bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant HSP90 Expression in Lymphocytes and HSP90 Response to Anti-PD-1 Therapy in Lymphoma Patients
Authors: Albakova Zarema , Mangasarova Yana , Albakov Akhmet , Nikulina Elena , Kravchenko Sergey , Sapozhnikov Alexander
Published: April 2022

HSP90 family of molecular chaperones has been shown to be implicated in various stages of tumor growth and development. Recent studies have highlighted the role of extracellular HSP90 in tumor immunology, however, the role that HSP90 plays in the regulation of immune responses and the impact of cancer immunotherapy, including immune checkpoint blockade, on HSP90 is still unclear. Here we assessed the surface and intracellular expression of constitutive cytosolic HSP90β isoform, mitochondrial HSP90 homolog TRAP1 and co-chaperone STIP1/HOP in T, NK, B and NKT cells derived from peripheral blood and bone marrow samples of patients with Hodgkin and B-cell Non-Hodgkin lymphomas. HSP90β and STIP1 were overexpressed in B lymphocytes, while TRAP1 expression was decreased in T, B, NK and NKT cells of lymphoma patients. HSP90 overexpression in B cells was not associated with malignant B cell clones, since no clonotypic B cells were detected by immunoglobulin heavy chain (IgH) gene rearrangements. PD-1 blockade was found to differently affect the intracellular and surface HSP90 in T, B, NK and NKT cells in patients with relapsed or refractory classical Hodgkin lymphoma. Modulating HSP90 was found to affect the NK cell degranulation response and IFNγ production in lymphoma patients. These findings provide the rationale to further explore HSP90 homologs for improving patient response to cancer immunotherapy.
Reproductive Dynamics of the Large Yellow Croaker Larimichthys crocea (Sciaenidae), A Commercially Important Fishery Species in China
Authors: Yan Li-ting , Jiang Yan , Xu Qing , Ding Guang-mao , Chen Xin-yi , Liu Min
Published: April 2022

The large yellow croaker Larimichthys crocea (Richardson, 1846) (Sciaenidae) is distributed in southern Yellow Sea, East China Sea, and northern South China Sea of China and is a commercially important nearshore fishery species. L. crocea was listed on the IUCN Red List as “Critically Endangered” in 2020 mainly due to the over-exploration of its spawning and over-wintering aggregations in the 1950s–1980s throughout its distribution region. However, detailed studies on reproductive dynamics of L. crocea were limited in the past three decades. In this study, the reproductive dynamics of L. crocea was examined in the traditional Guanjingyang (GJY) spawning ground, one of the 15 well-known ones in its distribution region. Samples were collected using set nets from April 2019 to November 2021 to ensure at least 20 samples for all 12 months. A total of 1,006 individuals were caught, ranging from 46 to 391 mm standard length (SL) and 1.45 to 1,110.05 g body weight (BW). A growth dimorphism was found between sexes with females heavier than males when body sizes exceeded 61 mm SL (non-parametric ANCOVA, p < 0.01). Gonad histology of all 1,006 individuals revealed, for the first time, that L. crocea was able to spawn almost year-round for both females and males. Two spawning peaks, spring and autumn, were identified in March and May and in November for females and in April to June and in October to November for males. The minimum sizes at sexual maturity were 160 mm SL for females and 112 mm SL for male. The sizes at 50% sexual maturity were 187.2 mm SL for females and 150.2 mm SL for males. Results showed that the minimum SL for female maturity decreased about 20% in the past six decades. The spawning peaks were 2 months earlier in spring and 1 month extension in autumn in GJY. Clearly, the national fishing moratorium regulation in May to August, an important fishery management measure in China, can only protect the spring spawning peak partly. Further evaluation on the influence of climate change on reproductive strategies and stock recruitment of L. crocea is highly recommended.
Gold Nanoclusters Potentially Facilitate Dentin Regeneration by Functioning Immunomodulation
Authors: Yang Lan , Xiao Lan , Liu Tianqing , Gao Wendong , Xiao Yin
Published: April 2022

It is presently difficult to achieve dental pulp vitality maintenance and regeneration in adult teeth. Dentin destruction results in the exposure of the dental pulp tissue to infectious oral environments, thereby triggering continuous severe pulp inflammation that impedes the self-regenerative capacity of the pulp. For these reasons, the regeneration of dentin bridges to block pulp tissue from the oral environment is an indispensable step. Nevertheless, this goal is difficult to achieve using present strategies, because the importance of immunoregulation in the pulp inflammatory microenvironment has been ignored. In our previous study, we found that the nanomaterial dihydrolipoic acid-functionalized gold nanoclusters (DHLA-AuNCs) efficiently regulated inflammatory responses in microglia (resident macrophages in the central nervous system), suggesting that DHLA-AuNCs may induce dentin bridge regeneration by regulating dental pulp macrophage responses. In the present study, we found that DHLA-AuNCs inhibited the M1 phenotype while promoting the M2 phenotype in macrophages in inflammatory conditions in vitro. This regulation of the inflammatory environment in dental pulp enhanced the differentiation of human dental pulp stromal cells (hDPC) toward odontoblasts, a beneficial effect on dentin regeneration. DHLA-AuNCs also had a direct role in the differentiation and mineralization of hDPC. These findings suggest that DHLA-AuNCs facilitate dentin regeneration through both efficient immunomodulation and direct induction of stromal cell differentiation/mineralization, providing a potential therapeutic nanomaterial for dentin bridge regeneration, effects that would be beneficial for dental pulp regeneration.
Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock
Authors: Hof Stefan , Truse Richard , Weber Lea , Herminghaus Anna , Schulz Jan , Weber Andreas P. M. , Maleckova Eva , Bauer Inge , Picker Olaf , Vollmer Christian
Published: April 2022

Introduction

Acute hemorrhage results in perfusion deficit and regional hypoxia. Since failure of intestinal integrity seem to be the linking element between hemorrhage, delayed multi organ failure, and mortality, it is crucial to maintain intestinal microcirculation in acute hemorrhage. During critical bleeding physicians increase FiO2to raise total blood oxygen content. Likewise, a systemic hypercapnia was reported to maintain microvascular oxygenation (μHbO2). Both, O2and CO2, may have adverse effects when applied systemically that might be prevented by local application. Therefore, we investigated the effects of local hyperoxia and hypercapnia on the gastric and oral microcirculation.

Methods

Six female foxhounds were anaesthetized, randomized into eight groups and tested in a cross-over design. The dogs received a local CO2-, O2-, or N2-administration to their oral and gastric mucosa. Hemorrhagic shock was induced through a withdrawal of 20% of estimated blood volume followed by retransfusion 60 min later. In control groups no shock was induced. Reflectance spectrophotometry and laser Doppler were performed at the gastric and oral surface. Oral microcirculation was visualized by incident dark field imaging. Systemic hemodynamic parameters were recorded continuously. Statistics were performed using a two-way-ANOVA for repeated measurements andpost hocanalysis was conducted by Bonferroni testing (p< 0.05).

Results

The gastric μHbO2decreased from 76 ± 3% to 38 ± 4% during hemorrhage in normocapnic animals. Local hypercapnia ameliorated the decrease of μHbO2from 78 ± 4% to 51 ± 8%. Similarly, the oral μHbO2decreased from 81 ± 1% to 36 ± 4% under hemorrhagic conditions and was diminished by local hypercapnia (54 ± 4%). The oral microvascular flow quality but not the total microvascular blood flow was significantly improved by local hypercapnia. Local O2-application failed to change microvascular oxygenation, perfusion or flow quality. Neither CO2nor O2changed microcirculatory parameters and macrocirculatory hemodynamics under physiological conditions.

Discussion

Local hypercapnia improved microvascular oxygenation and was associated with a continuous blood flow in hypercapnic individuals undergoing hemorrhagic shock. Local O2application did not change microvascular oxygenation, perfusion and blood flow profiles in hemorrhage. Local gas application and change of microcirculation has no side effects on macrocirculatory parameters.
Microbial Community-Level Physiological Profiles and Genetic Prokaryotic Structure of Burned Soils Under Mediterranean Sclerophyll Forests in Central Chile
Authors: Aponte Humberto , Galindo-Castañeda Tania , Yáñez Carolina , Hartmann Martin , Rojas Claudia
Published: April 2022

Forest fires alter soil microbial communities that are essential to support ecosystem recovery following land burning. These alterations have different responses according to soil abiotic pre- and post-fire conditions and fire severity, among others, and tend to decrease along vegetation recovery over time. Thus, understanding the effects of fires on microbial soil communities is critical to evaluate ecosystem resilience and restoration strategies in fire-prone ecosystems. We studied the state of community-level physiological profiles (CLPPs) and the prokaryotic community structure of rhizosphere and bulk soils from two fire-affected sclerophyll forests (one surveyed 17 months and the other 33 months after fire occurrence) in the Mediterranean climate zone of central Chile. Increases in catabolic activity (by average well color development of CLPPs), especially in the rhizosphere as compared with the bulk soil, were observed in the most recently affected site only. Legacy of land burning was still clearly shaping soil prokaryote community structure, as shown by quantitative PCR (qPCR) and Illumina MiSeq sequencing of the V4 region of the 16S rRNA gene, particularly in the most recent fire-affected site. The qPCR copy numbers and alpha diversity indexes (Shannon and Pielou’s evenness) of sequencing data decreased in burned soils at both locations. Beta diversity analyses showed dissimilarity of prokaryote communities at both study sites according to fire occurrence, and NO3– was the common variable explaining community changes for both of them. Acidobacteria and Rokubacteria phyla significantly decreased in burned soils at both locations, while Firmicutes and Actinobacteria increased. These findings provide a better understanding of the resilience of soil prokaryote communities and their physiological conditions in Mediterranean forests of central Chile following different time periods after fire, conditions that likely influence the ecological processes taking place during recovery of fire-affected ecosystems.
Characterization and Genomic Analysis of a Novel Jumbo Bacteriophage vB_StaM_SA1 Infecting Staphylococcus aureus With Two Lysins
Authors: Zhang Bingyan , Sun Huzhi , Zhao Feiyang , Wang Qian , Pan Qiang , Tong Yigang , Ren Huiying
Published: April 2022

The development of new antimicrobial agents is critically needed due to the alarming increase in antibiotic resistance in bacterial pathogens. Phages have been widely considered as effective alternatives to antibiotics. A novel phage vB_StaM_SA1 (hereinafter as SA1) that can infect multiple Staphylococcus strains was isolated from untreated sewage of a pig farm, which belonged to Myoviridae family. At MOI of 0.1, the latent period of phage SA1 was 55 min, and the final titer reached about 109 PFU/mL. The genome of phage SA1 was 260,727 bp, indicating that it can be classified as a jumbo phage. The genome of SA1 had 258 ORFs and a serine tRNA, while only 53 ORFs were annotated with functions. Phage SA1 contained a group of core genes that was characterized by multiple RNA polymerase subunits and also found in phiKZ-related jumbo phages. The phylogenetic tree showed that phage SA1 was a phiKZ-related phage and was closer to jumbo phages compared with Staphylococcus phages with small genome. Three proteins (lys4, lys210, and lys211) were predicted to be associated with lysins, and two proteins with lytic function were verified by recombinant expression and bacterial survival test. Both lys210 and lys211 possessed efficient bactericidal ability, and lys210 could lyse all test strains. The results show that phage SA1 and lys210/lys211 could be potentially used as antibiotic agents to treat Staphylococcus infection.
Streptomyces marincola sp. nov., a Novel Marine Actinomycete, and Its Biosynthetic Potential of Bioactive Natural Products
Authors: Shi Songbiao , Cui Linqing , Zhang Kun , Zeng Qi , Li Qinglian , Ma Liang , Long Lijuan , Tian Xinpeng
Published: April 2022

Marine actinomycetes are an important source of antibiotics, but many of them are yet to be explored in terms of taxonomy, ecology, and functional activity. In this study, two marine actinobacterial strains, designated SCSIO 64649T and SCSIO 03032, were isolated, and the potential for bioactive natural product discovery was evaluated based on genome mining, compound detection, and antimicrobial activity. Phylogenetic analysis of the 16S rRNA gene sequences showed that strain SCSIO 64649T formed a single clade with SCSIO 03032 (similarity 99.5%) and sister clades with the species Streptomyces specialis DSM 41924T (97.1%) and Streptomyces manganisoli MK44T (96.8%). The whole genome size of strain SCSIO 64649T was 6.63 Mbp with a 73.6% G + C content. The average nucleotide identity and digital DNA–DNA hybridization between strain SCSIO 64649T and its closest related species were well below the thresholds recommended for species delineation. Therefore, according to the results of polyphasic taxonomy analysis, the strains SCSIO 64649T and SCSIO 03032 are proposed to represent a novel species named Streptomyces marincola sp. nov. Furthermore, strains SCSIO 64649T and 03032 encode 37 putative biosynthetic gene clusters, and in silico analysis revealed that this new species has a high potential to produce unique natural products, such as a novel polyene polyketide compounds, two mayamycin analogs, and a series of post-translationally modified peptides. In addition, other important bioactive natural products, such as heronamide F, piericidin A1, and spiroindimicin A, were also detected in strain SCSIO 64649T. Finally, this new species’ metabolic crude extract showed a strong antimicrobial activity. Thanks to the integration of all these analyses, this study demonstrates that the novel species Streptomyces marincola has a unique and novel secondary metabolite biosynthetic potential that not only is beneficial to possible marine hosts but that could also be exploited for industrial applications.
Oral Administration of 5-Hydroxytryptophan Restores Gut Microbiota Dysbiosis in a Mouse Model of Depression
Authors: Wu Lijuan , Ran Lisha , Wu Yazeng , Liang Manyu , Zeng Jing , Ke Famin , Wang Fang , Yang Jian , Lao Xiaoqing , Liu Li , Wang Qin , Gao Xiaowei
Published: April 2022

5-Hydroxytryptophan (5-HTP) has positive clinical effects on various neuropsychiatric and metabiotic disorders, especially depression. Although it increases serotonin levels in the brain and gastrointestinal tract, its pharmacology remains largely unknown. Our goal was to determine the effects of 5-HTP on the mouse gut microbiome, which has a close relationship with depression through the “microbiota-gut-brain axis.” We confirmed that depressive disorder restructures the gut microbial community, and 5-HTP efficiently improves depressive symptoms in mice. Oral administration of 5-HTP significantly restored gut microbiota dysbiosis in mice with depression-like behaviors. The diversity and richness of gut microbial communities and relative abundance of specific microbial taxa at both phylum and genus levels were partially recovered. 5-HTP exhibited some positive effects on restoring the alterations in the concentrations of short-chain fatty acids and brain-derived neurotrophic factors caused by depression in mice. Our results may provide new insights into the pharmacology of 5-HTP in treating depression and other disorders.
The Metabolites of Lactobacillus fermentum F-B9-1 Relieved Dextran Sulfate Sodium-Induced Experimental Ulcerative Colitis in Mice
Authors: Su Le , Ma Feifan , An Zaiyong , Ji Xiuyu , Zhang Ping , Yue Qiulin , Zhao Chen , Sun Xin , Li Kunlun , Li Baojun , Liu Xinli , Zhao Lin
Published: April 2022

Because of the increased incidence and prevalence, ulcerative colitis (UC) has become a global health issue in the world. Current therapies for UC are not totally effective which result in persistent and recurrent symptom of many patients. Lactobacillus with anti-inflammatory effects might be beneficial to the prevention or treatment for UC. Here, we examined the ameliorative effects of the metabolites of Lactobacillus fermentum F-B9-1 (MLF) in Caco-2 cells and dextran sodium sulfate (DSS)-induced UC model mice. MLF displayed intestinal barrier-protective activities in Caco-2 cells by increasing the expression of Occludin and ZO-1. They also showed anti-inflammatory potential in interleukin (IL)-1β and IL-6. In order to further examine the in vivo anti-inflammatory effect of MLF, the MLF was gavaged in the DSS-induced UC model mice. The intragastric administration of MLF effectively alleviated colitis symptoms of weight loss, diarrhea, colon shortening, and histopathological scores, protected intestinal barrier function by increasing Occludin and ZO-1, and attenuated colonic and systemic inflammation by suppressing production of IL-1β and IL-6. Finally, the use of MLF remodeled the diversity of the gut microbiota and increased the number of beneficial microorganisms. Overall, the results demonstrated that MLF relieved DSS-induced UC in mice. And MLF might be an effective therapy method to UC in the clinic in the future.
Rhizosphere Bacteria From Panax notoginseng Against Meloidogyne hapla by Rapid Colonization and Mediated Resistance
Authors: Wu Wentao , Wang Jingjing , Wang Zhuhua , Guo Liwei , Zhu Shusheng , Zhu Youyong , Wang Yang , He Xiahong
Published: April 2022

Root-knot nematodes (RKNs) are soil-borne pathogens that severely affectPanax notoginsenggrowth and productivity. Thus, there is an urgent need for biological control agents or green nematicides to control root-knot nematodes. Rhizosphere bacteria can effectively control RKNs through different mechanisms. In this study, the three rhizosphereBacillusstrains, isolated from the root ofP. notoginseng, were evaluated for the nematicidal activity and biological control efficacy against root-knot nematodes. In addition, we also evaluated the colonization ability of the two bacterial strains with significant biocontrol effect and dynamic regulation of genes related to systemic resistance inP. notoginseng. The rhizosphereBacillus velezensisGJ-7 andBacillus cereusNS-2 showed high nematicidal activity againstMeloidogyne hapla in vitroand significantly reduced the number of root galls in three different control experiments. The results of colonization experiments showed that the strains GJ-7 and NS-2 colonizedP. notoginsengroot rapidly and stably. Additionally, the colonization of the strains NS-2 and GJ-7 activated the defense-responsive genes inP. notoginseng. These results indicated that theB. cereusstrain NS-2 andB. velezensisstrain GJ-7 have the potential for successful ecological niche occupation and enhance plant resistance and therefore could be considered as potential biocontrol agents against root-knot nematodes.
CodY Is a Global Transcriptional Regulator Required for Virulence in Group B Streptococcus
Authors: Pellegrini Angelica , Lentini Germana , Famà Agata , Bonacorsi Andrea , Scoffone Viola Camilla , Buroni Silvia , Trespidi Gabriele , Postiglione Umberto , Sassera Davide , Manai Federico , Pietrocola Giampiero , Firon Arnaud , Biondo Carmelo , Teti Giuseppe , Beninati Concetta , Barbieri Giulia
Published: April 2022

Group B Streptococcus (GBS) is a Gram-positive bacterium able to switch from a harmless commensal of healthy adults to a pathogen responsible for invasive infections in neonates. The signals and regulatory mechanisms governing this transition are still largely unknown. CodY is a highly conserved global transcriptional regulator that links nutrient availability to the regulation of major metabolic and virulence pathways in low-G+C Gram-positive bacteria. In this work, we investigated the role of CodY in BM110, a GBS strain representative of a hypervirulent lineage associated with the majority of neonatal meningitis. Deletion of codY resulted in a reduced ability of the mutant strain to cause infections in neonatal and adult animal models. The observed decreased in vivo lethality was associated with an impaired ability of the mutant to persist in the blood, spread to distant organs, and cross the blood-brain barrier. Notably, the codY null mutant showed reduced adhesion to monolayers of human epithelial cells in vitro and an increased ability to form biofilms, a phenotype associated with strains able to asymptomatically colonize the host. RNA-seq analysis showed that CodY controls about 13% of the genome of GBS, acting mainly as a repressor of genes involved in amino acid transport and metabolism and encoding surface anchored proteins, including the virulence factor Srr2. CodY activity was shown to be dependent on the availability of branched-chain amino acids, which are the universal cofactors of this regulator. These results highlight a key role for CodY in the control of GBS virulence.
Transcriptomic Changes of Bemisia tabaci Asia II 1 Induced by Chilli Leaf Curl Virus Trigger Infection and Circulation in Its Vector
Authors: Nekkanti Aarthi , Chakraborty Prosenjit , Ghosh Amalendu , Iquebal Mir Asif , Jaiswal Sarika , Baranwal Virendra Kumar
Published: April 2022

Bemisia tabaci (Hemiptera: Aleyrodidae) is a highly efficient vector in the spread of chilli leaf curl virus (ChiLCV, Begomovirus) which is a major constraint in the production of chilli in South Asia. Transcriptome analysis of B. tabaci post-6 h acquisition of ChiLCV showed differential expression of 80 (29 upregulated and 51 downregulated) genes. The maximum number of DEGs are categorized under the biological processes category followed by cellular components and molecular functions. KEGG analysis of DEGs showed that the genes are involved in the functions like metabolism, signaling pathways, cellular processes, and organismal systems. The expression of highly expressed 20 genes post-ChiLCV acquisition was validated in RT-qPCR. DEGs such as cytosolic carboxypeptidase 3, dual-specificity protein phosphatase 10, 15, dynein axonemal heavy chain 17, fasciclin 2, inhibin beta chain, replication factor A protein 1, and Tob1 were found enriched and favored the virus infection and circulation in B. tabaci. The present study provides an improved understanding of the networks of molecular interactions between B. tabaci and ChiLCV. The candidate genes of B. tabaci involved in ChiLCV transmission would be novel targets for the management of the B. tabaci-begomovirus complex.
Fusing Multimodal and Anatomical Volumes of Interest Features Using Convolutional Auto-Encoder and Convolutional Neural Networks for Alzheimer’s Disease Diagnosis
Authors: Abdelaziz Mohammed , Wang Tianfu , Elazab Ahmed
Published: April 2022

Alzheimer’s disease (AD) is an age-related disease that affects a large proportion of the elderly. Currently, the neuroimaging techniques [e.g., magnetic resonance imaging (MRI) and positron emission tomography (PET)] are promising modalities for AD diagnosis. Since not all brain regions are affected by AD, a common technique is to study some region-of-interests (ROIs) that are believed to be closely related to AD. Conventional methods used ROIs, identified by the handcrafted features through Automated Anatomical Labeling (AAL) atlas rather than utilizing the original images which may induce missing informative features. In addition, they learned their framework based on the discriminative patches instead of full images for AD diagnosis in multistage learning scheme. In this paper, we integrate the original image features from MRI and PET with their ROIs features in one learning process. Furthermore, we use the ROIs features for forcing the network to focus on the regions that is highly related to AD and hence, the performance of the AD diagnosis can be improved. Specifically, we first obtain the ROIs features from the AAL, then we register every ROI with its corresponding region of the original image to get a synthetic image for each modality of every subject. Then, we employ the convolutional auto-encoder network for learning the synthetic image features and the convolutional neural network (CNN) for learning the original image features. Meanwhile, we concatenate the features from both networks after each convolution layer. Finally, the highly learned features from the MRI and PET are concatenated for brain disease classification. Experiments are carried out on the ADNI datasets including ADNI-1 and ADNI-2 to evaluate our method performance. Our method demonstrates a higher performance in brain disease classification than the recent studies.
A Survey of Multifingered Robotic Manipulation: Biological Results, Structural Evolvements, and Learning Methods
Authors: Li Yinlin , Wang Peng , Li Rui , Tao Mo , Liu Zhiyong , Qiao Hong
Published: April 2022

Multifingered robotic hands (usually referred to as dexterous hands) are designed to achieve human-level or human-like manipulations for robots or as prostheses for the disabled. The research dates back 30 years ago, yet, there remain great challenges to effectively design and control them due to their high dimensionality of configuration, frequently switched interaction modes, and various task generalization requirements. This article aims to give a brief overview of multifingered robotic manipulation from three aspects: a) the biological results, b) the structural evolvements, and c) the learning methods, and discuss potential future directions. First, we investigate the structure and principle of hand-centered visual sensing, tactile sensing, and motor control and related behavioral results. Then, we review several typical multifingered dexterous hands from task scenarios, actuation mechanisms, and in-hand sensors points. Third, we report the recent progress of various learning-based multifingered manipulation methods, including but not limited to reinforcement learning, imitation learning, and other sub-class methods. The article concludes with open issues and our thoughts on future directions.
The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination
Authors: Rouillard Megan E. , Hu Jingwen , Sutter Pearl A. , Kim Hee Won , Huang Jeffrey K. , Crocker Stephen J.
Published: April 2022

HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP). We have recently determined that progenitor cells from multiple sclerosis patients exhibit a cellular senescent phenotype and release extracellular HMGB1 which directly impaired the maturation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes (OLs). Herein, we report that administration of recombinant HMGB1 into the spinal cord at the time of lysolecithin administration resulted in arrest of OPC differentiation in vivo, and a profound impairment of remyelination. To define the receptor by which extracellular HMGB1 mediates its inhibitory influence on OPCs to impair OL differentiation, we tested selective inhibitors against the four primary receptors known to mediate the effects of HMGB1, the toll-like receptors (TLRs)-2, -4, -9 or the receptor for advanced glycation end-products (RAGE). We found that inhibition of neither TLR9 nor RAGE increased OL differentiation in the presence of HMGB1, while inhibition of TLR4 resulted in partial restoration of OL differentiation and inhibiting TLR2 fully restored differentiation of OLs in the presence of HMGB1. Analysis of transcriptomic data (RNAseq) from OPCs identified an overrepresentation of NFκB regulated genes in OPCs when in the presence of HMGB1. We found that application of HMGB1 to OPCs in culture resulted in a rapid and concentration dependent shift in NFκB nuclear translocation which was also attenuated with coincident TLR2 inhibition. These data provide new information on how extracellular HMGB1 directly affects the differentiation potential of OPCs. Recent and past evidence for elevated HMGB1 released from senescent progenitor cells within demyelinated lesions in the MS brain suggests that a greater understanding of how this molecule acts on OPCs may unfetter the endogenous remyelination potential in MS.
Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway
Authors: Li Nan , Shu Jun , Yang Xiaoyan , Wei Wenshi , Yan Aijuan
Published: April 2022

The accumulation of abnormal aggregation of amyloid-β plaques is one of the most distinguishing pathologies of Alzheimer’s disease (AD) and is highly toxic to neurons. Exosomes have demonstrated great potential for AD therapy. However, the impact and underlying mechanism of M2 microglia-derived exosomes (M2-EXOs) in AD progression and outcome are seldom explored. Therefore, we employed an Aβ1-42 oligomer (Aβ)-induced AD model in neuronal HT-22 cells and 7-month-old APP/PS1 mice to investigate the effects of M2-EXOs on AD. We revealed that the AD cell model established by Aβ was accompanied by the upregulation of Aβ1-42, neuronal death, alternation of mitochondrial function and autophagy. M2-EXOs can be internalized by HT-22 cells and MAP2-positive neuronal cells in APP/PS1 mice, and exert neuroprotective functions. Specifically, the administration of M2-EXOs in the AD cell model partially increased cell viability, restored the destruction of mitochondrial membrane potential, and reduced the accumulation of reactive oxygen species inside the mitochondria and cells in a dose-dependent manner. Moreover, we demonstrated that PINK1/Parkin mediated mitophagy was enhanced, while incubation with M2-EXOs decreased beclin1, LC3II, PINK1, and Parkin expression levels. Finally, we observed that compared with APP/PS1 mice treated with PBS, the application of M2-EXOs could decrease Aβ plaque deposition and minus Aβ oligomer expression along with improved PINK1/Parkin pathway-mediated autophagy. Overall, our results imply that M2-EXOs play a protective role in the pathogenesis of AD by ameliorating PINK1/Parkin-mediated mitophagy, indicating that it may provide a novel therapeutic strategy to treat AD.
Pain Relief in a Trigeminal Neuralgia Model via Optogenetic Inhibition on Trigeminal Ganglion Itself With Flexible Optic Fiber Cannula
Authors: KC Elina , Islam Jaisan , Kim Soochong , Kim Hyong Kyu , Park Young Seok
Published: April 2022

The trigeminal ganglion (TG) is the primary site of aberration in trigeminal neuralgia (TN), and hence a crucial site where afferent input can be modulated. Here, we postulated that inhibiting TG via optogenetics using flexible optic cannula would diminish brainstem trigeminal nucleus caudalis (TNC) neuronal activity and pain behavior in TN rat model. Infraorbital nerve constriction was employed to induce TN in female Sprague-Dawley rats, while naive and sham rats served as controls. TG-directed microinjections of AAV virus containing either the optogenetic or null vector were delivered to rats in each group. In vivo electrophysiological responses were obtained from the ventral posteromedial nucleus (VPm) of the thalamus with simultaneous TG optogenetic stimulation using flexible optic cannula as well the effects on behavioral responses were investigated. Recordings in TN rats revealed a decrease in burst firing activity during yellow laser driven inhibition on TG, as well as considerably improved behavioral responses. In contrast, we noticed persistent hypersensitivity and increased tonic firing with blue laser stimulation which indicates that TG inhibition can synchronize trigeminal pain signal transmission in a TN animal model. The potential of an optogenetic approach in TG itself with flexible optic fiber to directly disrupt the trigeminal pain circuitry delivers fundamental underpinnings toward its prospective as a trigeminal neuralgia management.
Caloric Restriction Alleviates CFA-Induced Inflammatory Pain via Elevating β-Hydroxybutyric Acid Expression and Restoring Autophagic Flux in the Spinal Cord
Authors: Liu Chang , Zheng Xiaoting , Liu Lifang , Hu Yun , Zhu Qianyun , Zhang Jiawei , Wang Huan , Gu Er-wei , Yang Zhilai , Xu Guanghong
Published: April 2022

Inflammatory pain is the most common type of pain encountered in clinical practice; however, the currently available treatments are limited by insufficient efficacy and side effects. Therefore, new methods to relieve inflammatory pain targeting new mechanisms are urgently needed. Preclinical investigations have shown that CR (calorie restriction) exerts analgesic effects in neuropathic and cancer pain; however, the effect of CR on chronic inflammatory pain remains unknown. During calorie restriction, autophagy, a lysosome-dependent degradation process, can be activated to support cell survival. In the present study, we investigated the analgesic effects of CR on complete Freund’s adjuvant (CFA)-induced inflammatory pain. The accumulation of LC3-II and p62 showed impaired autophagic flux in the ipsilateral spinal cord of mice with CFA-induced inflammatory pain. CR alleviated mechanical allodynia and thermal hyperalgesia and reduced paw edema and pro-inflammatory factors following CFA administration. CR exerted an analgesic effect by restoring autophagic flux in the spinal cord. Regarding the mechanisms underlying the analgesic effects of CR, β-hydroxybutyric acid (BHB) was studied. CR increased BHB levels in the ipsilateral spinal cord. Furthermore, exogenous BHB administration exerted an analgesic effect by restoring autophagic flux in the spinal cords of CFA-induced inflammatory pain mice. Taken together, these results illustrated that CR relieved inflammatory pain by restoring autophagic flux in the spinal cord, while BHB controlled the benefits of CR, suggesting that CR or BHB might be a promising treatment for inflammatory pain.
Increasing Robustness of Brain–Computer Interfaces Through Automatic Detection and Removal of Corrupted Input Signals
Authors: Vasko Jordan L. , Aume Laura , Tamrakar Sanjay , Colachis Samuel C. IV , Dunlap Collin F. , Rich Adam , Meyers Eric C. , Gabrieli David , Friedenberg David A.
Published: April 2022

For brain–computer interfaces (BCIs) to be viable for long-term daily usage, they must be able to quickly identify and adapt to signal disruptions. Furthermore, the detection and mitigation steps need to occur automatically and without the need for user intervention while also being computationally tractable for the low-power hardware that will be used in a deployed BCI system. Here, we focus on disruptions that are likely to occur during chronic use that cause some recording channels to fail but leave the remaining channels unaffected. In these cases, the algorithm that translates recorded neural activity into actions, the neural decoder, should seamlessly identify and adjust to the altered neural signals with minimal inconvenience to the user. First, we introduce an adapted statistical process control (SPC) method that automatically identifies disrupted channels so that both decoding algorithms can be adjusted, and technicians can be alerted. Next, after identifying corrupted channels, we demonstrate the automated and rapid removal of channels from a neural network decoder using a masking approach that does not change the decoding architecture, making it amenable for transfer learning. Finally, using transfer and unsupervised learning techniques, we update the model weights to adjust for the corrupted channels without requiring the user to collect additional calibration data. We demonstrate with both real and simulated neural data that our approach can maintain high-performance while simultaneously minimizing computation time and data storage requirements. This framework is invisible to the user but can dramatically increase BCI robustness and usability.
Synaptic Vesicle Glycoprotein 2A: Features and Functions
Authors: Rossi Rachele , Arjmand Shokouh , Bærentzen Simone Larsen , Gjedde Albert , Landau Anne M.
Published: April 2022

In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.
Microbial Metabolites in Multiple Sclerosis: Implications for Pathogenesis and Treatment
Authors: Duarte-Silva Eduardo , Meuth Sven G. , Peixoto Christina Alves
Published: April 2022

Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.
Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule
Authors: Cai Ming , Wang Hongbiao , Song Haihan , Yang Ruoyu , Wang Liyan , Xue Xiangli , Sun Wanju , Hu Jingyun
Published: April 2022

Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.
Short-Term Oral Quercetin Supplementation Improves Post-exercise Insulin Sensitivity, Antioxidant Capacity and Enhances Subsequent Cycling Time to Exhaustion in Healthy Adults: A Pilot Study
Authors: Tsao Jung-Piao , Bernard Jeffrey R. , Hsu Hsiu-Chen , Hsu Chin-Lin , Liao Su-Fen , Cheng I-Shiung
Published: April 2022

Aim

Quercetin has been reported to have antioxidant and anti-inflammatory properties on health promotion in human studies. The main purpose of this study was to investigate the effect of short-term oral quercetin supplementation on post-exercise whole-body energy metabolism. This study also aimed to determine the effects of supplementation on oxygen stress, inflammation, muscle damage, and high-intensity cycling exercise performance.

Method

Twelve healthy participants, physically active students, were recruited to perform a randomized, single-blind crossover study. All subjects completed 7-days of quercetin (quercetin:1,000 mg per day for 7-days) and placebo supplementation in a randomized order. Supplement/placebo was combined with exercise consisting of 70% V̇O2max cycling for 60-min, followed by 3-h of recovery, then a subsequent single bout of cycling exercise with 75% V̇O2max to exhaustion. Time to exhaustion, indicators of muscle damage, as well as blood and gaseous parameters relating to energy metabolism, oxidative stress, inflammatory response, respectively, were determined.

Results

The results showed that 7-day quercetin supplementation significantly attenuated the post-exercise glucose-induced insulin response, increased total antioxidant capacity (TAC) and superoxidase dismutase (SOD) activities, and mitigated malondialdehyde (MDA) levels during the recovery period (p < 0.05). While subsequent 75% V̇O2max cycling performance was significantly improved after quercetin treatment and accompanied by lower responses of interleukin 6 and creatine kinase at 24-h. However, it’s noted that there were no significant responses in glucose, respiratory exchange rate, tumor necrosis factor-α (TNF-α), myoglobin, and high sensitivity C-reactive protein between quercetin and placebo trials.

Conclusion

Our findings concluded that 7-day oral quercetin supplementation enhances high-intensity cycling time to exhaustion, which may be due in part to the increase in whole-body insulin-stimulated glucose uptake and attenuation of exercise-induced oxygen stress and pro-inflammation. Therefore, quercetin may be considered an effective ergogenic aid for enhancing high-intensity cycling performance among young adults.
In vitro Study of Bifidobacterium lactis BL-99 With Fructooligosaccharide Synbiotics Effected on the Intestinal Microbiota
Authors: Zhang Qi , Zhao Wen , Zhao Yuyang , Duan Sufang , Liu Wei-Hsien , Zhang Chao , Sun Siyuan , Wang Tingting , Wang Xin , Hung Wei-Lian , Wang Ran
Published: April 2022

Probiotics and prebiotics relieve constipation by altering the composition of the intestinal microbiota. However, their synergistic mechanism of action remains unclear. Herein, an in vitro fermentation model was constructed to examine the synergistic effects of Bifidobacterium lactis BL-99 and fructooligosaccharide (FOS) on the regulation of intestinal microbiota from a population with constipation. The utilization of FOS was promoted by BL-99, and the increase rate being 22.33%. Relative to the BL-99 and the FOS groups, the BL-99_FOS group showed a highly significant increase in acetic acid content (P < 0.01) and a marked decrease in CO2 and H2S contents (P < 0.01) in the fermentation broth. In addition, the BL-99_FOS combination significantly changed the structure of the intestinal microbiota, enhanced the relative abundances of beneficial bacteria that relieved constipation, including Bifidobacterium, Fecalibacterium, Lactobacillus, Subdoligranulum, and Blautia, and decreased those of the harmful bacteria, including Bilophila and Escherichia-Shigella. These findings suggested that BL-99 and FOS synergistically regulated the composition and structure of the intestinal microbiota from the population with constipation and increased acetic acid and decreased CO2 and H2S levels, thereby providing a theoretical basis for the application of synbiotics.
Sequential CAR T-Cell Therapy After Autologous Stem Cell Transplantation for the Treatment of Relapsed/Refractory Intravascular Large B-Cell Lymphoma With Central Nervous System Involvement: A Case Report
Authors: Liu Wanying , Li Chunrui , Cao Yang , Wang Na , Huang Liang , Shang Zhen , Wang Jue , Huang Lifang , Xu Jinhuan , Xiao Min , Zhang Yicheng , Zhou Jianfeng , Chen Liting , Xiao Yi
Published: April 2022

Background

Intravascular large B-cell lymphoma (IVLBCL) is a rare, aggressive, large B-cell non-Hodgkin’s lymphoma. The prognosis of IVLBCL in patients with central nervous system recurrence after first-line chemotherapy treatment is extremely poor. Among immunotherapies, chimeric antigen receptor (CAR) T-cell immunotherapy has been recently found to be a highly effective treatment for B-cell lymphoma, especially for relapsed or refractory diffuse large B-cell lymphoma. However, no guidelines are available that provide a clear consensus regarding the management of patients with relapsed/refractory IVLBCL. Here, we report, for the first time, the use of autologous hematopoietic stem cell transplantation (ASCT) and CAR T-cell therapy in a patient with relapsed/refractory IVLBCL.

Case Presentation

A 42‐year‐old woman was diagnosed with IVLBCL based on liver biopsy and developed central nervous system (CNS) progression. The patient received ASCT combined with murine monoclonal anti-CD19 and anti-CD22 CAR T-cell therapy. She achieved complete remission for 22 months so far with negative minimal residual disease and continues to be followed up.

Conclusion

ASCT combined with CAR T-cell therapy was the best choice for treatment of relapsed/refractory IVLBCL, as it allowed the achievement of a lasting complete remission.