bluuebunny/crossref_metadata_2025 huggingface dataset:
Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming
Authors: Sadhu Srikanth , Rizvi Zaigham Abbas , Pandey Ramendra Pati , Dalal Rajdeep , Rathore Deepak Kumar , Kumar Bhoj , Pandey Manitosh , Kumar Yashwant , Goel Renu , Maiti Tushar K. , Johri Atul Kumar , Tiwari Ashutosh , Pandey Amit Kumar , Awasthi Amit
Published: March 2021

The global rise of antibiotic-resistant strains ofSalmonellahas necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug againstSalmonella. Further, using the proteome analysis ofSalmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival ofSalmonella viamTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival ofSalmonellawithin the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused bySalmonellainfection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values againstSalmonellainfection and might be useful for the treatment of other intracellular infections.
Lung Neutrophilic Recruitment and IL-8/IL-17A Tissue Expression in COVID-19
Authors: Azevedo Marina Luise Viola , Zanchettin Aline Cristina , Vaz de Paula Caroline Busatta , Motta Júnior Jarbas da Silva , Malaquias Mineia Alessandra Scaranello , Raboni Sonia Mara , Neto Plínio Cezar , Zeni Rafaela Chiuco , Prokopenko Amanda , Borges Nícolas Henrique , Godoy Thiago Mateus , Benevides Ana Paula Kubaski , de Souza Daiane Gavlik , Baena Cristina Pellegrino , Machado-Souza Cleber , de Noronha Lucia
Published: March 2021

The new SARS-CoV-2 virus differs from the pandemic Influenza A virus H1N1 subtype (H1N1pmd09) how it induces a pro-inflammatory response in infected patients. This study aims to evaluate the involvement of SNPs and tissue expression of IL-17A and the neutrophils recruitment in post-mortem lung samples from patients who died of severe forms of COVID-19 comparing to those who died by H1N1pdm09. Twenty lung samples from patients SARS-CoV-2 infected (COVID-19 group) and 10 lung samples from adults who died from a severe respiratory H1N1pdm09 infection (H1N1 group) were tested. The tissue expression of IL-8/IL-17A was identified by immunohistochemistry, and hematoxylin and eosin (H&E) stain slides were used for neutrophil scoring. DNA was extracted from paraffin blocks, and genotyping was done in real time-PCR for two IL17A target polymorphisms. Tissue expression increasing of IL-8/IL-17A and a higher number of neutrophils were identified in samples from the H1N1 group compared to the COVID-19 group. The distribution of genotype frequencies in the IL17A gene was not statistically significant between groups. However, the G allele (GG and GA) of rs3819025 was correlated with higher tissue expression of IL-17A in the COVID-19 group. SARS-CoV-2 virus evokes an exacerbated response of the host’s immune system but differs from that observed in the H1N1pdm09 infection since the IL-8/IL-17A tissue expression, and lung neutrophilic recruitment may be decreased. In SNP rs3819025 (G/A), the G allele may be considered a risk allele in the patients who died for COVID-19.
The Diverse Roles of Heme Oxygenase-1 in Tumor Progression
Authors: Luu Hoang Kim Ngan , Anstee Joanne E. , Arnold James N.
Published: March 2021

Heme oxygenase-1 (HO-1) is an inducible intracellular enzyme that is expressed in response to a variety of stimuli to degrade heme, which generates the biologically active catabolites carbon monoxide (CO), biliverdin and ferrous iron (Fe2+). HO-1 is expressed across a range of cancers and has been demonstrated to promote tumor progression through a variety of mechanisms. HO-1 can be expressed in a variety of cells within the tumor microenvironment (TME), including both the malignant tumor cells as well as stromal cell populations such as macrophages, dendritic cells and regulatory T-cells. Intrinsically to the cell, HO-1 activity provides antioxidant, anti-apoptotic and cytoprotective effects via its catabolites as well as clearing toxic intracellular heme. However, the catabolites of heme degradation can also diffuse outside of the cell to extrinsically modulate the wider TME, influencing cellular functionality and biological processes which promote tumor progression, such as facilitating angiogenesis and metastasis, as well as promoting anti-inflammation and immune suppression. Pharmacological inhibition of HO-1 has been demonstrated to be a promising therapeutic approach to promote anti-tumor immune responses and inhibit metastasis. However, these biological functions might be context, TME and cell type-dependent as there is also conflicting reports for HO-1 activity facilitating anti-tumoral processes. This review will consider our current understanding of the role of HO-1 in cancer progression and as a therapeutic target in cancer.
The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases
Authors: Yao Yao , Cai Xiaoyu , Ren Fujia , Ye Yiqing , Wang Fengmei , Zheng Caihong , Qian Ying , Zhang Meng
Published: March 2021

Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.
Domestication Shapes the Community Structure and Functional Metagenomic Content of the Yak Fecal Microbiota
Authors: Fu Haibo , Zhang Liangzhi , Fan Chao , Liu Chuanfa , Li Wenjing , Li Jiye , Zhao Xinquan , Jia Shangang , Zhang Yanming
Published: March 2021

Domestication is a key factor of genetic variation; however, the mechanism by which domestication alters gut microbiota is poorly understood. Here, to explore the variation in the structure, function, rapidly evolved genes (REGs), and enzyme profiles of cellulase and hemicellulose in fecal microbiota, we studied the fecal microbiota in wild, half-blood, and domestic yaks based on 16S rDNA sequencing, shotgun-metagenomic sequencing, and the measurement of short-chain-fatty-acids (SCFAs) concentration. Results indicated that wild and half-blood yaks harbored an increased abundance of the phylum Firmicutes and reduced abundance of the genus Akkermansia, which are both associated with efficient energy harvesting. The gut microbial diversity decreased in domestic yaks. The results of the shotgun-metagenomic sequencing showed that the wild yak harbored an increased abundance of microbial pathways that play crucial roles in digestion and growth of the host, whereas the domestic yak harbored an increased abundance of methane-metabolism-related pathways. Wild yaks had enriched amounts of REGs in energy and carbohydrate metabolism pathways, and possessed a significantly increased abundance of cellulases and endohemicellulases in the glycoside hydrolase family compared to domestic yaks. The concentrations of acetic, propionic, n-butyric, i-butyric, n-valeric, and i-valeric acid were highest in wild yaks. Our study displayed the domestic effect on the phenotype of composition, function in gut microbiota, and SCFAs associated with gut microbiota, which had a closely association with the growth performance of the livestock. These findings may enlighten the researchers to construct more links between economic characteristics and gut microbiota, and develop new commercial strains in livestock based on the biotechnology of gut microbiota.
Bioaugmentation of Native Fungi, an Efficient Strategy for the Bioremediation of an Aged Industrially Polluted Soil With Heavy Hydrocarbons
Authors: Medaura María Cecilia , Guivernau Miriam , Moreno-Ventas X. , Prenafeta-Boldú Francesc X. , Viñas Marc
Published: March 2021

The concurrence of structurally complex petroleum-associated contaminants at relatively high concentrations, with diverse climatic conditions and textural soil characteristics, hinders conventional bioremediation processes. Recalcitrant compounds such as high molecular weight polycyclic aromatic hydrocarbons (HMW-PAHs) and heavy alkanes commonly remain after standard soil bioremediation at concentrations above regulatory limits. The present study assessed the potential of native fungal bioaugmentation as a strategy to promote the bioremediation of an aged industrially polluted soil enriched with heavy hydrocarbon fractions. Microcosms assays were performed by means of biostimulation and bioaugmentation, by inoculating a defined consortium of six potentially hydrocarbonoclastic fungi belonging to the genera Penicillium, Ulocladium, Aspergillus, and Fusarium, which were isolated previously from the polluted soil. The biodegradation performance of fungal bioaugmentation was compared with soil biostimulation (water and nutrient addition) and with untreated soil as a control. Fungal bioaugmentation resulted in a higher biodegradation of total petroleum hydrocarbons (TPH) and of HMW-PAHs than with biostimulation. TPH (C14-C35) decreased by a 39.90 ± 1.99% in bioaugmented microcosms vs. a 24.17 ± 1.31% in biostimulated microcosms. As for the effect of fungal bioaugmentation on HMW-PAHs, the 5-ringed benzo(a)fluoranthene and benzo(a)pyrene were reduced by a 36% and 46%, respectively, while the 6-ringed benzoperylene decreased by a 28%, after 120 days of treatment. Biostimulated microcosm exhibited a significantly lower reduction of 5- and 6-ringed PAHs (8% and 5% respectively). Higher TPH and HMW-PAHs biodegradation levels in bioaugmented microcosms were also associated to a significant decrease in acute ecotoxicity (EC50) by Vibrio fischeri bioluminiscence inhibition assays. Molecular profiling and counting of viable hydrocarbon-degrading bacteria from soil microcosms revealed that fungal bioaugmentation promoted the growth of autochthonous active hydrocarbon-degrading bacteria. The implementation of such an approach to enhance hydrocarbon biodegradation should be considered as a novel bioremediation strategy for the treatment of the most recalcitrant and highly genotoxic hydrocarbons in aged industrially polluted soils.
Gene Silencing Through CRISPR Interference in Bacteria: Current Advances and Future Prospects
Authors: Zhang Riyu , Xu Wensheng , Shao Shuai , Wang Qiyao
Published: March 2021

Functional genetic screening is an important method that has been widely used to explore the biological processes and functional annotation of genetic elements. CRISPR/Cas (Clustered regularly interspaced short palindromic repeat sequences/CRISPR-associated protein) is the newest tool in the geneticist’s toolbox, allowing researchers to edit a genome with unprecedented ease, accuracy, and high-throughput. Most recently, CRISPR interference (CRISPRi) has been developed as an emerging technology that exploits the catalytically inactive Cas9 (dCas9) and single-guide RNA (sgRNA) to repress sequence-specific genes. In this review, we summarized the characteristics of the CRISPRi system, such as programmable, highly efficient, and specific. Moreover, we demonstrated its applications in functional genetic screening and highlighted its potential to dissect the underlying mechanism of pathogenesis. The recent development of the CRISPRi system will provide a high-throughput, practical, and efficient tool for the discovery of functionally important genes in bacteria.
Codelivery of Anticancer Drug and Photosensitizer by PEGylated Graphene Oxide and Cell Penetrating Peptide Enhanced Tumor-Suppressing Effect on Osteosarcoma
Authors: Zhang Yi-Fei , Wu Yun-Feng , Lan Tai-Jin , Chen Yao , Su Shi-Hong
Published: March 2021

Objective: Graphene oxide (GO) has been widely used for various biological and biomedical applications due to its unique physiochemical properties. This study aimed to investigate the effects of cell penetrating peptide (CPP) modified and polyethylene-glycol- (PEG-) grafted GO (pGO) loaded with photosensitive agent 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-alpha (HPPH) and Epirubicin (EPI) (HPPH/EPI/CPP-pGO) on tumor growth in osteosarcoma.

Methods: The HPPH/EPI/CPP-pGO were prepared, and then in vitro drug release assay was conducted. The detection of singlet oxygen (1O2) and cellular uptake of HPPH was performed as well. Next, the effects of control (saline solution), CPP-pGO, EPI, HPPH, HPPH/CPP-pGO, EPI/CPP-pGO, HPPH/EPI/pGO, and HPPH/EPI/CPP-pGO were evaluated by MTT assay, colony-forming assay, and cell apoptosis assay in MG-63 cells. Furthermore, the antitumor effects of HPPH/EPI/CPP-pGO on osteosarcoma xenograft mice were unraveled.

Results: The 1O2 generation and cellular uptake of HPPH were significantly increased after CPP and pGO modification compared with free HPPH. In addition, compared with control cells, CPP-pGO treatment had low cytotoxicity in MG-63 cells. Compared with free HPPH or EPI, HPPH/CPP-pGO or EPI/CPP-pGO treatment significantly inhibited cell viability and colony forming number, as well as inducing cell apoptosis. HPPH/EPI-pGO treatment showed stronger inhibition effects on MG-63 cells than HPPH/CPP-pGO or EPI/CPP-pGO, and HPPH/EPI/CPP-pGO was the most effective one. Similarly, in vivo experiments revealed that, compared with control group, the tumor size and weight of osteosarcoma xenograft mice were obviously decreased after free HPPH or EPI treatment, which were further reduced in other groups, especially in HPPH/EPI/CPP-pGO group.

Conclusion: HPPH/EPI/CPP-pGO had superior tumor-inhibiting effects in vitro and in vivo on osteosarcoma.
Modeling Working Memory in a Spiking Neuron Network Accompanied by Astrocytes
Authors: Gordleeva Susanna Yu. , Tsybina Yuliya A. , Krivonosov Mikhail I. , Ivanchenko Mikhail V. , Zaikin Alexey A. , Kazantsev Victor B. , Gorban Alexander N.
Published: March 2021

We propose a novel biologically plausible computational model of working memory (WM) implemented by a spiking neuron network (SNN) interacting with a network of astrocytes. The SNN is modeled by synaptically coupled Izhikevich neurons with a non-specific architecture connection topology. Astrocytes generating calcium signals are connected by local gap junction diffusive couplings and interact with neurons via chemicals diffused in the extracellular space. Calcium elevations occur in response to the increased concentration of the neurotransmitter released by spiking neurons when a group of them fire coherently. In turn, gliotransmitters are released by activated astrocytes modulating the strength of the synaptic connections in the corresponding neuronal group. Input information is encoded as two-dimensional patterns of short applied current pulses stimulating neurons. The output is taken from frequencies of transient discharges of corresponding neurons. We show how a set of information patterns with quite significant overlapping areas can be uploaded into the neuron-astrocyte network and stored for several seconds. Information retrieval is organized by the application of a cue pattern representing one from the memory set distorted by noise. We found that successful retrieval with the level of the correlation between the recalled pattern and ideal pattern exceeding 90% is possible for the multi-item WM task. Having analyzed the dynamical mechanism of WM formation, we discovered that astrocytes operating at a time scale of a dozen of seconds can successfully store traces of neuronal activations corresponding to information patterns. In the retrieval stage, the astrocytic network selectively modulates synaptic connections in the SNN leading to successful recall. Information and dynamical characteristics of the proposed WM model agrees with classical concepts and other WM models.
Recovery of Apraxia of Speech and Aphasia in Patients With Hand Motor Impairment After Stroke
Authors: Hybbinette Helena , Schalling Ellika , Plantin Jeanette , Nygren-Deboussard Catharina , Schütz Marika , Östberg Per , Lindberg Påvel G.
Published: March 2021

Objective:Aphasia and apraxia of speech (AOS) after stroke frequently co-occur with a hand motor impairment but few studies have investigated stroke recovery across motor and speech-language domains. In this study, we set out to test the shared recovery hypothesis. We aimed to (1) describe the prevalence of AOS and aphasia in subacute stroke patients with a hand motor impairment and (2) to compare recovery across speech-language and hand motor domains. In addition, we also explored factors predicting recovery from AOS.

Methods:Seventy participants with mild to severe paresis in the upper extremity were assessed; 50% of these (n= 35) had left hemisphere (LH) lesions. Aphasia, AOS and hand motor assessments and magnetic resonance imaging were conducted at 4 weeks (A1) and at 6 months (A2) after stroke onset. Recovery was characterized in 15 participants showing initial aphasia that also had complete follow-up data at 6 months.

Results:All participants with AOS and/or aphasia had LH lesions. In LH lesioned, the prevalence of aphasia was 71% and of AOS 57%. All participants with AOS had aphasia; 80% of the participants with aphasia also had AOS. Recovery in aphasia (n= 15) and AOS (n= 12) followed a parallel pattern to that observed in hand motor impairment and recovery correlated positively across speech-language and motor domains. The majority of participants with severe initial aphasia and AOS showed a limited but similar amount of recovery across domains. Lesion volume did not correlate with results from behavioral assessments, nor with recovery. The initial aphasia score was the strongest predictor of AOS recovery.

Conclusion:Our findings confirm the common occurrence of AOS and aphasia in left hemisphere stroke patients with a hand motor impairment. Recovery was similar across speech-language and motor domains, even in patients with severe impairment, supporting the shared recovery hypothesis and that similar brain recovery mechanisms are involved in speech-language and motor recovery post stroke. These observations contribute to the knowledge of AOS and its relation to motor and language functions and add information that may serve as a basis for future studies of post stroke recovery. Studies including neuroimaging and/or biological assays are required to gain further knowledge on shared brain recovery mechanisms.
The Differential Effects of Auditory and Visual Stimuli on Learning, Retention and Reactivation of a Perceptual-Motor Temporal Sequence in Children With Developmental Coordination Disorder
Authors: Blais Mélody , Jucla Mélanie , Maziero Stéphanie , Albaret Jean-Michel , Chaix Yves , Tallet Jessica
Published: March 2021

This study investigates the procedural learning, retention, and reactivation of temporal sensorimotor sequences in children with and without developmental coordination disorder (DCD). Twenty typically-developing (TD) children and 12 children with DCD took part in this study. The children were required to tap on a keyboard, synchronizing with auditory or visual stimuli presented as an isochronous temporal sequence, and practice non-isochronous temporal sequences to memorize them. Immediate and delayed retention of the audio-motor and visuo-motor non-isochronous sequences were tested by removing auditory or visual stimuli immediately after practice and after a delay of 2 h. A reactivation test involved reintroducing the auditory and visual stimuli after the delayed recall. Data were computed via circular analyses to obtain asynchrony, the stability of synchronization and errors (i.e., the number of supplementary taps). Firstly, an overall deficit in synchronization with both auditory and visual isochronous stimuli was observed in DCD children compared to TD children. During practice, further improvements (decrease in asynchrony and increase in stability) were found for the audio-motor non-isochronous sequence compared to the visuo-motor non-isochronous sequence in both TD children and children with DCD. However, a drastic increase in errors occurred in children with DCD during immediate retention as soon as the auditory stimuli were removed. Reintroducing auditory stimuli decreased errors in the audio-motor sequence for children with DCD. Such changes were not seen for the visuo-motor non-isochronous sequence, which was equally learned, retained and reactivated in DCD and TD children. All these results suggest that TD children benefit from both auditory and visual stimuli to memorize the sequence, whereas children with DCD seem to present a deficit in integrating an audio-motor sequence in their memory. The immediate effect of reactivation suggests a specific dependency on auditory information in DCD. Contrary to the audio-motor sequence, the visuo-motor sequence was both learned and retained in children with DCD. This suggests that visual stimuli could be the best information for memorizing a temporal sequence in DCD. All these results are discussed in terms of a specific audio-motor coupling deficit in DCD.
Output-Specific Adaptation of Habenula-Midbrain Excitatory Synapses During Cocaine Withdrawal
Authors: Clerke Joseph , Preston-Ferrer Patricia , Zouridis Ioannis S. , Tissot Audrey , Batti Laura , Voigt Fabian F. , Pagès Stephane , Burgalossi Andrea , Mameli Manuel
Published: March 2021

Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations’ activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.
RETRACTED: Downregulation of hsa_circ_0001836 Induces Pyroptosis Cell Death in Glioma Cells via Epigenetically Upregulating NLRP1
Authors: Liu Yong , Wu Hao , Jing Jiangpeng , Li Huanfa , Dong Shan , Meng Qiang
Published: March 2021

Background

It has been shown that circular RNAs (circRNAs) play a vital role in the progression of glioma. Recently, hsa_circ_0001836 was found to be upregulated in glioma tissues, but the role of hsa_circ_0001836 in glioma remains unclear.

Methods

EdU staining and flow cytometry assays were used to measure the viability and death of glioma cells. In addition, scanning electron microscopy (SEM) was used to observe the morphology of cells undergoing cell death.

Results

Hsa_circ_0001836 expression was upregulated in U251MG and SHG-44 cells. In addition, hsa_circ_0001836 knockdown significantly reduced the viability and proliferation of U251MG and SHG-44 cells. Moreover, hsa_circ_0001836 knockdown markedly induced the pyroptosis of U251MG and SHG-44 cells, evidenced by the increased expressions of NLRP1, cleaved caspase 1 and GSDMD-N. Meanwhile, methylation specific PCR (MSP) results indicated that hsa_circ_0001836 knockdown epigenetically increased NLRP1 expression via mediating DNA demethylation of NLRP1 promoter region. Furthermore, downregulation of hsa_circ_0001836 notably induced pyroptosis and inhibited tumor growth in a mouse xenograft model of glioma.

Conclusion

Collectively, hsa_circ_0001836 knockdown could induce pyroptosis cell death in glioma cells in vitro and in vivo via epigenetically upregulating NLRP1 expression. These findings suggested that hsa_circ_0001836 may serve as a potential therapeutic target for the treatment of glioma.
LINC01977 Promotes Breast Cancer Progression and Chemoresistance to Doxorubicin by Targeting miR-212-3p/GOLM1 Axis
Authors: Li Zheng , Li Yaming , Wang Xiaolong , Liang Yiran , Luo Dan , Han Dianwen , Li Chen , Chen Tong , Zhang Hanwen , Liu Ying , Wang Zekun , Chen Bing , Wang Lijuan , Zhao Wenjing , Yang Qifeng
Published: March 2021

Long non-coding RNAs(lncRNAs) play an important role in cancer initiation and progression. However, hub lncRNAs involved in breast cancer still remain underexplored. In this study, integrated bioinformatics analysis was used to define LINC01977 as a key oncogenic driver in breast cancer. Subsequently, in vitro assays showed that LINC01977 could significantly promote breast cancer progression and chemoresistance to doxorubicin. To further investigate its biological mechanism, we performed dual-luciferase reporter assay, real-time PCR, RNA immunoprecipitation (RIP), and rescue assay. Our results indicated that LINC01977 may function as ceRNA to prevent GOLM1 gene from miRNA-mediated repression by sponging miR-212-3p. Overall, LINC01977 can serve as a novel prognostic indicator, and help develop more effective therapeutic approaches for breast cancer patients.
Computational Drug Repositioning and Experimental Validation of Ivermectin in Treatment of Gastric Cancer
Authors: Rabben Hanne-Line , Andersen Gøran Troseth , Ianevski Aleksandr , Olsen Magnus Kringstad , Kainov Denis , Grønbech Jon Erik , Wang Timothy Cragin , Chen Duan , Zhao Chun-Mei
Published: March 2021

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches.

Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice).

Results: GC gene expression “signature” and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in “dose-depended” manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways.

Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.
Fractal Pull-in Stability Theory for Microelectromechanical Systems
Authors: Tian Dan , He Chun-Hui , He Ji-Huan
Published: March 2021

Pull-in instability was an important phenomenon in microelectromechanical systems (MEMS). In the past, MEMS were usually assumed to work in an ideal environment. But in the real circumstances, MEMS often work in dust-filled air, which is equivalent to working in porous media, that's mean fractal space. In this paper, we studied MEMS in fractal space and established the corresponding model. At the same time, we can control the occurrence time and stable time of pull-in by adjusting the value of the fractal index, and obtain a stable pull-in phenomenon.
Subtle Role for Adenylate Kinase 1 in Maintaining Normal Basal Contractile Function and Metabolism in the Murine Heart
Authors: Zervou Sevasti , McAndrew Debra J. , Whittington Hannah J. , Lake Hannah A. , Park Kyung Chan , Cha Kuan Minn , Ostrowski Philip J. , Eykyn Thomas R. , Schneider Jürgen E. , Neubauer Stefan , Lygate Craig A.
Published: March 2021

Aims

Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury.

Methods and Results

Cardiac-specific AK1 overexpressing mice (AK1-OE) had 31% higher AK1 activity (P = 0.009), with unchanged total creatine kinase and citrate synthase activities. Male AK1-OE exhibited mild in vivo dysfunction at baseline with lower LV pressure, impaired relaxation, and contractile reserve. LV weight was 19% higher in AK1-OE males due to higher tissue water content in the absence of hypertrophy or fibrosis. AK1-OE hearts had significantly raised creatine, unaltered total adenine nucleotides, and 20% higher AMP levels (P = 0.05), but AMP-activated protein kinase was not activated (P = 0.85). 1H-NMR revealed significant differences in LV metabolite levels compared to wild-type, with aspartate, tyrosine, sphingomyelin, cholesterol all elevated, whereas taurine and triglycerides were significantly lower. Ex vivo global no-flow I/R, caused four-of-seven AK1-OE hearts to develop terminal arrhythmia (cf. zero WT), yet surviving AK1-OE hearts had improved functional recovery. However, AK1-OE did not influence infarct size in vivo and arrhythmias were only observed ex vivo, probably as an artefact of adenine nucleotide loss during cannulation.

Conclusion

Modest elevation of AK1 may improve functional recovery following I/R, but has unexpected impact on LV weight, function and metabolite levels under basal resting conditions, suggesting a more nuanced role for AK1 underpinning myocardial energy homeostasis and not just as a response to stress.
SARS-CoV-2 Antigens Expressed in Plants Detect Antibody Responses in COVID-19 Patients
Authors: Makatsa Mohau S. , Tincho Marius B. , Wendoh Jerome M. , Ismail Sherazaan D. , Nesamari Rofhiwa , Pera Francisco , de Beer Scott , David Anura , Jugwanth Sarika , Gededzha Maemu P. , Mampeule Nakampe , Sanne Ian , Stevens Wendy , Scott Lesley , Blackburn Jonathan , Mayne Elizabeth S. , Keeton Roanne S. , Burgers Wendy A.
Published: March 2021

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has swept the world and poses a significant global threat to lives and livelihoods, with 115 million confirmed cases and at least 2.5 million deaths from Coronavirus disease 2019 (COVID-19) in the first year of the pandemic. Developing tools to measure seroprevalence and understand protective immunity to SARS-CoV-2 is a priority. We aimed to develop a serological assay using plant-derived recombinant viral proteins, which represent important tools in less-resourced settings.

Methods: We established an indirect ELISA using the S1 and receptor-binding domain (RBD) portions of the spike protein from SARS-CoV-2, expressed in Nicotiana benthamiana. We measured antibody responses in sera from South African patients (n = 77) who had tested positive by PCR for SARS-CoV-2. Samples were taken a median of 6 weeks after the diagnosis, and the majority of participants had mild and moderate COVID-19 disease. In addition, we tested the reactivity of pre-pandemic plasma (n = 58) and compared the performance of our in-house ELISA with a commercial assay. We also determined whether our assay could detect SARS-CoV-2-specific IgG and IgA in saliva.

Results: We demonstrate that SARS-CoV-2-specific immunoglobulins are readily detectable using recombinant plant-derived viral proteins, in patients who tested positive for SARS-CoV-2 by PCR. Reactivity to S1 and RBD was detected in 51 (66%) and 48 (62%) of participants, respectively. Notably, we detected 100% of samples identified as having S1-specific antibodies by a validated, high sensitivity commercial ELISA, and optical density (OD) values were strongly and significantly correlated between the two assays. For the pre-pandemic plasma, 1/58 (1.7%) of samples were positive, indicating a high specificity for SARS-CoV-2 in our ELISA. SARS-CoV-2-specific IgG correlated significantly with IgA and IgM responses. Endpoint titers of S1- and RBD-specific immunoglobulins ranged from 1:50 to 1:3,200. S1-specific IgG and IgA were found in saliva samples from convalescent volunteers.

Conclusion: We demonstrate that recombinant SARS-CoV-2 proteins produced in plants enable robust detection of SARS-CoV-2 humoral responses. This assay can be used for seroepidemiological studies and to measure the strength and durability of antibody responses to SARS-CoV-2 in infected patients in our setting.
Application of Bag-Controlled Release Fertilizer Facilitated New Root Formation, Delayed Leaf, and Root Senescence in Peach Trees and Improved Nitrogen Utilization Efficiency
Authors: Zhang Yafei , Luo Jingjing , Peng Futian , Xiao Yuansong , Du Anqi
Published: March 2021

It is very important to promote root growth and delay root and leaf senescence, to improve nitrogen absorption and utilization efficiency, and to improve the storage nutrition level of the tree, so as to improve the fruit quality and yield of peach. In this experiment, we compared and analyzed the effects of traditional fertilization and bag-controlled release fertilizer (BCRF) on the growth of shoots and roots, senescence of leaves and roots, and fruit yield and quality. Moreover, the impacts of BCRF on ammonia volatilization, nitrogen utilization rate, fine root turnover, and plant storage nutrients were also investigated. Compared with conventional fertilizer use, the application of BCRF significantly promoted the shoot growth of young peach trees. Additionally, BCRF delayed leaf senescence and increased root activity in autumn. This increased the storage nutrients of the peach tree. Compared with traditional fertilizer, ammonia volatilization reduced to 54.36% under BCRF application situation. BCRF also promoted the occurrence of fine roots and decreased the annual turnover rate. A 15N tracer test showed that, compared with traditional fertilizer, BCRF nitrogen utilization efficiency increased by 37.73% in peach trees under BCRF treatment significantly. The results from 3 consecutive years showed that the application of BCRF increased the yield of individual plants by 21.35% on average compared to the yield from plants receiving equal amounts of fertilizer applied by spreading (FSA). Thus, BCRF can promote the occurrence of fine roots and decrease the root annual turnover rate in peach trees, and it also improves the utilization efficiency of fertilizer, reduces ammonia volatilization, delays leaf senescence, and enhances storage nutrition, fruit yield, and fruit quality in peach trees.
Cross-Species Metabolic Profiling of Floral Specialized Metabolism Facilitates Understanding of Evolutional Aspects of Metabolism Among Brassicaceae Species
Authors: Liu Yuting , Watanabe Mutsumi , Yasukawa Sayuri , Kawamura Yuriko , Aneklaphakij Chaiwat , Fernie Alisdair R. , Tohge Takayuki
Published: March 2021

Plants produce a variety of floral specialized (secondary) metabolites with roles in several physiological functions, including light-protection, attraction of pollinators, and protection against herbivores. Pigments and volatiles synthesized in the petal have been focused on and characterized as major chemical factors influencing pollination. Recent advances in plant metabolomics have revealed that the major floral specialized metabolites found in land plant species are hydroxycinnamates, phenolamides, and flavonoids albeit these are present in various quantities and encompass diverse chemical structures in different species. Here, we analyzed numerous floral specialized metabolites in 20 different Brassicaceae genotypes encompassing both different species and in the case of crop species different cultivars including self-compatible (SC) and self-incompatible (SI) species by liquid chromatography-mass spectrometry (LC-MS). Of the 228 metabolites detected in flowers among 20 Brassicaceae species, 15 metabolite peaks including one phenylacyl-flavonoids and five phenolamides were detected and annotated as key metabolites to distinguish SC and SI plant species, respectively. Our results provide a family-wide metabolic framework and delineate signatures for compatible and incompatible genotypes thereby providing insight into evolutionary aspects of floral metabolism in Brassicaceae species.
Molecular Cytogenetic and Agronomic Characterization of the Similarities and Differences Between Wheat–Leymus mollis Trin. and Wheat–Psathyrostachys huashanica Keng 3Ns (3D) Substitution Lines
Authors: Li Jiachuang , Li Jiaojiao , Cheng Xueni , Zhao Li , Yang Zujun , Wu Jun , Yang Qunhui , Chen Xinhong , Zhao Jixin
Published: March 2021

Psathyrostachys huashanica Keng (2n = 2x = 14, NsNs) and Leymus mollis Trin. (2n = 4x = 28, NsNsXmXm) are valuable resources for wheat breeding improvement as they share the Ns genome, which contains diverse resistance genes. To explore the behaviors and traits of Ns chromosomes from the two species in wheat background, a series of wheat–P. huashanica and wheat–L. mollis substitution lines were developed. In the present study, line DH109 (F7 progeny of wheat–P. huashanica heptaploid line H8911 × durum wheat Trs-372) and line DM131 (F8 progeny of wheat–L. mollis octoploid line M842 × durum wheat Trs-372) were selected. Cytological observation combined with genomic in situ hybridization experiments showed that DH109 and DM131 each had 20 pairs of wheat chromosomes plus a pair of alien chromosomes (Ns chromosome), and the pair of alien chromosomes showed stable inheritance. Multiple molecular markers and wheat 55K SNP array demonstrated that a pair of wheat 3D chromosome in DH109 and in DM131 was substituted by a pair of P. huashanica 3Ns chromosome and a pair of L. mollis 3Ns chromosome, respectively. Fluorescence in situ hybridization (FISH) analysis confirmed that wheat 3D chromosomes were absent from DH109 and DM131, and chromosomal FISH karyotypes of wheat 3D, P. huashanica 3Ns, and L. mollis 3Ns were different. Moreover, the two lines had many differences in agronomic traits. Comparing with their wheat parents, DH109 expressed superior resistance to powdery mildew and fusarium head blight, whereas DM131 had powdery mildew resistance, longer spike, and more tiller number. Therefore, Ns genome from P. huashanica and L. mollis might have some different effects. The two novel wheat–alien substitution lines provide new ideas and resources for disease resistance and high-yield breeding on further utilization of 3Ns chromosomes of P. huashanica or L. mollis.
Potential Impact of Global Warming on Virus Propagation in Infected Plants and Agricultural Productivity
Authors: Amari Khalid , Huang Caiping , Heinlein Manfred
Published: March 2021

The increasing pace of global warming and climate instability will challenge the management of pests and diseases of cultivated plants. Several reports have shown that increases in environmental temperature can enhance the cell-to-cell and systemic propagation of viruses within their infected hosts. These observations suggest that earlier and longer periods of warmer weather may cause important changes in the interaction between viruses and their host’s plants, thus posing risks of new viral diseases and outbreaks in agriculture and the wild. As viruses target plasmodesmata (PD) for cell-to-cell spread, these cell wall pores may play yet unknown roles in the temperature-sensitive regulation of intercellular communication and virus infection. Understanding the temperature-sensitive mechanisms in plant-virus interactions will provide important knowledge for protecting crops against diseases in a warmer climate.
Functional Analysis of OsMED16 and OsMED25 in Response to Biotic and Abiotic Stresses in Rice
Authors: Zhang Huijuan , Zheng Dewei , Yin Longfei , Song Fengming , Jiang Ming
Published: March 2021

Mediator complex is a multiprotein complex that regulates RNA polymerase II-mediated transcription. Moreover, it functions in several signaling pathways, including those involved in response to biotic and abiotic stresses. We used virus-induced gene silencing (VIGS) to study the functions of two genes, namely OsMED16 and OsMED25 in response to biotic and abiotic stresses in rice. Both genes were differentially induced by Magnaporthe grisea (M. grisea), the causative agent of blast disease, hormone treatment, and abiotic stress. We found that both BMV: OsMED16- and BMV: OsMED25-infiltrated seedlings reduced the resistance to M. grisea by regulating the accumulation of H2O2 and expression of defense-related genes. Furthermore, BMV: OsMED16-infiltrated seedlings decreased the tolerance to cold by increasing the malondialdehyde (MDA) content and reducing the expression of cold-responsive genes.
Regulation of Lateral Root Development by Shoot-Sensed Far-Red Light via HY5 Is Nitrate-Dependent and Involves the NRT2.1 Nitrate Transporter
Authors: van Gelderen Kasper , Kang Chiakai , Li Peijin , Pierik Ronald
Published: March 2021

Plants are very effective in responding to environmental changes during competition for light and nutrients. Low Red:Far-Red (low R:FR)-mediated neighbor detection allows plants to compete successfully with other plants for available light. This above-ground signal can also reduce lateral root growth by inhibiting lateral root emergence, a process that might help the plant invest resources in shoot growth. Nitrate is an essential nutrient for plant growth andArabidopsis thalianaresponds to low nitrate conditions by enhancing nutrient uptake and reducing lateral and main root growth. There are indications that low R:FR signaling and low nitrate signaling can affect each other. It is unknown which response is prioritized when low R:FR light- and low nitrate signaling co-occur. We investigated the effect of low nitrate conditions on the low R:FR response of theA. thalianaroot system in agar plate media, combined with the application of supplemental Far-Red (FR) light to the shoot. We observed that under low nitrate conditions main and lateral root growth was reduced, but more importantly, that the response of the root system to low R:FR was not present. Consistently, a loss-of-function mutant of a nitrate transporter geneNRT2.1lacked low R:FR-induced lateral root reduction and its root growth was hypersensitive to low nitrate. ELONGATED HYPOCOTYL5 (HY5) plays an important role in the root response to low R:FR and we found that it was less sensitive to low nitrate conditions with regards to lateral root growth. In addition, we found that low R:FR increasesNRT2.1expression and that low nitrate enhancesHY5expression. HY5 also affectsNRT2.1expression, however, it depended on the presence of ammonium in which direction this effect was. Replacing part of the nitrogen source with ammonium also removed the effect of low R:FR on the root system, showing that changes in nitrogen sources can be crucial for root plasticity. Together our results show that nitrate signaling can repress low R:FR responses and that this involves signaling via HY5 and NRT2.1.
Effects of Dispositional Affect on the N400: Language Processing and Socially Situated Context
Authors: Dwivedi Veena D. , Selvanayagam Janahan
Published: March 2021

We examined whether the N400 Event-Related Potential (ERP) component would be modulated by dispositional affect during sentence processing. In this study, 33 participants read sentences manipulated by direct object type (congruent vs. incongruent) and object determiner type (definite vs. demonstrative). We were particularly interested in sentences of the form: (i) The connoisseur tasted thewineon the tour vs. (ii) The connoisseur tasted the #roof… We expected that processing incongruent direct objects (#roof) vs. congruent objects (wine) would elicit N400 effects. Previous ERP language experiments have shown that participants in (induced) positive and negative moods were differentially sensitive to semantic anomaly, resulting in different N400 effects. Presently, we ask whether individual dispositional affect scores (as measured by the Positive and Negative Affect Schedule; PANAS) would modulate N400 effects as shown previously. Namely, previous results showed larger N400 effects associated with happy moods and attenuated amplitudes associated with sad moods. Results revealed significant N400 effects, driven by the #roof vs. the wine, where larger amplitude differences were found for individuals showing smaller negative affect (NA) scores, thus partially replicating previous findings. We discuss our results in terms of theories of local (lexical) inhibition, such that low NA promotes stronger lexico-semantic links in sentences. Finally, our results support accounts of language processing that include social and biological characteristics of individuals during real-time sentence comprehension.
Different Influences of Negative and Neutral Emotional Interference on Working Memory in Trait Anxiety
Authors: Yang Huifang , Li Junqing , Zheng Xifu
Published: March 2021

To examine the interaction of working memory (WM) type with emotional interference in trait anxiety, event-related potentials were measured in a combined WM and emotional task. Participants completed a delayed matching-to-sample task of WM, and emotional pictures were presented during the maintenance interval. The results indicated that negative affect interfered with spatial WM; task-related changes in amplitude were observed in the late positive potential (LPP) and slow waves in both the high and low anxiety groups. We also found an interaction among WM type, emotion, and trait anxiety such that participants with high levels of trait anxiety showed an opposite neural response to verbal and spatial WM tasks compared with individuals with low trait anxiety during the sustained brain activity involved in processing negative or neutral pictures in the delay phase. Our results increase our understanding of the influence of emotions on recognition and the vulnerability of those with trait anxiety to emotional stimuli.