bluuebunny/crossref_metadata_2025 huggingface dataset:
Bistable Mathematical Model of Neutrophil Migratory Patterns After LPS-Induced Epigenetic Reprogramming
Authors: Ciupe Stanca M. , Boribong Brittany P. , Kadelka Sarah , Jones Caroline N.
Published: February 2021

The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displayed bistability between high and low ratios of primary to intermediary chemoattractant receptor densities. In particular, at equilibrium, we observe equal receptor densities for low LPS (< 15ng/mL); and dominance of receptors for the primary chemoattractant for high LPS (> 15ng/mL). The second model, which included additional interactions with an extracellular signal-regulated kinase in both phosphorylated and non-phosphorylated forms, has an additional dynamic outcome, oscillatory dynamics for both receptors, as seen in the data. In particular, it found equal receptor densities in the absence of oscillation for super-low and high LPS challenge (< 0.4 and 1.1 <LPS< 375 ng/mL); equal receptor densities with oscillatory receptor dynamics for super-low LPS (0.5 < LPS< 1.1ng/mL); and dominance of receptors for the primary chemoattractant for super-high LPS (>376 ng/mL). Predicting the mechanisms and the type of external LPS challenge responsible for neutrophils migration toward pro-inflammatory chemoattractants, migration toward pro-tolerant chemoattractants, or oscillatory movement is necessary knowledge in designing interventions against immune diseases, such as sepsis.
Dynamic Immune/Inflammation Precision Medicine: The Good and the Bad Inflammation in Infection and Cancer
Authors: Rossi Jean-François , Lu Zhao Yang , Massart Cesare , Levon Kalle
Published: February 2021

Normal or “good” inflammation process starts from a local cellular response against injury or any infectious agent, with the activation of neutrophils, macrophages, Langerhans cells, dendritic cells, and innate immune cells. Cytokines and chemokines are produced to amplify the local inflammatory process followed by the migration of immune cells to the regional lymph nodes where adaptive immune response is initiated. Systemic inflammation enhances the biological response to mobilize additional cells from central and peripheral immune/hematopoietic system. Local mechanisms to limit inflammation are initiated and lead to healing. During the normal inflammatory process, there is a balance between the production of inflammatory chemokines/cytokines such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6 and IL-1 and the production of compounds that limit inflammation and have an immune suppressive effect, such as IL-10 and Transforming Factor (TGF) β. IL-6 and IL-6/soluble IL-6 Receptor (R) complex stimulate liver cells to produce inflammatory proteins, which represents the systemic inflammation response. The magnitude and the duration of the systemic inflammatory response are linked to the cause, under genetic and epigenetic control. Significant inflammation as seen in septic shock, in severe forms of infections or in certain active cancers, represents the “bad inflammation”, correlated with a poor prognosis. In addition, the persistence of a chronic smoldering inflammation may lead to pathological situations which are observed in the majority of inflammatory, degenerative, dysmetabolic, or dysimmune diseases and cancer. Chronic smoldering inflammation is a cross between different pathological situations possibly linked. In addition, within the tumor microenvironment, inflammatory process results from different cellular mechanisms modulated by metabolic and vascular changes. On the contrary, a limited and balanced inflammation initiates the normal immune response, including the adaptive response which amplifies any immunotherapy, including vaccines. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells are associated with cytokine release syndrome, a clinical risk leading to the use of anti-cytokine drugs. Nowadays, it is time to monitor the dynamic inflammatory process for a better immune precision medicine in both infections and cancer.
Identification of Different Extracellular Vesicles in the Hydatid Fluid of Echinococcus granulosus and Immunomodulatory Effects of 110 K EVs on Sheep PBMCs
Authors: Yang Jing , Wu Jin'en , Fu Yong , Yan Lujun , Li Yating , Guo Xiaola , Zhang Yong'e , Wang Xiaoqiang , Shen Yujuan , Cho William C. , Zheng Yadong
Published: February 2021

Echinococcosis, mainly caused by Echinococcus granulosus, is one of the 17 neglected tropical diseases. Extracellular vesicles (EVs) play an essential role in the host–parasite interplay. However, the EVs in the hydatid fluid (HF) of E. granulosus are not fully characterized. Herein, three different types of HF EVs, designated as 2 K, 10 K, and 110 K EVs based on the centrifugal force used, were morphologically identified. A total of 97, 80, and 581 proteins were identified in 2 K, 10 K, and 110 K EVs, respectively, 39 of which were commonly shared. Moreover, 11, 8, and 25 miRNAs were detected, respectively, and all of the 7 selected miRNAs were validated by qPCR to be significantly lower abundant than that in protoscoleces. It was further deemed that 110 K EVs were internalized by sheep peripheral blood mononuclear cells (PBMCs) in a time-dependent manner and thus induced interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IRF5 were significantly upregulated and IL-1β, IL-17, and CD14 were significantly downregulated (p < 0.05). These data demonstrate the physical discrepancy of three HF EVs and an immunomodulatory effect of 110 K EVs on sheep PMBCs, suggesting a role in immune responses during E. granulosus infection.
IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling
Authors: Wang Zixi , Guan Di , Huo Jianxin , Biswas Subhra K. , Huang Yuhan , Yang Yuansheng , Xu Shengli , Lam Kong-Peng
Published: February 2021

Cell metabolism plays a pivotal role in regulating the effector functions of immune cells. Stimulatory cytokines, such as interleukin (IL)-2 or IL-12 and IL-15, activate glycolysis and oxidative phosphorylation in natural killer (NK) cells to support their enhanced effector functions. IL-10, a pleiotropic cytokine, is known to suppress macrophage activation but stimulate NK cells. However, it remains unclear if IL-10 has an effect on the metabolism of human NK cells and if so, what metabolic mechanisms are affected, and how these metabolic changes are regulated and contribute to the effector functions of NK cells. In this study, we demonstrate that IL-10 upregulates both glycolysis and oxidative phosphorylation in human NK cells, and these metabolic changes are crucial for the enhanced effector functions of NK cells. Mechanistically, we unravel that IL-10 activates the mammalian target of rapamycin complex 1 (mTORC1) to regulate metabolic reprogramming in human NK cells.
Neutrophil Extracellular Traps in SARS-CoV2 Related Pneumonia in ICU Patients: The NETCOV2 Study
Authors: Godement Mathieu , Zhu Jaja , Cerf Charles , Vieillard-Baron Antoine , Maillon Agathe , Zuber Benjamin , Bardet Valérie , Geri Guillaume
Published: February 2021

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poorly understood disease involving a high inflammatory status. Neutrophil extracellular traps (NETs) have been described as a new pathway to contain infectious diseases but can also participate in the imbalance of the inflammatory and the coagulation systems. NETs could be a therapeutic target in COVID-19 patients.

Methods: Consecutive patients with SARS-CoV2 related pneumonia admitted to the intensive care unit were included in a prospective bicentric study. Neutrophil extracellular trap concentrations were quantified in whole blood samples at day-1 and day-3 by flow cytometry. The primary outcome was the association between the blood NET quantification at ICU admission and the number of days with refractory hypoxemia defined by a PaO2/FIO2 ratio ≤100 mmHg.

Results: Among 181 patients admitted to the ICUs for acute respiratory failure related to SARS-CoV2 pneumonia, 58 were included in the analysis. Patients were 62 [54, 69] years old in median, mostly male (75.9%). The median number of days with severe hypoxemia was 4 [2, 6] days and day-28 mortality was 27.6% (n = 16). The blood level of NETs significantly decreased between day-1 and day-3 in patients who survived (59.5 [30.5, 116.6] to 47 [33.2, 62.4] p = 0.006; 8.6 [3.4, 18.0] to 4 [1.4, 10.7] p = 0.001 and 7.4 [4.0, 16.7] to 2.6 [1.0, 8.3] p = 0.001 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively) while it remained stable in patients who died (38.4 [26.0, 54.8] to 44.5 [36.4, 77.7] p = 0.542; 4.9 [1.3, 13.0] to 5.5 [2.8, 6.9] p = 0.839 and 4 [1.3, 13.6] to 2.7 [1.4, 4.5] p = 0.421 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively). In multivariable negative binomial regression, the blood level of MPO+ NETs was negatively associated with the number of days with severe hypoxemia within 7 days (0.84 [0.73, 0.97]), while neither Cit-H3+ NETs nor double-positive NETs were significantly associated with the primary outcome.

Conclusion: The whole blood level of NETs at day-1 was negatively associated with the number of days with severe hypoxemia in patients admitted to the intensive care unit for SARS-CoV2 related pneumonia. The lack of decrease of the blood level of NETs between day-1 and day-3 discriminated patients who died within day-28.
Core Values of Family Medicine in Europe: Current State and Challenges
Authors: Arvidsson Eva , Švab Igor , Klemenc-Ketiš Zalika
Published: February 2021

Background: Values are deeply held views that act as guiding beliefs for individuals and organizations. They state what is important in a profession. The aims of this study were to determine whether European countries have already developed (or are developing) documents on core values in family medicine; to gather the lists of core values already developed in countries; and to gather the opinions of participants on what the core family values in their countries are.

Methods: This was a qualitative study. The questionnaire was distributed as an e-survey via email to present and former members of the European Society for Quality and Safety in Family Practice (EQuiP), and other family medicine experts in Europe. The questionnaire included six items concerning core values in family medicine in the respondent's country: the process of defining core values, present core values, the respondents' suggestions for core values, and current challenges of core values.

Results: Core values in family medicine were defined or in a process of being defined in several European countries. The most common core values already defined were the doctor-patient relationship, continuity, comprehensiveness and holistic care, community orientation, and professionalism. Some countries expressed the need for an update of the current core values' list. Most respondents felt the core values of their discipline were challenged in today's world. The main values challenged were continuity, patient-centered care/the doctor-patient relationship and comprehensive and holistic care, but also prioritization, equity, and community orientation and cooperation. These were challenged by digital health, workload/lack of family physicians, fragmentation of care, interdisciplinary care, and societal trends and commercial interests.

Conclusion: We managed to identify suggestions for core values of family medicine at the European level. There is a clear need to adopt a definition of a value and tailor the discussion and actions on the family medicine core values accordingly. There is also a need to identify the core values of family medicine in European countries. This could strengthen the profession, promote its development and research, improve education, and help European countries to advocate for the profession.
Corneal Stromal Regeneration: A Review of Human Clinical Studies in Keratoconus Treatment
Authors: El Zarif Mona , Alió Jorge L. , Alió del Barrio Jorge L. , De Miguel Maria P. , Abdul Jawad Karim , Makdissy Nehman
Published: February 2021

The use of advanced therapies with stem cells to reconstruct the complex tissue of corneal stroma has gained interest in recent years. Besides, collagen-based scaffolds bioengineering has been offered as another alternative over the last decade. The outcomes of the first clinical experience with stem cells therapy on corneal stroma regeneration in patients with advanced keratoconus were recently reported. Patients were distributed into three experimental groups: Group 1 (G-1) patients underwent implantation of autologous adipose-derived adult stem cells (ADASCs) alone, Group 2 (G-2) received a 120 μm decellularized donor corneal stromal laminas, and Group 3 (G-3) received a 120 μm recellularized donor laminas with ADASCs. A follow up of 36 months of clinical data, and 12 months of confocal microscopy study was performed, the authors found significant clinical improvement in almost all studied mean values of primary and secondary outcomes. Corneal confocal microscopy demonstrated an increase in cell density in the host stroma, as well as in the implanted tissue. Using different approaches, allogenic small incision lenticule extraction (SMILE) implantation was applied in cases with advanced keratoconus. Some authors reported the implantation of SMILE intrastromal lenticules combined with accelerated collagen cross-linking. Others performed intrastromal implantation of negative meniscus-shaped corneal stroma lenticules. Others have compared the outcomes of penetrating keratoplasty (PKP) vs. small-incision Intralase femtosecond (IFS) intracorneal concave lenticule implantation (SFII). Femtosecond laser-assisted small incision sutureless intrasotromal lamellar keratoplasty (SILK) has been also investigated. The published evidence shows that the implantation of autologous ADASCs, decellularized or recellularized human corneal stroma, allogenic SMILE lenticules corneal inlay, and recombinant cross-linked collagen have shown initially to be potentially effective for the treatment of advanced keratoconus. In light of the present evidence available, it can be said that the era of corneal stromal regeneration therapy has been already started.
Resveratrol Improves Liver Steatosis and Insulin Resistance in Non-alcoholic Fatty Liver Disease in Association With the Gut Microbiota
Authors: Du Fan , Huang Rongfeng , Lin Dan , Wang Yuying , Yang Xiaohuang , Huang Xiaoyun , Zheng Biyun , Chen Zhixin , Huang Yuehong , Wang Xiaozhong , Chen Fenglin
Published: February 2021

Resveratrol (RSV) is a potential alternative therapy for non-alcoholic fatty liver disease (NAFLD) that has been evaluated in many clinical trials, but the mechanisms of RSV action have not been fully elucidated. Recent studies suggested that the gut microbiota is an important RSV target; therefore, we speculated that the gut microbiota might mediate the beneficial effects of RSV in NAFLD. To verify this hypothesis, we established a high-fat diet (HFD)-induced NAFLD mouse model, which was subjected to RSV gavage to evaluate the therapeutic effects. We observed that RSV reduced liver steatosis and insulin resistance in NAFLD. RSV significantly changed the diversity and composition of the gut microbiota according to 16S rRNA sequencing. Gut microbiota gene function prediction showed that the enrichment of pathways related to lipid and glucose metabolism decreased after RSV treatment. Furthermore, correlation analysis indicated that the improvements in NAFLD metabolic indicators were closely related to the altered gut microbiota. We further fermented RSV with the gut microbiota in vitro to verify that RSV directly affected the gut microbiota. Our data suggested that the gut microbiota might be an important target through which RSV exerts its anti-NAFLD effect.
Longitudinal Study of the Bulk Tank Milk Microbiota Reveals Major Temporal Shifts in Composition
Authors: Porcellato Davide , Smistad Marit , Bombelli Alberto , Abdelghani Ahmed , Jørgensen Hannah Joan , Skeie Siv B.
Published: February 2021

Introduction of microbial contaminations in the dairy value chain starts at the farm level and the initial microbial composition may severely affect the production of high-quality dairy products. Therefore, understanding the farm-to-farm variation and longitudinal shifts in the composition of the bulk tank milk microbiota is fundamental to increase the quality and reduce the spoilage and waste of milk and dairy products. In this study, we performed a double experiment to study long- and short-term longitudinal shifts in microbial composition using 16S rRNA gene amplicon sequencing. We analyzed milk from 37 farms, that had also been investigated two years earlier, to understand the stability and overall microbial changes over a longer time span. In addition, we sampled bulk tank milk from five farms every 1–2 weeks for up to 7 months to observe short-term changes in microbial composition. We demonstrated that a persistent and farm-specific microbiota is found in bulk tank milk and that changes in composition within the same farm are mostly driven by bacterial genera associated with mastitis (e.g., Staphylococcus and Streptococcus). On a long-term, we detected that major shift in milk microbiota were not correlated with farm settings, such as milking system, number of cows and quality of the milk but other factors, such as weather and feeding, may have had a greater impact on the main shifts in composition of the bulk tank milk microbiota. Our results provide new information regarding the ecology of raw milk microbiota at the farm level.
Cocaine-Seeking Behavior Induced by Orexin A Administration in the Posterior Paraventricular Nucleus of the Thalamus Is Not Long-Lasting: Neuroadaptation of the Orexin System During Cocaine Abstinence
Authors: Matzeu Alessandra , Martin-Fardon Rémi
Published: February 2021

Hypothalamic orexin (Orx) projections to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. Using an established model of cocaine dependence (i.e., long access [LgA] to cocaine), we previously showed that OrxA injections in the posterior PVT (pPVT) reinstated extinguished cocaine-seeking behavior in rats after an intermediate period of abstinence (2–3 weeks). Considering the long-lasting nature of drug-seeking behavior, the present study examined whether the priming effect of intra-pPVT OrxA administration was preserved after a period of protracted abstinence (4–5 weeks) in rats that self-administered cocaine under LgA conditions. Furthermore, to better understand whether a history of cocaine dependence affects the Orx system—particularly the hypothalamic Orx↔pPVT connection—the number of Orx-expressing cells in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) and number of orexin receptor 1 (OrxR1)- and OrxR2-expressing cells in the pPVT were quantified. Orexin A administration in the pPVT induced cocaine-seeking behavior after intermediate abstinence, as reported previously. At protracted abstinence, however, the priming effect of OrxA was absent. A higher number of cells that expressed Orx was observed in the LH/DMH/PFA at both intermediate and protracted abstinence. In the pPVT, the number of OrxR2-expressing cells was significantly higher only at intermediate abstinence, with no changes in the number of OrxR1-expressing cells. These data build on our previous findings that the hypothalamic Orx↔pPVT connection is strongly recruited shortly after cocaine abstinence and demonstrate that the priming effect of OrxA is not long lasting. Furthermore, these findings suggest that throughout abstinence, the Orx↔pPVT connection undergoes neuroadaptive changes, reflected by alterations of the number of OrxR2-expressing cells in the pPVT.
Herpes Simplex Virus Type 1 Neuronal Infection Triggers the Disassembly of Key Structural Components of Dendritic Spines
Authors: Acuña-Hinrichsen Francisca , Covarrubias-Pinto Adriana , Ishizuka Yuta , Stolzenbach María Francisca , Martin Carolina , Salazar Paula , Castro Maite A. , Bramham Clive R. , Otth Carola
Published: February 2021

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.
High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions
Authors: Zaychik Yifat , Fainstein Nina , Touloumi Olga , Goldberg Yehuda , Hamdi Liel , Segal Shir , Nabat Hanan , Zoidou Sofia , Grigoriadis Nikolaos , Katz Abram , Ben-Hur Tamir , Einstein Ofira
Published: February 2021

Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it’s model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia.

Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzedex vivofor reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines.

Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation.

Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.
Effect of a Humanized Diet Profile on Colonization Efficiency and Gut Microbial Diversity in Human Flora-Associated Mice
Authors: Dong Sashuang , Zeng BenHua , Hu Ling , Zhang Yuling , Xiong Jiaqi , Deng Jing , Huang Liyan , Liao ZhenLin , Wang Jie , Wei Hong , Fang Xiang
Published: February 2021

Human flora-associated (HFA) mouse models allow us to design interventions for human disease research to test specific hypotheses and explore the complex commensal microbiome while avoiding the ethical limitations of using humans as models to directly study intestinal flora diseases. However, few studies have investigated the effect of a humanized diet profile (coarse-feed diet; CFD) on colonization efficiency and gut microbial diversity in HFA mice. We tested the colonization efficiency and gut microbial diversity in germ-free Kunming (KM) mice fed a CFD or a purified feed diet (PFD) at 1, 2, and 4 weeks. Although the colonization efficiencies differed significantly (67.50–70.00% vs. 72.69–85.96%) in the HFA mice, the colonization efficiency of the PFD-fed HFA mice (85.96%) was significantly higher than that of the CFD-fed mice (69.61%) at 2 weeks. At 4 weeks, the colonization efficiency of the PFD-fed mice (72.69%) was comparable to that of the CFD-fed mice (70.00%). Additionally, the gut microbial diversity of the CFD-fed HFA mice was similar to that of a human fecal donor. Regarding the Kyoto Encyclopedia of Genes and Genomes colonic microbiota metabolic pathways, the CFD-fed HFA mice showed more similarities to the human donor than to the PFD-fed mice in amino sugar and nucleotide sugar metabolism, biosynthesis of amino acids, carbon metabolism, purine metabolism, and phosphotransferase systems. In conclusion, the humanized diet profiles of the CFD and PFD could help establish human microbiotas in mice. Constructing HFA mouse models fed a CFD for 4 weeks may be useful in researching human-derived intestinal diseases.
LSD1 Promotes Prostate Cancer Cell Survival by Destabilizing FBXW7 at Post-Translational Level
Authors: Qin Xu-ke , Du Yang , Liu Xiu-heng , Wang Lei
Published: February 2021

Prostate cancer (PCa) is the most common cancer in men and the fifth leading cause of cancer death worldwide. Unfortunately, castration-resistant prostate cancer (CRPCa) is incurable with surgical treat and prone to drug resistance. Therefore, it is of great importance to find a new target for treatment. LSD1 is up-regulated in PCa and related with prognosis. The high-expression LSD1 has been shown to be a potential target for treatment and is widely studied for its demethylase-activity. However, its demethylation-independent function remains to be elusive in PCa. Recent study shows that LSD1 can destabilize cancer suppressor protein FBXW7 without demethylation-function. Hence, we hope to investigate the impact of non-canonical function of LSD1 on PCa cell survival. We over-expressed FBXW7 gene through plasmid vector in LNCaP and PC3 cell lines and the result shows that up-regulated FBXW7 can suppress the viability of PC cell through suppressing oncoproteins, such as c-MYC, NOTCH-1. After FBXW7 function experiment on PC cell, we knock-down LSD1 gene in the same kinds of cell lines. In western blot assay, we detected that down-regulation of LSD1 will cause the increasing of FBXW7 protein level and decreasing of its targeting oncoproteins. And mRNA level of FBXW7 did not change significantly after LSD1 knock-down, which means LSD1 may destabilize FBXW7 by protein-protein interactions. Moreover, exogenous wild type LSD1 and catalytically deficient mutant K661A both can abrogate previous effect of LSD1 knock-down. Consequently, LSD1 may promote PC cell survival by destabilizing FBXW7 without its demethylase-activity. Next, we compared two kinds inhibitors, and found that SP-2509 (Allosteric inhibitor) treatment suppress the cancer cell survival by blocking the LSD1–FBXW7 interaction, which is an effect that GSK-2879552 (catalytic inhibitor) cannot achieve. This work revealed a pivotal function of LSD1 in PCa, and indicated a new direction of LSD1 inhibitor research for PCa treatment.
Analysis and Validation of circRNA-miRNA Network in Regulating m6A RNA Methylation Modulators Reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis Involving the Proliferation of Hepatocellular Carcinoma
Authors: Chi Fanwu , Cao Yong , Chen Yuhan
Published: February 2021

The m6A RNA methylation modulators play a crucial role in regulating hepatocellular carcinoma (HCC) progression. The circular RNA (circRNA) regulatory network in regulating m6A RNA methylation modulators in HCC remains largely unknown. In this study, 5 prognostic m6A RNA methylation modulators in HCC were identified from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. The differentially expressed microRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) between paired tumor and normal tissues were screened out from TCGA and or Gene Expression Omnibus (GEO) database to construct the circRNA-miRNA- m6A RNA methylation modulator regulatory network, which included three m6A RNA methylation modulators (HNRNPC, YTHDF1, and YTHDF2), 11 DEmiRNAs, and eight DEcircRNAs. Among the network, hsa-miR-139-5p expression was negatively correlated with YTHDF1. Hsa-miR-139-5p low or YTHDF1 high expression was correlated with high pathological grade, advanced stage and poor survival of HCC. Additionally, cell cycle, base excision repair, and homologous recombination were enriched in YTHDF1 high expression group by GSEA. A hub circRNA regulatory network was constructed based on hsa-miR-139-5p/YTHDF1 axis. Furthermore, hsa_circ_0007456(circMAP2K4) was validated to promote HCC cell proliferation by binding with hsa-miR-139-5p to promote YTHDF1 expression. Taken together, we identified certain circRNA regulatory network related to m6A RNA methylation modulators and provided clues for mechanism study and therapeutic targets for HCC.
High-Fat Diet-Related Obesity Promotes Urethane-Induced Lung Tumorigenesis in C57BL/6J Mice
Authors: Shi Dan , Wu Jingjing , Wu Youqile , Lin Xiaojing , Xu Cai , Lian Xuemei
Published: February 2021

Epidemiological studies have recently shown that obesity increases lung cancer risk, but the underlying biological connection is unclear. To determine whether high-fat diet (HFD)-induced obesity influences the susceptibility to chemical-induced lung tumorigenesis, a HFD feeding condition was combined with a multi-dose urethane-induced lung tumorigenesis model using C57BL/6J mice. In cell culture models, lung cancer cell lines A549 and H460 were used to investigate the effect of leptin on cell viability and its underlying mechanism of action. The results showed that obesity was induced with a 60 kcal% HFD feeding. Serum leptin levels increased with HFD feeding and further increased in urethane-administered and HFD-fed mice. Compared to the control diet-fed mice, the HFD-fed mice exhibited increased lung tumor burden and typical pro-tumorigenic STAT3 pathway activation in lung tissues after urethane administration. In vitro, leptin significantly increased the viability of lung cancer cell lines A549 and H460 in a dose-dependent manner by activation of STAT3, Bcl-2, and cyclin D1. These effects were significantly attenuated when PI3K or mTOR were inhibited by LY294002 or rapamycin, respectively. These results suggested that HFD-induced obesity could promote the development of lung tumorigenesis in C57BL/6J mice, and leptin-mediated activation of the PI3K/Akt/mTOR/STAT3 pathway was likely involved in this mechanism.
Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
Authors: Zhao Huange , Zhang Xian , Wang Min , Lin Yingying , Zhou Songlin
Published: February 2021

Background

Stigmasterol (SS) has been proven to possess potential anticancer activities in several cancer cell lines, but its molecular mechanism is still unknown. Thus, we investigated whether SS has the capabilities of inducing autophagy and its molecular mechanisms in gastric cancer cells.

Methods

We used CCK8 assay, clone formation assay, and EdU proliferation assay to assess the effects of SS on cell proliferation in SGC-7901 and MGC-803 cells in vitro, and its inhibition on the tumor growth of gastric cancer was observed in vivo. Apoptosis induced by SS was demonstrated using Hoechst and TUNEL staining, annexin V-FITC/PI assay. Immunofluorescence staining is used to detect the formation of autophagosomes triggered by SS. Apoptosis and autophagy related proteins were analyzed by western blot.

Results

The results indicated that SS treatment inhibited cell proliferation in SGC-7901 and MGC-803 cells. Furthermore, SS treatment induced apoptosis and autophagy by blocking Akt/mTOR signaling pathway. The pretreatment with the Akt inhibitor MK-2206 could promote apoptosis and autophagy induced by SS, predicting that Akt/mTOR pathway is involved in SS-induced apoptosis and autophagy. In addition, blockade of autophagy with 3-MA (an inhibitor of autophagy) enhanced SS-induced apoptosis in SGC-7901 and MGC-803 cells, implying that autophagy mediated by SS plays a cytoprotective role against apoptosis. Finally, an in vivo study demonstrated that tumor growth of gastric cancer was suppressed by SS in a xenograft model.

Conclusion

Our findings illustrate for the first time that SS simultaneously induces apoptosis and protective autophagy by inhibiting Akt/mTOR pathway in gastric cancer cells, and SS may become a potential anticancer drug in treating gastric cancer in the future.
The Predictive and Guidance Value of Signet Ring Cell Histology for Stage II/III Colon Cancer Response to Chemotherapy
Authors: Jiang Huici , Shao Dongxuan , Zhao Peiyu , Wu Yupeng
Published: February 2021

Purpose

To evaluate the predictive and guidance value of signet-ring cell carcinoma for chemotherapy response in stage II/III colon cancer.

Methods

Eligible patients were recruited from the Surveillance, Epidemiology and End Results (SEER) database. The differences between adenocarcinoma (AD) and SRCC groups in the incidence of patients’ demographic and clinical characteristics were analyzed by Pearson’s chi-squared (×2) test. Survival was analyzed using the Kaplan–Meier method, and the differences were determined by the log-rank test. Some Cox regression models were built to assess hazard ratios (HRs) of different variables with 95% confidence intervals (95% CIs).

Results

In stage II AD, it was found that the receipt of chemotherapy had significantly 12.6% decreased risk of cancer-specific mortality (HR = 0.874, 95% CI = 0.825–0.927, P < 0.001). In stage II SRCC, however, the receipt of chemotherapy had significantly 70.00% increased risk of cancer-specific mortality (HR = 1.700, 95% CI = 1.032–2.801, P = 0.037). In stage III AD, it was found that the receipt of chemotherapy had significantly 45.3% decreased risk of cancer-specific mortality (HR = 0.547, 95% CI = 0.530–0.564, P < 0.001). In stage III SRCC, the receipt of chemotherapy had significantly 24.6% decreased risk of cancer-specific mortality (HR = 0.754, 95% CI = 0.632–0.900, P = 0.002).

Conclusions

The cancer-specific survival (CSS) difference between AD and SRCC was not statistically significant in stage II colon cancer. We provided the first compelling evidence that chemotherapy should not be treated in stage II SRCC, while stage III SRCC should be treated with chemotherapy.
Molecular Characterization and Functional Analysis of the Hb-hsp90-1 Gene in Relation to Temperature Changes in Heterorhabditis bacteriophora
Authors: Fanelli Elena , Troccoli Alberto , Tarasco Eustachio , De Luca Francesca
Published: February 2021

Understanding how entomopathogenic nematodes respond to temperature changes and have adapted to the local environment is crucial to improve their potential as biocontrol agents. In order to improve understanding ofHeterorhabditis bacteriophora’s potential adaptability to future climate changes, full-length cDNA and the corresponding gene of heat shock protein 90 (Hsp90) were isolated and fully characterized. The reproductive potential of the Apulian strain ofH. bacteriophoraincreased when the temperature rose from 23 to 30°C, but no reproduction was found at 12°C. Expression analyses revealed thatHb-hsp90-1 was differentially expressed in Infective Juveniles (IJs) and adults (hermaphrodites, females and males). Up-regulation ofHb-hsp90-1 was higher during the recovery process inGalleria mellonellalarvae than adults, thus confirming the protective role ofHb-hsp90-1 in coping with the host environment. Silencing ofHb-hsp90-1 resulted in a significant reduction (76%) in the expression level. Silenced IJs took longer than untreated nematodes to infectG. mellonella, showing thatHb-hsp90-1 could be also involved in chemosensation. Furthermore, the number of adults and IJs recovered fromG. mellonellainfected with silenced nematodes and incubated at 30°C was higher than that obtained fromG. mellonellainfected with untreated nematodes. These data confirm the crucial role ofHb-hsp90-1 allowing acclimation to increased temperatures and modulation of the recovery process.
Development of Antibody-Fragment–Producing Rice for Neutralization of Human Norovirus
Authors: Sasou Ai , Yuki Yoshikazu , Kurokawa Shiho , Sato Shintaro , Goda Yuki , Uchida Masao , Matsumoto Naomi , Sagara Hiroshi , Watanabe Yuji , Kuroda Masaharu , Sakon Naomi , Sugiura Kotomi , Nakahashi-Ouchida Rika , Ushijima Hiroshi , Fujihashi Kohtaro , Kiyono Hiroshi
Published: February 2021

Human norovirus is the leading cause of acute nonbacterial gastroenteritis in people of all ages worldwide. Currently, no licensed norovirus vaccine, pharmaceutical drug, or therapy is available for the control of norovirus infection. Here, we used a rice transgenic system, MucoRice, to produce a variable domain of a llama heavy-chain antibody fragment (VHH) specific for human norovirus (MucoRice-VHH). VHH is a small heat- and acid-stable protein that resembles a monoclonal antibody. Consequently, VHHs have become attractive and useful antibodies (Abs) for oral immunotherapy against intestinal infectious diseases. MucoRice-VHH constructs were generated at high yields in rice seeds by using an overexpression system with RNA interference to suppress the production of the major rice endogenous storage proteins. The average production levels of monomeric VHH (7C6) to GII.4 norovirus and heterodimeric VHH (7C6-1E4) to GII.4 and GII.17 noroviruses in rice seed were 0.54 and 0.28% (w/w), respectively, as phosphate buffered saline (PBS)-soluble VHHs. By using a human norovirus propagation system in human induced pluripotent stem-cell-derived intestinal epithelial cells (IECs), we demonstrated the high neutralizing activity of MucoRice expressing monomeric VHH (7C6) against GII.4 norovirus and of heterodimeric VHH (7C6-1E4) against both GII.4 and GII.17 noroviruses. In addition, MucoRice-VHH (7C6-1E4) retained neutralizing activity even after heat treatment at 90°C for 20 min. These results build a fundamental platform for the continued development of MucoRice-VHH heterodimer as a candidate for oral immunotherapy and for prophylaxis against GII.4 and GII.17 noroviruses in not only healthy adults and children but also immunocompromised patients and the elderly.
Our Virtual Tribe: Sustaining and Enhancing Community via Online Music Improvisation
Authors: MacDonald Raymond , Burke Robert , De Nora Tia , Sappho Donohue Maria , Birrell Ross
Published: February 2021

This article documents experiences of Glasgow Improvisers Orchestra’s virtual, synchronous improvisation sessions during COVID-19 pandemic via interviews with 29 participants. Sessions included an international, gender balanced, and cross generational group of over 70 musicians all of whom were living under conditions of social distancing. All sessions were recorded using Zoom software. After 3 months of twice weekly improvisation sessions, 29 interviews with participants were undertaken, recorded, transcribed, and analyzed. Key themes include how the sessions provided opportunities for artistic development, enhanced mood, reduced feelings of isolation, and sustained and developed community. Particular attention is placed upon how improvisation as a universal, real time, social, and collaborative process facilitates interaction, allowing the technological affordances of software (latencies, sound quality, and gallery/speaker view) and hardware (laptop, tablet, instruments, microphones, headphones, and objects in room) to become emergent properties of artistic collaborations. The extent to which this process affects new perceptual and conceptual breakthroughs for practitioners is discussed as is the crucial and innovative relationship between audio and visual elements. Analysis of edited films of the sessions highlight artistic and theoretical and conceptual issues discussed. Emphasis is given to how the domestic environment merges with technologies to createThe Theatre of Home.
A Bio-Psycho-Social Co-created Intervention for Young Adults With Multiple Sclerosis (ESPRIMO): Rationale and Study Protocol for a Feasibility Study
Authors: Donisi Valeria , Gajofatto Alberto , Mazzi Maria Angela , Gobbin Francesca , Busch Isolde Martina , Ghellere Annamaria , Klonova Alina , Rudi Doriana , Vitali Francesca , Schena Federico , Del Piccolo Lidia , Rimondini Michela
Published: February 2021

Background

Multiple sclerosis (MS), the most common neurological disease that causes disability in youth, does not only affect physical functions but is also associated with cognitive impairment, fatigue, depression, and anxiety and can significantly impact health-related quality of life (HRQoL). Since MS is generally diagnosed at a young age—a period of great significance for personal, relational, and professional development—adaptation can become highly challenging. Therefore, enhancing the competence of young people to adaptively cope with these potential challenges is of utmost importance in order to promote their potentialities and talents. It has been shown that psychological interventions targeting MS patients can enhance resilience and HRQoL and that regular physical activity (PA) and social engagement can improve psychological well-being. However, literature on the development of global interventions based on the bio-psycho-social model of the disease is missing. Even less attention has been paid to interventions dedicated to young adults with MS (YawMS) and to the involvement of patients in the development of such programs.

Aims

In collaboration with MS patients, this study aims to develop a bio-psycho-social intervention (ESPRIMO) for YawMS, aiming to improve their HRQoL and to explore its feasibility, acceptability, and effects.

Methods

To tailor the intervention to the specific needs of YawMS, “patient engagement principles” will be adopted in the co-creation phase, performing a web survey and focus groups with patients and healthcare professionals. In the intervention phase, a pilot sample of 60 young adults with MS will be enrolled. The co-created intervention, composed of group sessions over a 12-week period, will cover psycho-social strategies and include physical activities. Adopting a longitudinal, pre–post evaluation design, self-report questionnaires measuring HRQoL and other bio-psycho-social features (e.g., resilience, well-being, mindfulness traits, self-efficacy, perceived social support, psychological symptoms, illness perception, committed action, fatigue, attitudes, subjective norms, perceived behavioral control, motivation, perception of autonomy support for PA, barriers and intentions to PA) will be administered, the quantity and quality of PA will be measured, and a questionnaire developed by the authors will be used to evaluate the feasibility and acceptability of the ESPRIMO intervention.
Effect of Fragrant Primula Flowers on Physiology and Psychology in Female College Students: An Empirical Study
Authors: Jiang Songlin , Deng Li , Luo Hao , Li Xi , Guo Baimeng , Jiang Mingyan , Jia Yin , Ma Jun , Sun Lingxia , Huang Zhuo
Published: February 2021

Indoor plants can positively impact physical and mental health in daily life. However, the benefits of viewing indoor plants may be enhanced if the plants emit a fragrant aroma. In this crossover-design study, we measured the physiological and psychological effects of fragrant and non-fragrant Primula plants on 50 female college students, and explored whether aroma stimulation had additive benefits for this group. Non-fragrant Primula malacoides Franch was used as a control stimulus, and Primula forbesii Franch, which has a floral fragrance, was used as an experimental stimulus. We measured blood pressure, pulse rate, and electroencephalogram (EEG) to evaluate physiological responses, and used a mood state profile and the semantic differential (SD) method to evaluate psychological responses. We found that mean blood pressure and pulse rate decreased significantly after the experiment in both conditions. EEGs showed that the mean values of high alpha waves, high beta waves, and relaxation scores were significantly higher in the experimental vs. control condition. The average scores on each subscale of the psychological questionnaire improved after the experiment in both conditions, and the vitality (V) subscale and total emotional state scores were significantly better in the experimental vs. control condition. The results of the SD method showed that the sense of relaxation and comfort were significantly higher in the experimental vs. control condition. Compared with the non-fragrant Primula, the fragrant Primula induced relatively better physiological and psychological effects.