bluuebunny/crossref_metadata_2025 huggingface dataset:
miRNA Regulation of NK Cells Antiviral Response in Children With Severe and/or Recurrent Herpes Simplex Virus Infections
Authors: Lenart Marzena , Działo Edyta , Kluczewska Anna , Węglarczyk Kazimierz , Szaflarska Anna , Rutkowska-Zapała Magdalena , Surmiak Marcin , Sanak Marek , Pituch-Noworolska Anna , Siedlar Maciej
Published: January 2021

Severe and/or recurrent infection with Herpes simplex virus (HSV) is observed in a large group of patients treated in clinical immunology facilities. Atypical and prolonged HSV infection is the most common clinical manifestation of disturbed NK cell development and functions, yet the molecular basis of these disorders is still largely unknown. Since recent findings indicated the importance of miRNA in regulating NK cell development, maturation and functions, the aim of our study was to investigate miRNA expression pattern in NK cells in patients with severe and/or recurrent infections with HSV and analyze the role of these miRNAs in NK cell antiviral response. As a result, miRNA expression pattern analysis of human best known 754 miRNAs revealed that patients with severe and/or recurrent HSV infection had substantially upregulated expression of four miRNAs: miR-27b, miR-199b, miR-369-3p and miR-491-3p, when compared to healthy controls. Selective inhibition of miR-27b, miR-199b, miR-369-3p and miR-491-3p expression in NK-92 cells resulted in profound upregulation of 4 genes (APOBEC3G, MAP2K3, MAVS and TLR7) and downregulation of 36 genes taking part in antiviral response or associated with signaling pathways of Toll-like receptors (TLR), NOD-like receptors, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and type I IFN-related response. Additionally, flow cytometry analysis revealed that miR-369-3p and miR-491-3p inhibitors downregulated NK cell intracellular perforin expression, while the expression of granzyme B and IFNγ remained unchanged. Taken together, our study suggests a novel mechanism which may promote recurrence and severity of HSV infection, based on miRNAs-dependent posttranscriptional regulation of genes taking part in antiviral response of human NK cells.
RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis
Authors: Tatomir Alexandru , Beltrand Austin , Nguyen Vinh , Boodhoo Dallas , Mekala Armugam , Cudrici Cornelia , Badea Tudor C. , Muresanu Dafin F. , Rus Violeta , Rus Horea
Published: January 2021

Astrocytes are increasingly recognized as critical contributors to multiple sclerosis pathogenesis. We have previously shown that lack of Response Gene to Complement 32 (RGC-32) alters astrocyte morphology in the spinal cord at the peak of experimental autoimmune encephalomyelitis (EAE), suggesting a role for RGC-32 in astrocyte differentiation. In this study, we analyzed the expression and distribution of astrocytes and astrocyte progenitors by immunohistochemistry in spinal cords of wild-type (WT) and RGC-32-knockout (KO) mice with EAE and of normal adult mice. Our analysis showed that during acute EAE, WT astrocytes had a reactive morphology and increased GFAP expression, whereas RGC-32 KO astrocytes had a morphology similar to that of radial glia and an increased expression of progenitor markers such as vimentin and fatty acid binding protein 7 (FABP7). In control mice, GFAP expression and astrocyte density were also significantly higher in the WT group, whereas the number of vimentin and FABP7-positive radial glia was significantly higher in the RGC-32 KO group. In vitro studies on cultured neonatal astrocytes from WT and RGC-32 KO mice showed that RGC-32 regulates a complex array of molecular networks pertaining to signal transduction, growth factor expression and secretion, and extracellular matrix (ECM) remodeling. Among the most differentially expressed factors were insulin-like growth factor 1 (IGF1), insulin-like growth factor binding proteins (IGFBPs), and connective tissue growth factor (CTGF); their expression was downregulated in RGC-32-depleted astrocytes. The nuclear translocation of STAT3, a transcription factor critical for astrogliogenesis and driving glial scar formation, was also impaired after RGC-32 silencing. Taken together, these data suggest that RGC-32 is an important regulator of astrocyte differentiation during EAE and that in the absence of RGC-32, astrocytes are unable to fully mature and become reactive astrocytes.
Immune Privilege: The Microbiome and Uveitis
Authors: Mölzer Christine , Heissigerova Jarmila , Wilson Heather M. , Kuffova Lucia , Forrester John V.
Published: January 2021

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated “non-infectious” uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.
The Immunobiogram, a Novel In Vitro Assay to Evaluate Treatment Resistance in Patients Receiving Immunosuppressive Therapy
Authors: Portoles Jose Maria , Jimenez Carlos , Janeiro Dario , Lopez-Oliva Maria O. , Ortega-Carrion Alvaro , Blanquez Daniel , Arribas Luis , Gomez Carlos , Diez Teresa , Pascual Julio , Portero Isabel
Published: January 2021

Immunosuppressive drugs are widely used to treat several autoimmune disorders and prevent rejection after organ transplantation. However, intra-individual variations in the pharmacological response to immunosuppressive therapy critically influence its efficacy, often resulting in poor treatment responses and serious side effects. Effective diagnostic tools that help clinicians to tailor immunosuppressive therapy to the needs and immunological profile of the individual patient thus constitute a major unmet clinical need. In vitro assays that measure immune cell responses to immunosuppressive drugs constitute a promising approach to individualized immunosuppressive therapy. Here, we present the Immunobiogram, a functional pharmacodynamic immune cell-based assay for simultaneous quantitative measurement of a patient’s immune response to a battery of immunosuppressive drugs. Peripheral blood mononuclear cells collected from patients are immunologically stimulated to induce activation and proliferation and embedded in a hydrogel mixture in which they are exposed to a concentration gradient of the immunosuppressants of interest. Analysis of samples from kidney transplant patients using this procedure revealed an association between the sensitivity of individual patients to the immunosuppressive regimen and their immunological risk of transplant rejection. Incorporation of the Immunobiogram assay into clinical settings could greatly facilitate personalized optimization and monitoring of immunosuppressive therapy, and study of the mechanisms underlying resistance to immunosuppressants.
Effect of Three Pesticides Used in Salmon Farming on Ammonium Uptake in Central-Southern and Northern Patagonia, Chile
Authors: Valdés-Castro Valentina , Fernandez Camila
Published: January 2021

Chile is the second largest global producer of farmed salmon. The growth of salmon production has not been free of environmental challenges, such as the increasing use of pesticides to control the parasitic load of the sea lice Caligus rogercresseyi. The lack of the specificity of pesticides can potentially affect non-target organisms, as well as the structure and functioning of aquatic ecosystems. The aim of this study, was to understand the effect of pesticides on natural microbial communities to the addition of the anti-lice pesticide azamethiphos, deltamethrin and emamectin benzoate, and their potential impact in ammonium uptake rates in the coast off central-southern Chile and Northern Patagonia. The addition of pesticides on natural microbial communities resulted in a rapid response in ammonium uptake, which was significant for the single use of pesticide, azamethiphos and emamectin benzoate, as well as the combination, azamethiphos, deltamethrin and emamectin benzoate. In northern Patagonia, azamethiphos addition produced a 53% decrease in photoautotrophic uptake. However, an increase, although variable, was observed in chemoautotrophic uptake. Emamectin benzoate produced a 36 to 77% decrease in chemo and photoautotrophic ammonium uptake, respectively. The combined use of pesticides, also produced up to 42% decrease in both photo and chemoautotrophic assimilation. We conclude that the use of pesticides in salmon farming produces diverse responses at the microbial level, stimulating and/or inhibiting microbial communities with subsequent impact on nitrogen budgets. Further studies are necessary to understand the impact of pesticides in the ecology of central-southern and northern Patagonia, Chile.
Trophic Structure of Neuston Across Tropical and Subtropical Oceanic Provinces Assessed With Stable Isotopes
Authors: Albuquerque Rui , Bode Antonio , González-Gordillo Juan Ignacio , Duarte Carlos M. , Queiroga Henrique
Published: January 2021

The marine neuston, organisms living in the vicinity of the ocean surface, is one of the least studied zooplankton groups. Neuston occupies a restricted ecological niche and is affected by a wide range of endogenous and exogenous processes while also being a food source to zooplankton fish migrating from the deep layers and seabirds. In this study, the neustonic communities were characterized along the Malaspina global expedition sampling tropical and subtropical oceanic provinces using stable carbon and nitrogen isotopes to explore their trophic structure and relationships with environmental variables. The differences in stable isotopes mirrored the patterns in environmental characteristics of each province. High δ13C values were associated with atmospheric carbon inputs, while the presence of dinoflagellates, coccolithophorids, and upwelling influence is related to low δ13C values. Similarly, provinces presenting high δ15N values were associated with denitrification and nitrate diffusive fluxes, whereas the presence of low δ15N is attributable to nitrogen supplied through N2 fixation by diazotrophs. Neuston showed a large overlap among the isotopic niches of four functional groups, with chaetognaths and detritivores generally exhibiting a smaller degree of overlap compared to carnivores and omnivores/herbivores. These results support the hypothesis of a common trophic structure in the neuston community across the ocean. However, the size of the niche, small in coastal areas and those influenced by upwelling and large in oligotrophic regions, and their overlap, low in more productive provinces and high in oligotrophic provinces, may be associated with food availability. Small trophic niches are associated with a dominance of specialized over-opportunistic feeding in productive environments.
Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins—An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic
Authors: Yu Mingjia , Zhang Tianji , Zhang Wei , Sun Qianyun , Li Hongmei , Li Jin-ping
Published: January 2021

Owing to the high mortality and the spread rate, the infectious disease caused by SARS-CoV-2 has become a major threat to public health and social economy, leading to over 70 million infections and 1. 6 million deaths to date. Since there are currently no effective therapeutic or widely available vaccines, it is of urgent need to look for new strategies for the treatment of SARS-CoV-2 infection diseases. Binding of a viral protein onto cell surface heparan sulfate (HS) is generally the first step in a cascade of interaction that is required for viral entry and the initiation of infection. Meanwhile, interactions of selectins and cytokines (e.g., IL-6 and TNF-α) with HS expressed on endothelial cells are crucial in controlling the recruitment of immune cells during inflammation. Thus, structurally defined heparin/HS and their mimetics might serve as potential drugs by competing with cell surface HS for the prevention of viral adhesion and modulation of inflammatory reaction. In this review, we will elaborate coronavirus invasion mechanisms and summarize the latest advances in HS–protein interactions, especially proteins relevant to the process of coronavirus infection and subsequent inflammation. Experimental and computational techniques involved will be emphasized.
Predicting Grating Orientations With Cross-Frequency Coupling and Least Absolute Shrinkage and Selection Operator in V1 and V4 of Rhesus Monkeys
Authors: Li Zhaohui , Du Yue , Xiao Youben , Yin Liyong
Published: January 2021

Orientation selectivity, as an emergent property of neurons in the visual cortex, is of critical importance in the processing of visual information. Characterizing the orientation selectivity based on neuronal firing activities or local field potentials (LFPs) is a hot topic of current research. In this paper, we used cross-frequency coupling and least absolute shrinkage and selection operator (LASSO) to predict the grating orientations in V1 and V4 of two rhesus monkeys. The experimental data were recorded by utilizing two chronically implanted multi-electrode arrays, which were placed, respectively, in V1 and V4 of two rhesus monkeys performing a selective visual attention task. The phase–amplitude coupling (PAC) and amplitude–amplitude coupling (AAC) were employed to characterize the cross-frequency coupling of LFPs under sinusoidal grating stimuli with different orientations. Then, a LASSO logistic regression model was constructed to predict the grating orientation based on the strength of PAC and AAC. Moreover, the cross-validation method was used to evaluate the performance of the model. It was found that the average accuracy of the prediction based on the combination of PAC and AAC was 73.9%, which was higher than the predicting accuracy with PAC or AAC separately. In conclusion, a LASSO logistic regression model was introduced in this study, which can predict the grating orientations with relatively high accuracy by using PAC and AAC together. Our results suggest that the principle behind the LASSO model is probably an alternative direction to explore the mechanism for generating orientation selectivity.
Influence of Background Musical Emotions on Attention in Congenital Amusia
Authors: Fernandez Natalia B. , Vuilleumier Patrik , Gosselin Nathalie , Peretz Isabelle
Published: January 2021

Congenital amusia in its most common form is a disorder characterized by a musical pitch processing deficit. Although pitch is involved in conveying emotion in music, the implications for pitch deficits on musical emotion judgements is still under debate. Relatedly, both limited and spared musical emotion recognition was reported in amusia in conditions where emotion cues were not determined by musical mode or dissonance. Additionally, assumed links between musical abilities and visuo-spatial attention processes need further investigation in congenital amusics. Hence, we here test to what extent musical emotions can influence attentional performance. Fifteen congenital amusic adults and fifteen healthy controls matched for age and education were assessed in three attentional conditions: executive control (distractor inhibition), alerting, and orienting (spatial shift) while music expressing either joy, tenderness, sadness, or tension was presented. Visual target detection was in the normal range for both accuracy and response times in the amusic relative to the control participants. Moreover, in both groups, music exposure produced facilitating effects on selective attention that appeared to be driven by the arousal dimension of musical emotional content, with faster correct target detection during joyful compared to sad music. These findings corroborate the idea that pitch processing deficits related to congenital amusia do not impede other cognitive domains, particularly visual attention. Furthermore, our study uncovers an intact influence of music and its emotional content on the attentional abilities of amusic individuals. The results highlight the domain-selectivity of the pitch disorder in congenital amusia, which largely spares the development of visual attention and affective systems.
Event-Related Alpha-Band Power Changes During Self-reflection and Working Memory Tasks in Healthy Individuals
Authors: Matsuoka Takahiro , Shimode Takaki , Ota Toshio , Matsuo Koji
Published: January 2021

Dysfunctional attentional control is observed in patients with mental disorders. However, there is no established neurophysiological method to assess attention in such patients. We showed a discrepancy in alpha-band power in the tasks that evoked internal and external attention event-related alpha-band power changes in healthy subjects during self-reflection (SR) and working memory (WM) tasks in a preliminary study. In this study, we aimed at elucidating event-related alpha-band power changes in healthy subjects during the tasks, addressing the shortcomings of the previous study. Sixteen healthy volunteers were examined for the event-related power (ERpow) change during the tasks. The results demonstrated the discrepancy of alpha-band ERpow at 8, 10, and 12 Hz in the parieto-occipital area between the WM and SR tasks for a period between a target stimulus and a command stimulus, where a participant switched to internal attention from external attention according to the SR task and remained at external attention according to the WM task. The results suggest that alpha-band ERpow in this area is associated with the direction of attention in response to cognitive stimuli, indicating that the findings of ERpow during the two tasks would potentially aid in the clarification of the pathophysiology of the dysfunctional change in attention in patients with psychiatric disorders.
Analysis of Human Gait Using Hybrid EEG-fNIRS-Based BCI System: A Review
Authors: Khan Haroon , Naseer Noman , Yazidi Anis , Eide Per Kristian , Hassan Hafiz Wajahat , Mirtaheri Peyman
Published: January 2021

Human gait is a complex activity that requires high coordination between the central nervous system, the limb, and the musculoskeletal system. More research is needed to understand the latter coordination's complexity in designing better and more effective rehabilitation strategies for gait disorders. Electroencephalogram (EEG) and functional near-infrared spectroscopy (fNIRS) are among the most used technologies for monitoring brain activities due to portability, non-invasiveness, and relatively low cost compared to others. Fusing EEG and fNIRS is a well-known and established methodology proven to enhance brain–computer interface (BCI) performance in terms of classification accuracy, number of control commands, and response time. Although there has been significant research exploring hybrid BCI (hBCI) involving both EEG and fNIRS for different types of tasks and human activities, human gait remains still underinvestigated. In this article, we aim to shed light on the recent development in the analysis of human gait using a hybrid EEG-fNIRS-based BCI system. The current review has followed guidelines of preferred reporting items for systematic reviews and meta-Analyses (PRISMA) during the data collection and selection phase. In this review, we put a particular focus on the commonly used signal processing and machine learning algorithms, as well as survey the potential applications of gait analysis. We distill some of the critical findings of this survey as follows. First, hardware specifications and experimental paradigms should be carefully considered because of their direct impact on the quality of gait assessment. Second, since both modalities, EEG and fNIRS, are sensitive to motion artifacts, instrumental, and physiological noises, there is a quest for more robust and sophisticated signal processing algorithms. Third, hybrid temporal and spatial features, obtained by virtue of fusing EEG and fNIRS and associated with cortical activation, can help better identify the correlation between brain activation and gait. In conclusion, hBCI (EEG + fNIRS) system is not yet much explored for the lower limb due to its complexity compared to the higher limb. Existing BCI systems for gait monitoring tend to only focus on one modality. We foresee a vast potential in adopting hBCI in gait analysis. Imminent technical breakthroughs are expected using hybrid EEG-fNIRS-based BCI for gait to control assistive devices and Monitor neuro-plasticity in neuro-rehabilitation. However, although those hybrid systems perform well in a controlled experimental environment when it comes to adopting them as a certified medical device in real-life clinical applications, there is still a long way to go.
Cellular Senescence Triggers Altered Circadian Clocks With a Prolonged Period and Delayed Phases
Authors: Ahmed Rezwana , Nakahata Yasukazu , Shinohara Kazuyuki , Bessho Yasumasa
Published: January 2021

Senescent cells, which show the permanent growth arrest in response to various forms of stress, accumulate in the body with the progression of age, and are associated with aging and age-associated diseases. Although the senescent cells are growth arrested, they still demonstrate high metabolic rate and altered gene expressions, indicating that senescent cells are still active. We recently showed that the circadian clock properties, namely phase and period of the cells, are altered with the establishment of replicative senescence. However, whether cellular senescence triggers the alteration of circadian clock properties in the cells is still unknown. In this study we show that the oxidative stress-induced premature senescence induces the alterations of the circadian clock, similar to the phenotypes of the replicative senescent cells. We found that the oxidative stress-induced premature senescent cells display the prolonged period and delayed phases. In addition, the magnitude of these changes intensified over time, indicating that cellular senescence changes the circadian clock properties. Our current results corroborate with our previous findings and further confirm that cellular senescence induces altered circadian clock properties, irrespective of the replicative senescence or the stress-induced premature senescence.
Perspectives on the Treatment of Advanced Thyroid Cancer: Approved Therapies, Resistance Mechanisms, and Future Directions
Authors: Porter Ashleigh , Wong Deborah J.
Published: January 2021

For differentiated thyroid cancer (DTC), systemic therapy with radioactive iodine (RAI) is utilized for radiosensitive disease, while for radioiodine refractory (RAIR) disease, current standard of care is treatment with multikinase tyrosine kinase inhibitors (TKI). For BRAF-mutant DTC or anaplastic thyroid cancer (ATC), treatment with inhibitors targeting BRAF and MEK are important advances. RET-inhibitors for RET-mutated medullary thyroid cancer (MTC) recently have been FDA-approved for metastatic disease. Nevertheless, treatment of thyroid cancer resistant to current systemic therapies remains an important area of need. Resistance mechanisms are being elucidated, and novel therapies including combinations of BRAF and MEK inhibitors with RAI or other targeted therapies or TKIs combined with checkpoint inhibition are current areas of exploration.
LINC00667 Sponges miR-4319 to Promote the Development of Nasopharyngeal Carcinoma by Increasing FOXQ1 Expression
Authors: Liao Bing , Yi Yun , Zeng Lei , Wang Zhi , Zhu Xinhua , Liu Jianguo , Xie Bingbin , Liu Yuehui
Published: January 2021

Accumulating evidence has indicated that lncRNAs regulate various biological and pathological processes in diverse malignant tumors. The roles of LINC00667 in cancer development have been explored in glioma, hepatocellular carcinoma and non-small cell lung cancer, but not in nasopharyngeal carcinoma (NPC). In the present study, we characterize the role and molecular mechanism of LINC00667 in NPC progression. It was found that LINC00667 was overexpressed in NPC cells compared to normal cells. Silencing LINC00667 suppressed the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in NPC cells. In addition, bioinformatics analysis revealed that LINC00667 acted as a ceRNA to absorb miR-4319. Further investigations illustrated that miR-4319 had low expression in NPC cells and functioned as a tumor suppressor in the progression of NPC. Mechanistic study identified forkhead box Q1 (FOXQ1) as a functional target of miR-4319. The effect of LINC00667 in NPC development was mediated by the miR-4319/FOXQ1 axis. Analysis on tumorxenograft mouse model demonstrated that knockdown of LINC00667 repressed NPC tumor growth in vivo and confirmed the in vitro results. Our present study suggested that LINC00667 promoted the malignant phenotypes of NPC cells by competitively binding to miR-4319 to up-regulate FOXQ1 expression. Our results reveled that LINC00667 could be a diagnostic and therapeutic target for NPC patients.
Association Between Furosemide Exposure and Clinical Outcomes in a Retrospective Cohort of Critically Ill Children
Authors: Dai Xiaomei , Chen Jiao , Li Wenjing , Bai Zhenjiang , Li Xiaozhong , Wang Jian , Li Yanhong
Published: January 2021

Furosemide is commonly prescribed in critically ill patients to increase the urine output and prevent fluid overload (FO) and acute kidney injury (AKI), but not supported by conclusive evidence. There remain conflicting findings on whether furosemide associates with AKI and adverse outcomes. Information on the impact of furosemide on adverse outcomes in a general population of pediatric intensive care unit (PICU) is limited. The aim of the cohort study was to investigate the associations of furosemide with AKI and clinical outcomes in critically ill children.

Study Design: We retrospectively reviewed a cohort of 456 critically ill children consecutively admitted to PICU from January to December 2016. The exposure of interest was the use of furosemide in the first week after admission. FO was defined as ≥5% of daily fluid accumulation, and mean FO was considered significant when mean daily fluid accumulation during the first week was ≥5%. The primary outcomes were AKI in the first week after admission and mortality during PICU stay. AKI diagnosis was based on Kidney Disease: Improving Global Outcomes criteria with both serum creatinine and urine output.

Results: Furosemide exposure occurred in 43.4% of all patients (n = 456) and 49.3% of those who developed FO (n = 150) in the first week after admission. Patients who were exposed to furosemide had significantly less degree of mean daily fluid accumulation than those who were not (1.10 [−0.33 to 2.61%] vs. 2.00 [0.54–3.70%], P < 0.001). There was no difference in the occurrence of AKI between patients who did and did not receive furosemide (22 of 198 [11.1%] vs. 36 of 258 [14.0%], P = 0.397). The mortality rate was 15.4% (70 of 456), and death occurred more frequently among patients who received furosemide than among those who did not (21.7 vs. 10.5%, P = 0.002). Furosemide exposure was associated with increased odds for mortality in a multivariate logistic regression model adjusted for body weight, gender, illness severity assessed by PRISM III score, the presence of mean FO, and AKI stage [adjusted odds ratio (AOR) 1.95; 95%CI, 1.08–3.52; P = 0.026].

Conclusion: Exposure to furosemide might be associated with increased risk for mortality, but not AKI, in critically ill children.
Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic Aldehyde Reduces Atherosclerosis and Attenuates Low-Shear Stress-Induced Vascular Endothelial Cell Dysfunction
Authors: Zhang Lei , Li Yuan , Ma Xin , Liu Jiali , Wang Xiaojie , Zhang Lingxiao , Li Chao , Li Yunlun , Yang Wenqing
Published: January 2021

Background: The Fufang Danshen formula is a clinically important anti-atherosclerotic preparation in traditional Chinese medicine. However, its anti-atherosclerotic effect is not well recognized, and the mechanisms of its combined active ingredients, namely Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde (RRP), remain unclear. The purpose of this study was to investigate the anti-atherosclerotic effects and potential mechanism of RRP in ApoE−/− mice and in low-shear stress-injured vascular endothelial cells.

Methods: ApoE−/− mice were randomly divided into three groups: model group, rosuvastatin group, and RRP group, with C57BL/6J mice as the control group. Oil-red O, hematoxylin and eosin, Masson, and Movat staining were utilized for the observation of aortic plaque. Changes in the blood lipid indexes were observed with an automatic biochemistry analyzer. ET-1, eNOS, TXA2, and PGI2 levels were analyzed by enzyme-linked immunosorbent assay. In vitro, a fluid shear stress system was used to induce cell injury. Piezo1 expression in HUVECs was silenced using siRNA. Changes in morphology, proliferation, migration, and tube formation activity of cells were observed after RRP treatment. Quantitative Real-Time PCR and western blot analysis were employed to monitor mRNA and protein expression.

Results: RRP treatment reduced the atherosclerotic area and lipid levels and improved endothelial function in ApoE−/− mice. RRP significantly repaired cell morphology, reduced excessive cell proliferation, and ameliorated migration and tube formation activity. In addition, RRP affected the FAK-PI3K/Akt signaling pathway. Importantly, Piezo1 silencing abolished the protective effects of RRP.

Conclusion: RRP has anti-atherosclerotic effects and antagonizes endothelial cell damage via modulating the FAK-PI3K/Akt signaling pathway. Piezo1 is a possible target of RRP in the treatment of atherosclerosis. Thus, RRP has promising therapeutic potential and broad application prospect for atherosclerosis.
FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response
Authors: Chen Jun , Wang Xue , Hu Jian , Du Jingting , Dordoe Confidence , Zhou Qiulin , Huang Wenting , Guo Ruili , Han Fanyi , Guo Kaiming , Ye Shasha , Lin Li , Li Xiaokun
Published: January 2021

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In anin vitroTNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model andin vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.
A Phase I Clinical Study Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men
Authors: Zhang Hong , Wang Hong , Wei Haijing , Chen Hong , Liu Jingrui , Li Cuiyun , Zhu Xiaoxue , Li Xiaojiao , Yu Jinchen , Zhou Yinbo , Yang Xiaolei , Wang Zhaohe , Wu Min , Ding Yanhua
Published: January 2021

Objective: The study aimed to explore the bioequivalence of a proposed biosimilar BAT1806 to its reference products marketed in the EU and US (RoActemra-EU and Actemra-US) among healthy Chinese men. The tolerance, immunogenicity, and pharmacokinetics (PK) of the three drugs were also investigated.

Methods: In this randomized, double-blind, single-dose, three-arm, parallel study, a single-dose of 4 mg/kg of the reference products, or the biosimilar was administered to the participants. The participants were followed up for 57 days, and PK, immunogenicity, and tolerance evaluations were completed during this period.

Results: The PK parameters were similar in all three groups: BAT1806 (n = 45), RoActemra-EU (n = 42), and Actemra-US (n = 42). The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0–t and AUC0–∞ were 86.90–104.41% for BAT1806 vs. RoActemra-EU, 91.70–106.15% for BAT1806 vs Actemra-US, and 90.04–105.53% for Actemra-US vs RoActemra-EU. For all comparisons, the 90% CIs for the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit of 80.00–125.00%. The intersubject variability ranged from 14.5% to 21.5%, which was considerably low. Among the participants, 19 (42.2%), 10 (23.8%), and 12 (28.6%) from the BAT1806, RoActemra-EU, and Actemra-US groups were, respectively, found to be positive for anti-drug antibodies, while 14 (31.1%), nine (21.4%), and 12 (28.6%) were positive for neutralizing antibodies. Nevertheless, these antibodies did not affect the drug concentrations, and the outcomes in the bioequivalence tests were similar after sensitivity analysis. Treatment-related and treatment-emergent adverse events (TEAEs) were recorded in 27, 34, and 32 participants in the BAT1806, RoActemra-EU, and Actemra-US groups, respectively. The most common treatment-related adverse events observed were a decrease in neutrophil, and white blood cell counts.

Conclusion: The PK characteristics of BAT1806 were similar to those of the reference products, RoActemra-EU and Actemra-US. Both BAT1806 and the reference products exhibited low intersubject variability and similar safety profiles.

Clinical trial registration number:http://www.chinadrugtrials.org.cn/index.html, CTR20180039; https://clinicaltrials.gov/NCT03606876
Rational Design of A Novel Small-Molecule HIV-1 Inactivator Targeting Both gp120 and gp41 of HIV-1
Authors: Pu Jing , Dai Yu , Wang Qian , Lu Lu , Zhang Junqi , Xu Wei , Xie Lan , Wang Shengqi , Yu Fei , He Xiaoyang , Jiang Shibo
Published: January 2021

Virus inactivator can inactivate cell-free virions without relying on their replication cycle, potentially reducing the impact of viral infection on cells. Previously, we successfully constructed a HIV-1 protein inactivator, 2DLT, by conjugating the D1D2 region of CD4 to the fusion inhibitor T1144 via a 35-amino acid linker. Therefore, it targets both the CD4 binding site in gp120 and NHR region in gp41. Considering that small-molecule agents have the advantages of fast production, low cost, good stability, and oral availability, we herein report the design of a new small-molecule HIV-1 inactivator, FD028, by conjugating FD016 (an analog of NBD-556, a gp120-CD4 binding inhibitor) with FD017 (an analog of 11d, an HIV-1 fusion inhibitor). The results showed that FD028 inactivated cell-free virions at a moderate nanomolar concentration by targeting both HIV-1 gp120 and gp41. Moreover, FD028 has broad-spectrum inhibition and inactivation activity against HIV-1 resistant strains and primary isolates of different subtypes without significant cytotoxicity. Therefore, FD028 has potential for further development as an HIV-1 inactivator-based therapeutic.
Identification and Functional Characterization of Two Putative Pheromone Receptors in the Potato Tuber Moth, Phthorimaea operculella
Authors: He Xiaoli , Cai Yajie , Zhu Jinglei , Zhang Mengdi , Zhang Yadong , Ge Yang , Zhu Zengrong , Zhou Wenwu , Wang Guirong , Gao Yulin
Published: January 2021

Pheromones are a kind of signal produced by an animal that evoke innate responses in conspecifics. In moth, pheromone components can be detected by specialized olfactory receptor neurons (OSNs) housed in long sensilla trichoids on the male antennae. The pheromone receptors (PRs) located in the dendrite membrane of OSNs are responsible for pheromone sensing in most Lepidopteran insects. The potato tuber moth Phthorimaea operculella is a destructive pest of Solanaceae crops. Although sex attractant is widely used in fields to monitor the population of P. operculella, no study has been reported on the mechanism the male moth of P. operculella uses to recognize sex pheromone components. In the present study, we cloned two pheromone receptor genes PopeOR1 and PopeOR3 in P. operculella. The transcripts of them were highly accumulated in the antennae of male adults. Functional analysis using the heterologous expression system of Xenopus oocyte demonstrated that these two PR proteins both responded to (E, Z)-4,7–13: OAc and (E, Z, Z)-4,7,10–13: OAc, the key sex pheromone components of P. operculella, whilst they responded differentially to these two ligands. Our findings for the first time characterized the function of pheromone receptors in gelechiid moth and could promote the olfactory based pest management of P. operculella in the field.
nifH Gene Sequencing Reveals the Effects of Successive Monoculture on the Soil Diazotrophic Microbial Community in Casuarina equisetifolia Plantations
Authors: Zhou Liuting , Li Jianjuan , Pokhrel Ganga Raj , Chen Jun , Zhao Yanlin , Bai Ying , Zhang Chen , Lin Wenxiong , Wu Zeyan , Wu Chengzhen
Published: January 2021

The growth and productivity of Casuarina equisetifolia is negatively impacted by planting sickness under long-term monoculture regimes. In this study, Illumina MiSeq sequencing targeting nifH genes was used to assess variations in the rhizospheric soil diazotrophic community under long-term monoculture rotations. Principal component analysis and unweighted pair-group method with arithmetic means (UPGMA) clustering demonstrated distinct differences in diazotrophic community structure between uncultivated soil (CK), the first rotation plantation (FCP), the second rotation plantation (SCP), and the third rotation plantation (TCP). Taxonomic analysis showed that the phyla Proteobacteria increased while Verrucomicrobia decreased under the consecutive monoculture (SCP and TCP). The relative abundance of Paraburkholderia, Rhodopseudomonas, Bradyrhizobium, Geobacter, Pseudodesulfovibrio, and Frankia increased significantly while Burkholderia, Rubrivivax, and Chlorobaculum declined significantly at the genus level under consecutive monoculture (SCP and TCP). Redundancy analysis (RDA) showed that Burkholderia, Rubrivivax, and Chlorobaculum were positively correlated with total nitrogen and available nitrogen. In conclusion, continuous C. equisetifolia monoculture could change the structure of diazotrophic microbes in the rhizosphere, resulting in the imbalance of the diazotrophic bacteria population, which might be a crucial factor related to replanting disease in this cultivated tree species.
Identification of Weeds Based on Hyperspectral Imaging and Machine Learning
Authors: Li Yanjie , Al-Sarayreh Mahmoud , Irie Kenji , Hackell Deborah , Bourdot Graeme , Reis Marlon M. , Ghamkhar Kioumars
Published: January 2021

Weeds can be major environmental and economic burdens in New Zealand. Traditional methods of weed control including manual and chemical approaches can be time consuming and costly. Some chemical herbicides may have negative environmental and human health impacts. One of the proposed important steps for providing alternatives to these traditional approaches is the automated identification and mapping of weeds. We used hyperspectral imaging data and machine learning to explore the possibility of fast, accurate and automated discrimination of weeds in pastures where ryegrass and clovers are the sown species. Hyperspectral images from two grasses (Setaria pumila [yellow bristle grass] and Stipa arundinacea [wind grass]) and two broad leaf weed species (Ranunculus acris [giant buttercup] and Cirsium arvense [Californian thistle]) were acquired and pre-processed using the standard normal variate method. We trained three classification models, namely partial least squares-discriminant analysis, support vector machine, and Multilayer Perceptron (MLP) using whole plant averaged (Av) spectra and superpixels (Sp) averaged spectra from each weed sample. All three classification models showed repeatable identification of four weeds using both Av and Sp spectra with a range of overall accuracy of 70–100%. However, MLP based on the Sp method produced the most reliable and robust prediction result (89.1% accuracy). Four significant spectral regions were found as highly informative for characterizing the four weed species and could form the basis for a rapid and efficient methodology for identifying weeds in ryegrass/clover pastures.
Species-Specific Responses of Root Morphology of Three Co-existing Tree Species to Nutrient Patches Reflect Their Root Foraging Strategies
Authors: Yang Zhenya , Zhou Benzhi , Ge Xiaogai , Cao Yonghui , Brunner Ivano , Shi Jiuxi , Li Mai-He
Published: January 2021

Root foraging strategies of plants may be critical to the competition for nutrient resources in the nutrient patches, but little is known about these of co-existing tree species in subtropical regions. This study aimed to elucidate root foraging strategies of three co-existing tree species in nutrient heterogeneous soils by exploring their root distribution, root morphology, photosynthates allocation and nutrient accumulation. Seedlings of the three tree species [moso bamboo (Phyllostachys edulis), Chinese fir (Cunninghamia lanceolata), and masson pine (Pinus massoniana)] were grown for 8months under one homogeneous soil [uniform nitrogen (N) plus phosphorus (P)] and three heterogeneous soils (localized N supply, localized P supply, or localized N plus P supply). The biomass, root morphological parameters (i.e., root length and root surface area), specific root length (SRL), non-structural carbohydrates (NSCs, i.e., mobile sugar and starch) in roots, total N and total P of plants were measured. The plasticity and distribution of root system were analyzed by calculating the root response ratio (RRR) and root foraging precision (FP), respectively. The results are as follows (i) Chinese fir tended to forage more N by promoting root proliferation in the N-rich patch, while root proliferation of bamboo and pine did not change. For P, bamboo absorbed more P by promoting root proliferation in the P-rich patch. The total P content of Pine and Chinese fir under localized P supply treatment remain the same despite the fact that the root length in the P-rich patch and the FP increased. (ii) Chinese fir foraged more N by increasing root length and decreasing SRL in the NP-rich patch; bamboo foraged more N and P by increasing root length and SRL in the NP-rich patch. The FP and foraging scale (FS) of both bamboo and Chinese fir were significantly improved under localized N plus P treatment. (iii) The concentrations of NSC were positively correlated with root morphological plasticity for moso bamboo and Chinese fir. Our results indicated that higher morphological plasticity is exhibited in moso bamboo and Chinese fir than masson pine in nutrient heterogeneous soils, allowing them to successfully forage for more nutrients.
2-Year-Olds Learning From 2D Media With and Without Parental Support: Comparing Two Forms of Joint Media Engagement With Passive Viewing and Learning From 3D
Authors: Heimann Mikael , Hedendahl Louise , Ottmer Elida , Kolling Thorsten , Koch Felix-Sebastian , Birberg Thornberg Ulrika , Sundqvist Annette
Published: January 2021

The study investigates to what degree two different joint media engagement (JME) strategies affect children’s learning from two-dimensional (2D)-media. More specifically, we expected an instructed JME strategy to be more effective than a spontaneous, non-instructed, JME strategy. Thirty-five 2-year old children saw a short video on a tablet demonstrating memory tasks together with a parent. The parents were randomized into two groups: One group (N = 17) was instructed to help their child by describing the actions they saw on the video while the other group (N = 18) received no specific instruction besides “do as you usually do.” The parents in the instructed group used significantly more words and verbs when supporting their child but both groups of children did equally well on the memory test. In a second step, we compared the performance of the two JME groups with an opportunistic comparison group (N = 95) tested with half of the memory tasks live and half of the tasks on 2D without any JME support. Results showed that the JME intervention groups received significantly higher recall scores than the no JME 2D comparison group. In contrast, the three-dimensional (3D) comparison group outperformed both JME groups. In sum, our findings suggest that JME as implemented here is more effective in promoting learning than a no JME 2D demonstration but less so than the standard 3D presentation of the tasks.
Moving With Pain: What Principles From Somatic Practices Can Offer to People Living With Chronic Pain
Authors: Meehan Emma , Carter Bernie
Published: January 2021

This article brings together research from the fields of chronic pain management and somatic practices to develop a novel framework of principles to support people living with persistent pain. These include movement-based approaches to awareness of the internal body (interoception), the external environment (exteroception) and movement in space (proprioception). These significantly work with the lived subjective experiences of people living with pain, to become aware of body signals and self-management of symptoms, explore fear and pleasure of movement, and understand how social environments impact on pain. This analysis has potential to create new ways of supporting, understanding and articulating pain experiences, as well as shaping the future of somatic practices for chronic pain.