bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the Interactions Interference Between the PH and START Domain of CERT by Limonoid and HPA Inhibitors
Authors: Ghoula Mariem , Le Marec Axelle , Magnan Christophe , Le Stunff Hervé , Taboureau Olivier
Published: November 2020

The multi domain ceramide transfer protein (CERT) which contains the domains START and PH, is a protein that allows the transport of ceramide from the endoplasmic reticulum to the Golgi and so it plays a major role in sphingolipid metabolism. Recently, the crystal structure of the PH-START complex has been released, suggesting an inhibitory action of START to the binding of the PH domain to the Golgi apparatus and thus limiting the CERT activity. Our study presents a combination of docking and molecular dynamic simulations of N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPA) analogs and limonoids compounds known to inhibit CERT. Through our computational study, we compared the binding affinity of 14 ligands at both domains (START and PH) and also at the START-PH interface, including several mutations known to play a role in the CERT’s activity. At the difference of HPA compounds, limonoids have a stronger binding affinity for the START-PH interface. Furthermore, 2 inhibitors (HPA-12 and isogedunin) were investigated through molecular dynamic (MD) simulations. 50 ns of molecular dynamic simulations have displayed the stability of isogedunin as well as keys residues in the binding of this molecule at the interface of the PH-START complex. Therefore, this study suggests a novel inhibitory mechanism of CERT for limonoid compounds involving the stabilization of the START-PH interface. This could help to develop new and potentially more selective inhibitors of this transporter, which is a potent target in cancer therapy.
Sleep Deprivation Induces Cognitive Impairment by Increasing Blood-Brain Barrier Permeability via CD44
Authors: Sun Jing , Wu Jusheng , Hua Fuzhou , Chen Yong , Zhan Fenfang , Xu Guohai
Published: November 2020

Sleep deprivation occurs frequently in older adults, which can result in delirium and cognitive impairment. CD44 is a key molecular in blood-brain barrier (BBB) regulation. However, whether CD44 participates in the role of sleep deprivation in cognitive impairment remains unclear. In this study, the effect of sleep deprivation on cognitive ability, tissue inflammation, BBB permeability, and astrocyte activity were evaluated in vivo. The differentially expressed genes (DEGs) were identified by RNA sequencing. A CD44 overexpression in the BBB model was performed in vitro to assess the effect and mechanisms of CD44. Sleep deprivation impaired the learning and memory ability and increased the levels of inflammatory cytokines, along with increased BBB permeability and activated astrocytes in hippocampus tissue. RNA sequencing of the hippocampus tissue revealed that 329 genes were upregulated in sleep deprivation-induced mice compared to control mice, and 147 genes were downregulated. GO and pathways showed that DEGs were mainly involved in BBB permeability and astrocyte activation, including nervous system development, neuron development, and brain development, and neuroactive ligand-receptor interaction. Moreover, the PCR analysis revealed that CD44 was dramatically increased in mice with sleep deprivation induction. The overexpression of CD44 in astrocytes promoted BBB permeability in vitro and induced the expression of the downstream gene NANOG. Our results indicate that sleep deprivation upregulated CD44 expression in hippocampus tissue, and increased BBB permeability, resulting in cognitive impairment.
Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis Through Immunophenotyping
Authors: Hannikainen Paavali A. , Kosa Peter , Barbour Christopher , Bielekova Bibiana
Published: November 2020

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders, such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological disease (OIND) controls to identify MS specific changes.

The goals of this blinded training and validation study of MS patients and embedded controls, representing 1,240 prospectively acquired paired CSF/blood samples from 588 subjects was (1) to define physiological age-/gender-related changes in CSF cells, (2) to define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific, and (3) to compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab, and ocrelizumab) on MS-related cellular abnormalities using propensity score matching.

Physiological gender differences are less pronounced in the CSF compared to blood, and age-related changes suggest decreased immunosurveillance of CNS by activated HLA-DR+T cells associated with natural aging. Results from patient samples support the concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells, and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue, forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. Although low-efficacy drugs tend to normalize it, high-efficacy drugs overshoot some aspects of CSF physiology, suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug efficacy on MS disability progression.

Video summarizing all results may become useful educational tool.
Repeatability of Neural and Autonomic Responses to Acute Psychosocial Stress
Authors: Goodman Adam M. , Diggs Michael David , Balachandran Neha , Kakulamarri Pranav S. , Oster Robert A. , Allendorfer Jane B. , Szaflarski Jerzy P.
Published: November 2020

FMRI Montreal Imaging Stress Tasks (MIST) have been shown to activate endocrine and autonomic stress responses that are mediated by a prefrontal cortex (PFC)-hippocampus-amygdala circuit. However, the stability of the neurobehavioral responses over time and the ability to monitor response to clinical interventions has yet to be validated. The objective of this study was to compare the fMRI and physiologic responses to acute psychosocial stress in healthy volunteers during initial and follow-up visits approximately 13 weeks later, simulating a typical duration of clinical intervention. We hypothesized that responses to stress would remain highly conserved across the 2 visits in the absence of an intervention. 15 healthy volunteers completed a variant of control math task (CMT) and stress math task (SMT) conditions based on MIST. Neural responses were modeled using an event-related design with estimates for math performance and auditory feedback for each task condition. For each visit, measures of stress reactivity included differential fMRI and heart rate (SMT-CMT), as well as salivary alpha-amylase before and after scanning sessions. The results revealed that differential fMRI, as well as increased heart rate and salivary alpha-amylase from before and after scanning remained similar between visits. Intraclass correlation coefficient (ICC) values revealed areas of reliable task-dependent BOLD fMRI signal response across visits for peaks of clusters for the main effect of condition (SMT vs CMT) within dorsal anterior cingulate cortex (ACC), insula, and hippocampus regions during math performance and within subgenual ACC, posterior cingulate cortex, dorsolateral PFC regions during auditory feedback. Given that the neurobehavioral response to acute stress remained highly conserved across visits in the absence of an intervention, this study confirms the utility for MIST for assessing longitudinal changes in controlled trials that can identify underlying neurobiological mechanisms involved in mediating the efficacy of stress-reduction interventions.
MIRRAGGE – Minimum Information Required for Reproducible AGGregation Experiments
Authors: Martins Pedro M. , Navarro Susanna , Silva Alexandra , Pinto Maria F. , Sárkány Zsuzsa , Figueiredo Francisco , Pereira Pedro José Barbosa , Pinheiro Francisca , Bednarikova Zuzana , Burdukiewicz Michał , Galzitskaya Oxana V. , Gazova Zuzana , Gomes Cláudio M. , Pastore Annalisa , Serpell Louise C. , Skrabana Rostislav , Smirnovas Vytautas , Ziaunys Mantas , Otzen Daniel E. , Ventura Salvador , Macedo-Ribeiro Sandra
Published: November 2020

Reports on phase separation and amyloid formation for multiple proteins and aggregation-prone peptides are recurrently used to explore the molecular mechanisms associated with several human diseases. The information conveyed by these reports can be used directly in translational investigation, e.g., for the design of better drug screening strategies, or be compiled in databases for benchmarking novel aggregation-predicting algorithms. Given that minute protocol variations determine different outcomes of protein aggregation assays, there is a strong urge for standardized descriptions of the different types of aggregates and the detailed methods used in their production. In an attempt to address this need, we assembled the Minimum Information Required for Reproducible Aggregation Experiments (MIRRAGGE) guidelines, considering first-principles and the established literature on protein self-assembly and aggregation. This consensus information aims to cover the major and subtle determinants of experimental reproducibility while avoiding excessive technical details that are of limited practical interest for non-specialized users. The MIRRAGGE table (template available in Supplementary Information) is useful as a guide for the design of new studies and as a checklist during submission of experimental reports for publication. Full disclosure of relevant information also enables other researchers to reproduce results correctly and facilitates systematic data deposition into curated databases.
High-Fat Diet and Feeding Regime Impairs Number, Phenotype, and Cytotoxicity of Natural Killer Cells in C57BL/6 Mice
Authors: Spielmann Julia , Naujoks Wiebke , Emde Matthias , Allweyer Martin , Kielstein Heike , Quandt Dagmar , Bähr Ina
Published: November 2020

Overweight and obesity are major public health challenges worldwide. Obesity is associated with a higher risk for the development of several cancer types, but specific mechanisms underlying the link of obesity and cancer are still unclear. Natural killer (NK) cells are circulating lymphoid cells promoting the elimination of virus-infected and tumor cells. Previous investigations demonstrated conflicting results concerning the influence of obesity on functional NK cell parameters in small animal models. The aim of the present study was to clarify potential obesity-associated alterations of murine NK cells in vivo, implementing different feeding regimes. Therefore, C57BL/6 mice were fed a normal-fat diet (NFD) or high-fat diet (HFD) under restrictive and ad libitum feeding regimes. Results showed diet and feeding-regime dependent differences in body weight, visceral fat mass and plasma cytokine concentrations. Flow cytometry analyses demonstrated significant changes in total cell counts as well as frequencies of immune cell populations in peripheral blood comparing mice fed NFD or HFD in an ad libitum or restrictive manner. Mice fed the HFD showed significantly decreased frequencies of total NK cells and the mature CD11b+CD27+ NK cell subset compared to mice fed the NFD. Feeding HFD resulted in significant changes in the expression of the maturation markers KLRG1 and CD127 in NK cells. Furthermore, real-time PCR analyses of NK-cell related functional parameters in adipose tissue revealed significant diet and feeding-regime dependent differences. Most notable, real-time cytotoxicity assays demonstrated an impaired cytolytic activity of splenic NK cells toward murine colon cancer cells in HFD-fed mice compared to NFD-fed mice. In conclusion, our data demonstrate that feeding a high-fat diet influences the frequency, phenotype and function of NK cells in C57BL/6 mice. Interestingly, restricted feeding of HFD compared to ad libitum feeding resulted in a partial prevention of the obesity-associated alterations on immune cells and especially on NK cells, nicely fitting with the current concept of an advantage for interval fasting for improved health.
Expression Profile of Circular RNAs in Oral Squamous Cell Carcinoma
Authors: Shao Yanxiong , Song Yuhan , Xu Siming , Li Siyi , Zhou Haiwen
Published: November 2020

Background

Circular RNAs (circRNAs) are involved in the pathogenesis of several diseases. Among oral maxillofacial cancers, oral squamous cell carcinoma (OSCC) has the highest incidence. However, the role of circRNAs in OSCC is still not clear. The aim of our study was to evaluate the circRNA expression profile in OSCC and explore further the potential role of circRNAs in the pathogenesis of OSCC.

Methods

CircRNA sequencing was performed in 6 pairs of samples of OSCC and normal oral mucosal tissues. Expression of selected circRNAs was validated by qRT-PCR. GO and KEGG analyses were performed and binding relationships between circRNAs and miRNAs were predicted. The hsa_circ_0001766/miR-877-3p/VEGFA axis was selected to further elucidate its role in OSCC.

Results

We showed that there were 122 differentially expressed (DE) circRNAs. Eight out of 10 selected circRNAs were validated by qRT-PCR. GO and KEGG analyses indicated that the identified DE circRNAs might be involved in the progression of OSCC. Then, after identification by Sanger sequencing and RNase R assay, the upregulated hsa_circ_0001766 was selected to investigate its potential role in OSCC. Bioinformatics analysis showed that hsa_circ_0001766 might act as a competing endogenous RNA (ceRNA) that sponged miR-877-3p to upregulate VEGFA expression. We selected OSCC cell lines SCC9 and SCC25. PCR results showed that the expression of hsa_circ_0001766 and VEGFA was upregulated in SCC9 and SCC25. Subsequently, using western blot, PCR, CCK8, and colony formation assays, we found that knocking down circRNA0001766 inhibited the expression of VEGFA and the proliferation of OSCC cells. Following this, miR-877-3p inhibitor reversed the inhibitory effect of si-hsa_circ_0001766 on expression of VEGFA and proliferation of OSCC cells.

Conclusions

In conclusion, our study revealed the possible role of circRNAs in the pathogenesis of OSCC, and identified the potential role of the hsa_circ_0001766/miR-877-3p/VEGFA axis in OSCC progression.
Assessment of Ablation Therapy in Pancreatic Cancer: The Radiologist’s Challenge
Authors: Granata Vincenza , Grassi Roberta , Fusco Roberta , Setola Sergio Venanzio , Palaia Raffaele , Belli Andrea , Miele Vittorio , Brunese Luca , Grassi Roberto , Petrillo Antonella , Izzo Francesco
Published: November 2020

This article provides an overview of imaging assessment of ablated pancreatic cancer. Only studies reporting radiological assessment on pancreatic ablated cancer were retained. We found 16 clinical studies that satisfied the inclusion criteria. Radiofrequency ablation and irreversible electroporation have become established treatment modalities because of their efficacy, low complication rates, and availability. Microwave Ablation (MWA) has several advantages over radiofrequency ablation (RFA), which may make it more attractive to treat pancreatic cancer. Electrochemotherapy (ECT) is a very interesting emerging technique, characterized by low complication rate and safety profile. According to the literature, the assessment of the effectiveness of ablative therapies is difficult by means of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria that are not suitable to evaluate the treatment response considering that are related to technique used, the timing of reassessment, and the imaging procedure being used to evaluate the efficacy. RFA causes various appearances on imaging in the ablated zone, correlating to the different effects, such as interstitial edema, hemorrhage, carbonization, necrosis, and fibrosis. Irreversible electroporation (IRE) causes the creation of pores within the cell membrane causing cell death. Experimental studies showed that Diffusion Weigthed Imaging (DWI) extracted parameters could be used to detect therapy effects. No data about functional assessment post MWA is available in literature. Morphologic data extracted by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) do not allow to differentiate partial, complete, or incomplete response after ECT conversely to functional parameters, obtained with Position Emission Tomography (PET), MRI, and CT.
Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma
Authors: Sabbatino Francesco , Liguori Luigi , Malapelle Umberto , Schiavi Francesca , Tortora Vincenzo , Conti Valeria , Filippelli Amelia , Tortora Giampaolo , Ferrone Cristina R. , Pepe Stefano
Published: November 2020

Introduction

Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.

Case presentation

We present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.

Conclusion

These findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.
Myasthenia Gravis Is Not an Independent Prognostic Factor of Thymoma: Results of a Propensity Score Matching Trial of 470 Patients
Authors: Zhai Yirui , Wei Yong , Hui Zhouguang , Gao Yushun , Luo Yang , Zhou Zongmei , Feng Qinfu , Li Yuemin
Published: November 2020

Objective

The association between the prognosis of thymoma and MG remains controversial. Differences in clinical characteristics and treatments between patients with and without MG may affect the findings of those studies. We designed this propensity score matching trial to investigate whether MG is an independent prognostic predictor in thymoma.

Methods

Patients with pathologically diagnosed thymoma and MG were enrolled in the MG group. Moreover, the propensity score matching method was used to select patients who were diagnosed with thymoma without MG from the database of two participating centers. Matched factors included sex, age, Masaoka stage, pathological subtypes, and treatments. Matched patients were enrolled in the non-MG group. Chi-squared test was used to compare the characteristics of the two groups. Overall survival, local-regional relapse-free survival, distant metastasis-free survival, progression-free survival, and cancer-specific survival were calculated from the diagnosis of thymoma using the Kaplan–Meier method.

Results

Between April 1992 and October 2018, 235 patients each were enrolled in the MG and non-MG groups (1:1 ratio). The median ages of patients in the MG and non-MG groups were 46 years old. The World Health Organization pathological subtypes were well balanced between the two groups (B2 + B3: MG vs. non-MG group, 63.0 vs. 63.4%, p = 0.924). Most patients in both groups had Masaoka stages I–III (MG vs. non-MG group, 90.2 vs. 91.5%, p = 0.631). R0 resections were performed in 86.8 and 90.2% of the MG and non-MG groups, respectively (p = 0.247). The median follow-up time of the two groups was 70.00 months (MG vs. non-MG group, 73.63 months vs. 68.00 months). Five-year overall survivals were 92.5 and 90.3%, 8-year overall survivals were 84.2 and 84.2%, and 10-year overall survivals were 80.2 and 81.4% (p = 0.632) in the MG and non-MG groups, respectively. No differences were found in the progression-free survival, distant metastasis-free survival, and local-regional relapse-free survival between the two groups.

Conclusion

MG is not an independent or direct prognostic factor of thymoma, although it might be helpful in diagnosis thymoma at an early stage, leading indirectly to better prognosis.
Safety and Efficacy of Immune Checkpoint Inhibitors for Patients With Metastatic Urothelial Carcinoma and End-Stage Renal Disease: Experiences From Real-World Practice
Authors: Kuo Ming-Chun , Su Po-Jung , Huang Chun-Chieh , Luo Hao-Lun , Chiu Tai-Jan , Li Shau-Hsuan , Wu Chia-Che , Liu Ting-Ting , Cheng Yuan-Tso , Kang Chih-Hsiung , Su Yu-Li
Published: November 2020

Background

Immune checkpoint inhibitors (ICIs) are used widely for treating metastatic urothelial carcinoma (mUC). In practical settings, evidence is lacking on the efficacy of ICIs in some difficult-to-treat patients, such as those with end-stage renal disease (ESRD). Herein, we evaluate the safety and efficacy of ICIs for patients with mUC and ESRD.

Methods

For this retrospective study, patients with mUC who were given ICIs at Kaohsiung Chang Gang Memorial Hospital and Linkou Chang Gung Memorial Hospital between April 2016 and November 2019 were consecutively enrolled. All clinicopathologic data, treatment responses, and adverse events were recorded. The immune-related adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between ESRD and non-ESRD groups.

Results

In total, 129 patients with mUC were enrolled, with 11 patients categorized as the ESRD group. Among these patients with ESRD receiving ICIs, 7 of 11 (63.6%) had high-grade (grade ≥3) AEs, chiefly hematologic toxicity. Some rarely encountered AEs were noted, including toxic epidermal necrolysis, tuberculosis reactivation, ascites, and cytokine release syndrome. Patients in the ESRD group had numerically higher ORR (54.5% vs. 28.8%, p = 0.09), PFS (7.1 vs. 3.5 months, p = 0.42), and OS (not reached vs. 15.4 months) than the non-ESRD group. A multivariate Cox regression model demonstrated that leukocytosis (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.23–5.63; p = 0.01) and neutrophil-to-lymphocyte ratio (HR 2.91; 95% CI: 1.30–6.53; p = 0.01) were independent prognostic factors.

Conclusion

Administration of ICIs in patients with mUC and ESRD demonstrated a modest antitumor activity, and should be used with caution for increasing risk of hematologic toxicity.
Hepatocellular Senescence: Immunosurveillance and Future Senescence-Induced Therapy in Hepatocellular Carcinoma
Authors: Liu Peng , Tang Qinghe , Chen Miaomiao , Chen Wenjian , Lu Yanli , Liu Zhongmin , He Zhiying
Published: November 2020

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The lack of effective targeted drugs has become a challenge on treating HCC patients. Cellular senescence is closely linked to the occurrence, development, and therapy of tumor. Induction of cellular senescence and further activation of immune surveillance provides a new strategy to develop HCC targeted drugs, that is, senescence-induced therapy for HCC. Precancerous hepatocytes or HCC cells can be induced into senescent cells, subsequently producing senescence-associated secretory phenotype (SASP) factors. SASP factors recruit and activate various types of immune cells, including T cells, NK cells, macrophages, and their subtypes, which carry out the role of immune surveillance and elimination of senescent cells, ultimately preventing the occurrence of HCC or inhibiting the progression of HCC. Specific interventions in several checkpoints of senescence-mediated therapy will make positive contributions to suppress tumorigenesis and progression of HCC, for instance, by applying small molecular compounds to induce cellular senescence or selecting cytokines/chemokines to activate immunosurveillance, supplementing adoptive immunocytes to remove senescent cells, and screening chemical drugs to induce apoptosis of senescent cells or accelerate clearance of senescent cells. These interventional checkpoints become potential chemotherapeutic targets in senescence-induced therapy for HCC. In this review, we focus on the frontiers of senescence-induced therapy and discuss senescent characteristics of hepatocytes during hepatocarcinogenesis as well as the roles and mechanisms of senescent cell induction and clearance, and cellular senescence-related immunosurveillance during the formation and progression of HCC.
To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells
Authors: Fontán-Lozano Ángela , Morcuende Sara , Davis-López de Carrizosa Mª América , Benítez-Temiño Beatriz , Mejías Rebeca , Matarredona Esperanza R.
Published: November 2020

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.
Opioids in Post-stroke Pain: A Systematic Review and Meta-Analysis
Authors: Scuteri Damiana , Mantovani Elisa , Tamburin Stefano , Sandrini Giorgio , Corasaniti Maria Tiziana , Bagetta Giacinto , Tonin Paolo
Published: November 2020

Background: Post-stroke pain is one of the most common sequelae of stroke, which stands among the leading causes of death and adult-acquired disability worldwide. The role and clinical efficacy of opioids in post-stroke pain syndromes is still debated.

Objectives: Due to the important gap in knowledge on the management of post-stroke pain, this systematic review aimed at assessing the efficacy of opioids in post-stroke pain syndromes.

Methods: A literature search was conducted on databases relevant for medical scientific literature, i.e. PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases from databases inception until August 31st, 2020 for clinical trials assessing the effects of opioids and opioid antagonists on pain reduction and pain related symptoms in patients with post-stroke pain syndromes. Studies assessing the effects of other medications (e.g., tricyclic antidepressant, pregabalin) or non - pharmacological management strategies (e.g., neurostimulation techniques) were excluded. The selected studies have been subjected to examination of the risk of bias.

Results: The literature search retrieved 83,435 results. After duplicates removal, 34,285 articles were title and abstract screened. 25 full texts were assessed and 8 articles were identified to be eligible for inclusion in the qualitative summary and narrative analysis, of which three were placebo-controlled and two were dose-response. Among placebo-controlled studies, two evaluated the analgesic effect of morphine and one assessed the effects of the opioid antagonist naloxone on patients with central post-stroke pain. With regard to dose-response studies, both were on patients with central post-stroke pain, one assessing the efficacy of levorphanol, and the other on naloxone. Seven out of eight included studies showed an overall slight analgesic effect of opioids, with less consistent effects on other pain-related symptoms (e.g., mood, quality of life). The randomized controlled trials were subjected to meta-analysis and rating of the quality of evidence for the two outcomes considered according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system. The overall results are inconclusive because of the small number of studies and of patients.

Conclusions: The limited number of the included studies and their heterogeneity in terms of study design do not support the efficacy of opioids in post-stroke pain and in pain-related outcomes. Large double-blind randomized clinical trials with objective assessment of pain and related symptoms are needed to further investigate this topic.
Optical Fiber Sensors for Metal Ions Detection Based on Novel Fluorescent Materials
Authors: Cai Yi , Li Ming , Wang Minghao , Li Jin , Zhang Ya-nan , Zhao Yong
Published: November 2020

Recently, novel fluorescent probes based on biomaterials and luminescent nanomaterials for metal ions attract tremendous attentions, owing to their advantages of simple operation, high sensitivity and rapid response for metals detection. Immobilized on the optical fiber sensor, fluorescent probes reveal the advantages while facing outdoor detection challenges. Therefore, numerous fluorescent optical fiber sensors for metal ions have been developed for online and in-situ detection to predict and prevent the environmental problems. Differ from refractometer-based fiber sensors, the structures of the fiber sensors based on fluorescent materials are usually simple, and the characters of the materials and the fabrication processes of fiber sensors are more significant to the sensing performances. This paper summarized the studies of optical fiber sensors for metal detection based on novel fluorescent materials to help researchers get the highlights of recent notable advancements and obtain the better potential prospects.
The Concept of Cooperative Dynamics in Simulations of Soft Matter
Authors: Polanowski Piotr , Sikorski Andrzej
Published: November 2020

In this review we compiled recent advances concerning the cooperative motion in crowded soft matter systems. We tried to answer the question how to perform dynamic Monte Carlo simulations of dense macromolecular systems effectively. This problem is not simple due to the fact that the movement in such systems is strictly correlated which leads to cooperative phenomena. The influence of crowding was found interesting especially for two-dimensional cases, e.g., in membranes where the presence of macromolecules, proteins and cytoskeleton often changed the mean-square displacement as a function of the lag time and anomalous diffusion appeared. Simple models are frequently used to shed a light on molecular transport in biological systems. The emphasis was given to the Dynamic Lattice Liquid model. The latter model became a basis for a parallel algorithm that takes into account coincidences of elementary molecular motion attempts resulting in local cooperative structural transformations. The emphasis is put on influence of the model of molecular transport on the diffusion. The comparison to alternative approaches like single agent model was carried out.
Association of Hyperuricemia With Immune Disorders and Intestinal Barrier Dysfunction
Authors: Lv Qiulan , Xu Daxing , Zhang Xuezhi , Yang Xiaomin , Zhao Peng , Cui Xuena , Liu Xiu , Yang Wan , Yang Guanpin , Xing Shichao
Published: November 2020

Background

More than 30–40% of uric acid is excreted via the intestine, and the dysfunction of intestinal epithelium disrupts uric acid excretion. The involvement of gut microbiota in hyperuricemia has been reported in previous studies, but the changes and mechanisms of intestinal immunity in hyperuricemia are still unknown.

Methods

This study developed a urate oxidase (Uox)-knockout (Uox–/–) mouse model for hyperuricemia using CRISPR/Cas9 technology. The lipometabolism was assessed by measuring changes in biochemical indicators. Furthermore, 4-kDa fluorescein isothiocyanate–labeled dextran was used to assess gut barrier function. Also, 16S rRNA sequencing was performed to examine the changes in gut microbiota in mouse feces. RNA sequencing, Western blot, Q-PCR, ELISA, and immunohistochemical analysis were used for measuring gene transcription, the number of immune cells, and the levels of cytokines in intestinal tissues, serum, kidney, liver, pancreas, and vascellum.

Results

This study showed that the abundance of inflammation-related microbiota increased in hyperuricemic mice. The microbial pattern recognition–associated Toll-like receptor pathway and inflammation-associated TNF and NF-kappa B signaling pathways were significantly enriched. The increased abundance of inflammation-related microbiota resulted in immune disorders and intestinal barrier dysfunction by upregulating TLR2/4/5 and promoting the release of IL-1β and TNF-α. The levels of epithelial tight junction proteins occludin and claudin-1 decreased. The expression of the pro-apoptotic gene Bax increased. The levels of LPS and TNF-α in systemic circulation increased in hyperuricemic mice. A positive correlation was observed between the increase in intestinal permeability and serum levels of uric acid.

Conclusion

Hyperuricemia was characterized by dysregulated intestinal immunity, compromised intestinal barrier, and systemic inflammation. These findings might serve as a basis for future novel therapeutic interventions for hyperuricemia.
Multi-Head Self-Attention Model for Classification of Temporal Lobe Epilepsy Subtypes
Authors: Gu Peipei , Wu Ting , Zou Mingyang , Pan Yijie , Guo Jiayang , Xiahou Jianbing , Peng Xueping , Li Hailong , Ma Junxia , Zhang Ling
Published: November 2020

As a long-standing chronic disease, Temporal Lobe Epilepsy (TLE), resulting from abnormal discharges of neurons and characterized by recurrent episodic central nervous system dysfunctions, has affected more than 70% of drug-resistant epilepsy patients across the world. As the etiology and clinical symptoms are complicated, differential diagnosis of TLE mainly relies on experienced clinicians, and specific diagnostic biomarkers remain unclear. Though great effort has been made regarding the genetics, pathology, and neuroimaging of TLE, an accurate and effective diagnosis of TLE, especially the TLE subtypes, remains an open problem. It is of a great importance to explore the brain network of TLE, since it can provide the basis for diagnoses and treatments of TLE. To this end, in this paper, we proposed a multi-head self-attention model (MSAM). By integrating the self-attention mechanism and multilayer perceptron method, the MSAM offers a promising tool to enhance the classification of TLE subtypes. In comparison with other approaches, including convolutional neural network (CNN), support vector machine (SVM), and random forest (RF), experimental results on our collected MEG dataset show that the MSAM achieves a supreme performance of 83.6% on accuracy, 90.9% on recall, 90.7% on precision, and 83.4% on F1-score, which outperforms its counterparts. Furthermore, effectiveness of varying head numbers of multi-head self-attention is assessed, which helps select the optimal number of multi-head. The self-attention aspect learns the weights of different signal locations which can effectively improve classification accuracy. In addition, the robustness of MSAM is extensively assessed with various ablation tests, which demonstrates the effectiveness and generalizability of the proposed approach.
Validation of mDurance, A Wearable Surface Electromyography System for Muscle Activity Assessment
Authors: Molina-Molina Alejandro , Ruiz-Malagón Emilio J. , Carrillo-Pérez Francisco , Roche-Seruendo Luis E. , Damas Miguel , Banos Oresti , García-Pinillos Felipe
Published: November 2020

The mDurance® system is an innovative digital tool that combines wearable surface electromyography (sEMG), mobile computing and cloud analysis to streamline and automatize the assessment of muscle activity. The tool is particularly devised to support clinicians and sport professionals in their daily routines, as an assessment tool in the prevention, monitoring rehabilitation and training field. This study aimed at determining the validity of the mDurance system for measuring muscle activity by comparing sEMG output with a reference sEMG system, the Delsys® system. Fifteen participants were tested during isokinetic knee extensions at three different speeds (60, 180, and 300 deg/s), for two muscles (rectus femoris [RF] and vastus lateralis [VL]) and two different electrodes locations (proximal and distal placement). The maximum voluntary isometric contraction was carried out for the normalization of the signal, followed by dynamic isokinetic knee extensions for each speed. The sEMG output for both systems was obtained from the raw sEMG signal following mDurance's processing and filtering. Mean, median, first quartile, third quartile and 90th percentile was calculated from the sEMG amplitude signals for each system. The results show an almost perfect ICC relationship for the VL (ICC > 0.81) and substantial to almost perfect for the RF (ICC > 0.762) for all variables and speeds. The Bland-Altman plots revealed heteroscedasticity of error for mean, quartile 3 and 90th percentile (60 and 300 deg/s) for RF and at mean and 90th percentile for VL (300 deg/s). In conclusion, the results indicate that the mDurance® sEMG system is a valid tool to measure muscle activity during dynamic contractions over a range of speeds. This innovative system provides more time for clinicians (e.g., interpretation patients' pathologies) and sport trainers (e.g., advising athletes), thanks to automatic processing and filtering of the raw sEMG signal and generation of muscle activity reports in real-time.
The LRR-RLK Protein HSL3 Regulates Stomatal Closure and the Drought Stress Response by Modulating Hydrogen Peroxide Homeostasis
Authors: Liu Xuan-shan , Liang Chao-chao , Hou Shu-guo , Wang Xin , Chen Dong-hua , Shen Jian-lin , Zhang Wei , Wang Mei
Published: November 2020

Guard cells shrink in response to drought stress and abscisic acid (ABA) signaling, thereby reducing stomatal aperture. Hydrogen peroxide (H2O2) is an important signaling molecule acting to induce stomatal closure. As yet, the molecular basis of control over the level of H2O2 in the guard cells remains largely unknown. Here, the leucine-rich repeat (LRR)—receptor-like kinase (RLK) protein HSL3 has been shown to have the ability to negatively regulate stomatal closure by modulating the level of H2O2 in the guard cells. HSL3 was markedly up-regulated by treating plants with either ABA or H2O2, as well as by dehydration. In the loss-of-function hsl3 mutant, both stomatal closure and the activation of anion currents proved to be hypersensitive to ABA treatment, and the mutant was more tolerant than the wild type to moisture deficit; the overexpression of HSL3 had the opposite effect. In the hsl3 mutant, the transcription of NADPH oxidase gene RbohF involved in H2O2 production showed marked up-regulation, as well as the level of catalase activity was weakly inducible by ABA, allowing H2O2 to accumulate in the guard cells. HSL3 was concluded to participate in the regulation of the response to moisture deficit through ABA-induced stomatal closure triggered by the accumulation of H2O2 in the guard cells.
Quantifying the Effects of Vegetation Restorations on the Soil Erosion Export and Nutrient Loss on the Loess Plateau
Authors: Zhao Jun , Feng Xiaoming , Deng Lei , Yang Yanzheng , Zhao Zhong , Zhao Pengxiang , Peng Changhui , Fu Bojie
Published: November 2020

The transport of eroded soil to rivers changes the nutrient cycles of river ecosystems and has significant impacts on the regional eco-environment and human health. The Loess Plateau, a leading vegetation restoration region in China and the world, has experienced severe soil erosion and nutrient loss, however, the extent to which vegetation restoration prevents soil erosion export (to rivers) and it caused nutrient loss is unknown. To evaluate the effects of the first stage of the Grain for Green Project (GFGP) on the Loess Plateau (started in 1999 and ended in 2013), we analyzed the vegetation change trends and quantified the effects of GFGP on soil erosion export (to rivers) and it caused nutrient loss by considering soil erosion processes. The results were as follows: (1) in the first half of study period (from 1982 to 1998), the vegetation cover changed little, but after the implementation of the first stage of the GFGP (from 1999 to 2013), the vegetation cover of 75.0% of the study area showed a significant increase; (2) The proportion of eroded areas decreased from 41.8 to 26.7% as a result of the GFGP, and the erosion intensity lessened in most regions; the implementation significantly reduce the soil nutrient loss; (3) at the county level, soil erosion export could be avoided significantly by the increasing of vegetation greenness in the study area (R = −0.49). These results illustrate the relationships among changes in vegetation cover, soil erosion and nutrient export, which could provide a reference for local government for making ecology-relative policies.
Monoclonal Antibodies B38 and H4 Produced in Nicotiana benthamiana Neutralize SARS-CoV-2 in vitro
Authors: Shanmugaraj Balamurugan , Rattanapisit Kaewta , Manopwisedjaroen Suwimon , Thitithanyanont Arunee , Phoolcharoen Waranyoo
Published: November 2020

The ongoing coronavirus disease 2019 (COVID-19) outbreak caused by novel zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially reported in Wuhan city, Hubei Province of China, in late December 2019. The rapid global spread of the virus calls for the urgent development of vaccines or therapeutics for human applications to combat the coronavirus infection. Monoclonal antibodies (mAbs) have been utilized as effective therapeutics for treating various infectious diseases. In the present study, we evaluated the feasibility of plant expression system for the rapid production of recently identified therapeutically suitable human anti-SARS-CoV-2 mAbs B38 and H4. Transient co-expression of heavy-chain and light-chain sequences of both the antibodies by using plant expression geminiviral vector resulted in rapid accumulation of assembled mAbs in Nicotiana benthamiana leaves within 4 days post-infiltration. Furthermore, both the mAbs were purified from the plant crude extracts with single-step protein A affinity column chromatography. The expression level of mAb B38 and H4 was estimated to be 4 and 35 μg/g leaf fresh weight, respectively. Both plant-produced mAbs demonstrated specific binding to receptor binding domain (RBD) of SARS-CoV-2 and exhibited efficient virus neutralization activity in vitro. To the best of our knowledge, this is the first report of functional anti-SARS-CoV-2 mAbs produced in plants, which demonstrates the ability of using a plant expression system as a suitable platform for the production of effective, safe, and affordable SARS-CoV-2 mAbs to fight against the spread of this highly infectious pathogen.
Phytonutritional Content and Aroma Profile Changes During Postharvest Storage of Edible Flowers
Authors: Marchioni Ilaria , Pistelli Laura , Ferri Benedetta , Copetta Andrea , Ruffoni Barbara , Pistelli Luisa , Najar Basma
Published: November 2020

Edible flowers are niche horticultural products, routinely used as cooking ingredients in the food industry. Currently, new species are required with the aim of enlarging the number of species with a long shelf-life, healthy nutraceutical compounds, and new fragrance and tastes.Ageratum houstonianumMill,Tagetes lemmoniiA. Gray,Salvia dorisianaStandl, andPelargonium odoratissimum(L.) L’Hér “Lemon” were selected for their different morphological characteristics and color. Fresh flowers were analyzed to characterize their phytonutritional content and aroma profile. Postharvest was determined up to 6 days of cold storage at 4°C in transparent polypropylene boxes. Visual quality and cellular membrane damage were observed. The relative content of different antioxidant constituents (e.g., polyphenols, flavonoids, anthocyanins, ascorbic acid), nutritional compounds (soluble sugars, crude proteins), the antioxidant scavenging activity, and the volatile profile were determined and correlated to the quality of shelf-life of the different species. The yellowT. lemmoniifreshly picked flowers showed the highest ascorbic acid and flavonoids content, which was maintained during the cold storage, as well as the best visual quality. Limited changes in metabolites were detected in the light blueA. houstonianumduring postharvest, although the visual quality is severely compromised. MagentaS. dorisianaand light pinkP. odoratissimumshowed similar changes in antioxidant constituents during cold storage. For the first time, the volatile compounds have been identified in the four species. Sesquiterpene hydrocarbons are the main class in fresh flowers ofA. houstonianum,S. dorisiana, andP. odoratissimum, while monoterpene hydrocarbons are abundant inT. lemmonii.The cold storage influenced mainlyP. odoratissimumandS. dorisianaflavor initially dominated by the increase in total monoterpenes at 6 days, reaching a relative content of 90%. BothA. houstonianumandT. lemmoniiconserved the prevalence of the same class of constituents in all the analyzed conditions, even though the cold storage influenced the major compound abundance. On the basis of the results,T. lemmoniiwas the most interesting species with the longest shelf-life due to its phytonutritional and aromatic constituents. Results indicated the peculiar metabolic and physiological attitude of flowers species to cold storage.