Ruelle Tommaso , Razeti Maria Grazia , Boni Luca , Anserini Paola , Del Mastro Lucia , Lambertini Matteo
Published: June 2021

Background

Offering ovarian function and/or fertility preservation strategies in premenopausal women with newly diagnosed breast cancer candidates to undergo chemotherapy is standard of care. However, few data are available on uptake and main reasons for refusing these options.

Methods

The PREFER study (NCT02895165) is an observational, prospective study enrolling premenopausal women with early breast cancer, aged between 18 and 45 years, candidates to receive (neo)adjuvant chemotherapy. Primary objective is to collect information on acceptance rates and reasons for refusal of the proposed strategies for ovarian function and/or fertility preservation available in Italy.

Results

At the study coordinating center, 223 patients were recruited between November 2012 and December 2020. Median age was 38 years (range 24 – 45 years) with 159 patients (71.3%) diagnosed at ≤40 years. Temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) was accepted by 58 out of 64 (90.6%) patients aged 41-45 years and by 151 out of 159 (95.0%) of those aged ≤40 years. Among patients aged ≤40 years, 57 (35.8%) accepted to access the fertility unit to receive a complete oncofertility counseling and 29 (18.2%) accepted to undergo a cryopreservation technique. Main reasons for refusal were fear of delaying the initiation of antineoplastic treatments and contraindications to the procedure or lack of interest in future childbearing. Patients with hormone-receptor positive breast cancer had a tendency for a higher acceptance rates of ovarian function and/or fertility preservation strategies than those with hormone-receptor negative disease.

Conclusions

More than 90% of premenopausal women with early breast cancer, and particularly those with hormone receptor-positive disease, were concerned about the potential risk of chemotherapy-induced premature ovarian insufficiency and/or infertility and accepted GnRHa administration. Less than 1 out of 5 women aged ≤40 years accepted to undergo cryopreservation strategies.
Metabolomics Monitoring of Treatment Response to Brain Tumor Immunotherapy
Authors: Dastmalchi Farhad , Deleyrolle Loic P. , Karachi Aida , Mitchell Duane A. , Rahman Maryam
Published: June 2021

Immunotherapy has revolutionized care for many solid tissue malignancies, and is being investigated for efficacy in the treatment of malignant brain tumors. Identifying a non-invasive monitoring technique such as metabolomics monitoring to predict patient response to immunotherapy has the potential to simplify treatment decision-making and to ensure therapy is tailored based on early patient response. Metabolomic analysis of peripheral immune response is feasible due to large metabolic shifts that immune cells undergo when activated. The utility of this approach is under investigation. In this review, we discuss the metabolic changes induced during activation of an immune response, and the role of metabolic profiling to monitor immune responses in the context of immunotherapy for malignant brain tumors. This review provides original insights into how metabolomics monitoring could have an important impact in the field of tumor immunotherapy if achievable.
A Metastasis-Related lncRNA Signature Correlates With the Prognosis in Clear Cell Renal Cell Carcinoma
Authors: Dou Qian , Gao Shun , Gan Hua , Kang Zhao , Zhang Han , Yang Yichun , Tong Hang
Published: June 2021

To explore the role of metastasis-related long noncoding RNA (lncRNA) signature for predicting the prognosis of clear cell renal cell carcinoma (ccRCC) patients. Firstly, metastasis-associated genes were identified to establish a metastasis-related lncRNA signature by statistical analysis. Secondly, the ccRCC patients were grouped into high-risk or low-risk group according to the established signature, and the different pathways between the 2 groups were identified by gene set enrichment analysis (GSEA). Finally, investigations involving PCR, transwell migration and invasion assay were carried out to further confirm our findings. The metastasis-related lncRNA signature was successfully constructed according to 7-metastasis-related genes (ADAM12, CD44, IL6, TFPI2, TGF-β1, THBS2, TIMP3). The diagnostic efficacy and the clinically predictive capacity of the signature were evaluated. Most of the values of the area under the time‐dependent receiver‐operating characteristic (ROC) were greater than 0.70. The nomogram constructed by integrating clinical data and risk scores confirmed that the risk score calculated from our signature was a good prognosis predictor. GSEA analysis showed that some tumor-related pathways were enriched in the high-risk group, while metabolism-related pathways were enriched in the low-risk group. In carcinoma tissues, the SSR3-6, WISP1-2 were highly expressed, but the expression of UBAC2-6 was low there. Knocking down SSR3-6 decreased the ability of migration and invasion in ccRCC cells. In conclusion, we successfully constructed a metastasis-related lncRNA signature, which could accurately predict the survival and prognosis of ccRCC patients.
Autophagy Blockade by Ai Du Qing Formula Promotes Chemosensitivity of Breast Cancer Stem Cells Via GRP78/β-Catenin/ABCG2 Axis
Authors: Liao Mianmian , Wang Caiwei , Yang Bowen , Huang Danping , Zheng Yifeng , Wang Shengqi , Wang Xuan , Zhang Juping , Tang Chunbian , Xu Zheng , He Yu , Huang Ruolin , Zhang Fengxue , Wang Zhiyu , Wang Neng
Published: June 2021

Accumulating evidence suggests that the root of drug chemoresistance in breast cancer is tightly associated with subpopulations of cancer stem cells (CSCs), whose activation is largely dependent on taxol-promoting autophagy. Our pilot study identified GRP78 as a specific marker for chemoresistance potential of breast CSCs by regulating Wnt/β-catenin signaling. Ai Du Qing (ADQ) is a traditional Chinese medicine formula that has been utilized in the treatment cancer, particularly during the consolidation phase. In the present study, we investigated the regulatory effects and molecular mechanisms of ADQ in promoting autophagy-related breast cancer chemosensitivity. ADQ with taxol decreasing the cell proliferation and colony formation of breast cancer cells, which was accompanied by suppressed breast CSC ratio, limited self-renewal capability, as well as attenuated multi-differentiation. Furthermore, autophagy in ADQ-treated breast CSCs was blocked by taxol via regulation of β-catenin/ABCG2 signaling. We also validated that autophagy suppression and chemosensitizing activity of this formula was GRP78-dependent. In addition, GRP78 overexpression promoted autophagy-inducing chemoresistance in breast cancer cells by stabilizing β-catenin, while ADQ treatment downregulated GRP78, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and consequently attenuated the chemoresistance-promoted effect of GRP78. In addition, both mouse breast cancer xenograft and zebrafish xenotransplantation models demonstrated that ADQ inhibited mammary tumor growth, and the breast CSC subpopulation showed obscure adverse effects. Collectively, this study not only reveals the chemosensitizating mechanism of ADQ in breast CSCs, but also highlights the importance of GRP78 in mediating autophagy-promoting drug resistance via β-catenin/ABCG2 signaling.
MicroRNA-10a-3p Improves Cartilage Degeneration by Regulating CH25H-CYP7B1-RORα Mediated Cholesterol Metabolism in Knee Osteoarthritis Rats
Authors: Li Xiaochen , Zhang Li , Shi Xiaoqing , Liao Taiyang , Zhang Nongshan , Gao Yifan , Xing Runlin , Wang Peimin
Published: June 2021

Osteoarthritis (OA) is a worldwide degenerative joint disease that seriously impaired the quality of life of patients. OA has been established as a disease with metabolic disorder. Cholesterol 25-hydroxylase (CH25H) was proved to play a key role in cartilage cholesterol metabolism. However, the biological function and mechanism of CH25H in OA remains further investigation. Growing researches have proved the vital roles of miRNAs in OA progression. In this study, we screened out miR-10a-3p through high-throughput miRNA sequencing which may bind to CH25H. Molecular mechanism investigation indicated that miR-10a-3p is an upstream target of CH25H. Functional exploration revealed miR-10a-3p suppressed the inflammatory responses, cholesterol metabolism and extracellular matrix (ECM) degradation in primary chondrocytes. Moreover, rescue assays implied that miR-10a-3p reversed CH25H plasmids induced inflammatory cytokine production and ECM degradation. Furthermore, the OA rat model was established to explore the function of miR-10a-3p in vivo. The results showed that miR-10a-3p can recover the OA features through targeting CH25H/CYP7B1/RORα axis. In conclusion, these findings implied a crucial role of miR-10a-3p/CH25H/CYP7B1/RORα axis in OA, which may provide a promising therapeutic strategy for OA.
Horizontal MicroRNA Transfer by Platelets – Evidence and Implications
Authors: Mussbacher Marion , Pirabe Anita , Brunnthaler Laura , Schrottmaier Waltraud C. , Assinger Alice
Published: June 2021

For decades, platelets have been known for their central role in hemostasis and their ability to release bioactive molecules, allowing inter-platelet communication and crosstalk with the immune system and vascular cells. However, with the detection of microRNAs in platelets and platelet-derived microvesicles (MVs), a new level of inter-cellular regulation was revealed. By shedding MVs from their plasma membrane, platelets are able to release functional microRNA complexes that are protected from plasma RNases. Upon contact with macrophages, endothelial cells and smooth muscle cells platelet microRNAs are rapidly internalized and fine-tune the functionality of the recipient cell by post-transcriptional reprogramming. Moreover, microRNA transfer by platelet MVs allows infiltration into tissues with limited cellular access such as solid tumors, thereby they not only modulate tumor progression but also provide a potential route for drug delivery. Understanding the precise mechanisms of horizontal transfer of platelet microRNAs under physiological and pathological conditions allows to design side-specific therapeutic (micro)RNA delivery systems. This review summarizes the current knowledge and the scientific evidence of horizontal microRNA transfer by platelets and platelet-derived MVs into vascular and non-vascular cells and its physiological consequences.
Breaking Beyond the Borders of the Brain: Self-Control as a Situated Ability
Authors: Yahya Jumana
Published: June 2021

“I just couldn’t control myself” are the infamous last words of a person that did something that they knew they should not have done. Consistent self-control is difficult to achieve, but it is also instrumental in achieving ambitious goals. Traditionally, the key to self-control has been assumed to reside in the brain. Recently, an alternative has come to light through the emergence of situated theories of self-control, which emphasize the causal role of specific situated factors in producing successful self-control. Some clinical interventions for motivational or impulse control disorders also incorporate certain situated factors in therapeutic practices. Despite remaining a minority, situated views and practices based on these theories have planted the seeds of a paradigm shift in the self-control literature, moving away from the idea that self-control is an ability limited to the borders of the brain. The goal of this paper is to further motivate this paradigm shift by arguing that certain situated factors show strong promise as genuine causes of successful self-control, but this potential role is too often neglected by theorists and empirical researchers. I will present empirical evidence which suggests that three specific situated factors – clenched muscles, calming or anxiety-inducing environmental cues, and social trust – exhibit a specialized effect of increasing the likelihood of successful self-control. Adopting this situated view of the ability to regulate oneself works to reinforce and emphasize the emerging trend to design therapies based on situated cognition, makes self-control more accessible and less overwhelming for laypeople and those who struggle with impulse control disorders, and opens a new avenue of empirical investigation.
Irony and Perspective-Taking in Children: The Roles of Norm Violations and Tone of Voice
Authors: Köder Franziska , Falkum Ingrid Lossius
Published: June 2021

In order to understand most, if not any communicative act, the listener needs to make inferences about what the speaker intends to convey. This perspective-taking process is especially challenging in the case of nonliteral uses of language such as verbal irony (e.g., “Thanks for your help!” uttered to someone who has not provided the expected support). Children have been shown to have difficulties with the comprehension of irony well into the school years, but the factors that hamper or facilitate children’s perspective-taking in irony comprehension are not well understood. This study takes as its starting point the relevance-theoretic echoic analysis of verbal irony, and focuses on two of irony’s distinctive features as defined by this theory: (i) the normative bias and (ii) the characteristic tone of voice. In this study, we investigated the comprehension of irony in children aged 3–8. We manipulated these two factors, namely, the violation of different types of norms and the use of different tones of voice – to see how they affected children’s processing and interpretation of irony. Using an irony comprehension task that combined picture selection and eye-tracking, we found that the type of norm violation affected 4-to 5-year-olds’ offline understanding of irony, with a better performance on moral compared with social norm violations. Tone of voice had an effect on gaze behavior in adults, but not children, although a parodic, pretense-oriented tone of voice tended to lead to more looks to the angry compared with the happy emoticon at the offset of the ironical utterance, potentially facilitating children’s irony understanding. Our results show that the understanding of irony can be detected on explicit measures around age 6 – with the emergence of second-order perspective-taking abilities – but that a sensitivity to some of irony’s features can be detected several years earlier. Finally, our study provides a novel input to the debate on the existence of a so-called literal stage in pragmatic development, in particular regarding 3-year-olds’ differential performance on the offline and online measures of irony understanding, suggesting that they are not naively mistaking ironical utterances for “ordinary” literal ones.
A Three-Dimensional Spatial Metaphorical Representation of Generation Implied in Han Kin Terms
Authors: Li Huijuan , Zhang Jijia , Zhang Entao
Published: June 2021

Abstract concepts can be represented in the brain by means of metaphors. Generation refers to seniority in the family or clan, implies the implementation of different attitudes required by kinship, and contains profound psychological, emotional, and social factors. Generation as an abstract concept is related to concepts such as power, social status, importance, and time. The conceptual metaphor theory based on the embodied theory proposes that abstract concepts are represented by actual sensorimotor experiences. Generation implied in Han kin terms is often represented by multiple spatial terms. According to conceptual metaphor theory, the current study predicted that generation could be represented by multiple spatial metaphors. We designed six experiments to investigate this issue. The results showed that (1) the up–down and left–right positions in which kinship words were presented affected the processing of the concept of generation; (2) the processing of kinship words also affected up–down and left–right spatial information perception; and (3) the processing of the concept of generation could also automatically activate the front–back spatial operation and induce the embodied simulation of body movement. In sum, the results suggested that generation might be represented by the three-dimensional spatial metaphor of vertical, horizontal, and sagittal axes, which are influenced by the sensorimotor system.
The Impact of Intolerance of Uncertainty on Test Anxiety: Student Athletes During the COVID-19 Pandemic
Authors: Li Guilin , Zhou Jie , Yang Gang , Li Bing , Deng Qing , Guo Liya
Published: June 2021

Test anxiety caused by intolerance of uncertainty has a negative impact on the physical and mental health of student athletes, especially in the context of the coronavirus disease 2019 (COVID-19) pandemic. A total of 556 grade three high school student athletes in Chongqing, China, were investigated using the Test Anxiety Scale (TAS), Intolerance of Uncertainty Scale-12 (IUS-12), Perceived Social Support Scale, and Coping Style Scale for Middle School Students. Results reveal that more than half the student athletes experienced test anxiety, and the severity was above average during the COVID-19 pandemic. There was a significant correlation between intolerance of uncertainty, perceived social support, coping style, and test anxiety. A positive correlation was found between test anxiety, intolerance of uncertainty, and coping style toward emotions, and a negative correlation between test anxiety, perceived social support, and coping style toward problems. Intolerance of uncertainty has a direct predictive effect on test anxiety, and perceived social support and coping style play a chain mediator role between intolerance of uncertainty and test anxiety. By constructing the mediating effect model, we can, to some extent, reveal the mechanism of the influence of intolerance of uncertainty on test anxiety. This study has a certain reference value for the prevention of test anxiety in student athletes in the context of the COVID-19 pandemic.
The Development and Validation of the Psychological Needs of Cancer Patients Scale
Authors: Chen Yao , Lin Fangyan , Wang Bo , Tang Yung-lung , Li Jun , Xiong Lin
Published: June 2021

In the present research, the Psychological Needs of Cancer Patients Scale (PNCPS) was developed and validated. Based on Group 1 (400 cancer patients), the exploratory factor analysis identified a 23-item scale with six factors: value and esteem (five items, i.e., reconsider the meaning and purpose of life), independence and control (six items, i.e., private space), mental car (three items, i.e., vent negative emotions), disease care (three items, i.e., acquire knowledge about disease), belonging and companionship (three items, i.e., spend more time at home), and security (three items, i.e., living conditions be better). The structure identified with Group 1 was further tested, based on Group 2 (199 cancer patients), for reliability and validity. The results showed that PNCPS has a clear factor structure and good psychometric characteristics. By taking into account the cultural background of Chinese patients, this scale will advance the study of the psychological needs of those with malignant tumors and thus has a certain reference value for other countries.
Structural Changes in Israeli Family Farms: Long-Run Trends in the Farm Size Distribution and the Role of Part-Time Farming
Authors: Kimhi Ayal , Tzur-Ilan Nitzan
Published: June 2021

Israeli agriculture has experienced rapid structural changes in recent decades, including the massive exit of farmers, a resulting increase in average farm size, a higher farm specialization and a higher reliance on non-farm income sources. The higher farm heterogeneity makes it necessary to examine changes in the entire farm size distribution rather than the common practice of analyzing changes in the average farm size alone. This article proposes a nonparametric analysis in which the change in the distribution of farm sizes between two periods is decomposed into several components, and the contributions of subgroups of farms to this change are analyzed. Using data on Israeli family farms, we analyze the changes in the farm size distribution in two separate time periods that are characterized by very different economic environments, focusing on the different contributions of full-time farms and part-time farms to the overall distributional changes. We found that between 1971 and 1981, a period characterized by stability and prosperity, the farm size distribution has shifted to the right with relatively minor changes in higher moments of the distribution. On the other hand, between 1981 and 1995, a largely unfavorable period to Israeli farmers, the change in the distribution was much more complex. While the overall change in the size distribution of farms was smaller in magnitude than in the earlier period, higher moments of the distribution were not less important than the increase in the mean and led to higher dispersion of farm sizes. Between 1971 and 1981, the contributions of full- and part-time farms to the change in the size distribution were quite similar. Between 1981 and 1995, however, full-time farms contributed mostly to the growth in the average farm size, while the average farm size among part-time farms actually decreased, and their contribution to the higher dispersion of farm sizes was quantitatively larger. This highlights the need to analyze the changes in the entire farm size distribution rather than focusing on the mean alone, and to allow for differences between types of farms.
The Survival of Family Farms: Socioemotional Wealth (SEW) and Factors Affecting Intention to Continue the Business
Authors: Plana-Farran Manel , Gallizo José Luis
Published: June 2021

This article addresses the problem of succession in family farms in a context of generational change. Family businesses are characterized by their long-term orientation and by having a positive effect through environmental goals that remain in place generation after generation. The general increase in average age among farmers is seen as a barrier to more sustainable land use, and the survival of family farming therefore depends on the availability of a successor in the family. Socioemotional wealth (hereafter, SEW) is understood as the affective endowment of family members. This study adopts the SEW dimensions conceptually validated to analyse the effects of psychological and socioeconomic factors on potential successors’ intentions. The results of a survey administered to students attending agricultural schools in Catalonia show that intentions to assume the management and ownership of the family farm increase in line with individuals’ interest in creating their own business, their ability to take over the farm, and their emotional inclination to continue the family legacy. In addition, SEW was measured in relation to the potential successor and not the incumbent, as has typically been the case in previous work, bringing this important research subject as a principal actor. Finally, an empirical validation of a short FIBER scale, i.e., REI scale, was obtained that relates individuals’ intentions to succeed the family farm to the socioemotional wealth of business families, testing suitability of the REI scale as a measure of intention to succeed.
Deficit Irrigation as a Tool to Optimize Fruit Quality in Abbé Fetél Pear
Authors: Venturi Melissa , Manfrini Luigi , Perulli Giulio Demetrio , Boini Alexandra , Bresilla Kushtrim , Corelli Grappadelli Luca , Morandi Brunella
Published: June 2021

Climate change is leading to higher plant water requirements and rootstock can play a role in tree adaptation, since the more vigorous ones are also likely to be more stress resistant. Pear trees of the cv. Abbé Fetél grafted on BA29 (more vigorous) and SYDO (more dwarfing) quince were irrigated according to three different treatments: 110 C, 80 DI and 60 DI, corresponding to 110%, 80% and 60% of the crop evapotranspiration rate (ETc), respectively. Shoot and fruit growth, water potentials, leaf gas exchanges and dry matter content were monitored during the season. Fruit quality was evaluated at harvest and after 6 months of storage at 1 °C. Results show how for both rootstocks, 60 DI significantly decreased their stem (Ψstem) and leaf (Ψleaf) water potentials as well as leaf gas exchanges. In SYDO, final fruit size was affected by irrigation, with lower values on 60 DI, but in BA29, no differences were found between treatments. After storage, BA29 60 DI fruit showed a higher soluble solid content, while in SYDO fruit, firmness was more affected by irrigation level. In conclusion, despite a slight decrease in fruit size, reduced irrigation led to fruit with higher quality features that were also maintained after a long period of storage.