bluuebunny/crossref_metadata_2025 huggingface dataset:
Oridonin Prolongs the Survival of Mouse Cardiac Allografts by Attenuating the NF-κB/NLRP3 Pathway
Authors: Du Xiaoxiao , Que Weitao , Hu Xin , Yu Xiao , Guo Wen-Zhi , Zhang Shuijun , Li Xiao-Kang
Published: September 2021

Background

Oridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts.

Methods

The cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro.

Results

Ori with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression.

Conclusions

Our findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.
Construction of Interferon-Gamma-Related Gene Signature to Characterize the Immune-Inflamed Phenotype of Glioblastoma and Predict Prognosis, Efficacy of Immunotherapy and Radiotherapy
Authors: Ji Hang , Ba Yixu , Ma Shuai , Hou Kuiyuan , Mi Shan , Gao Xin , Jin Jiaqi , Gong Qin , Liu Ting , Wang Fang , Liu Zhihui , Li Shupeng , Du Jianyang , Hu Shaoshan
Published: September 2021

Interferon-gamma (IFNG) has profound impacts on tumor-immune interaction and is of great clinical significance for multiple cancers. Exploring the role of IFNG in glioblastoma (GBM) may optimize the current treatment paradigm of this disease. Here, multi-dimensional data of 429 GBM samples were collected. Various bioinformatics algorithms were employed to establish a gene signature that characterizes immunological features, genomic alterations, and clinical characteristics associated with the IFNG response. In this way, a novel IFNG-related gene signature (IFNGrGS, including TGFBI, IL4I1, ACP5, and LUM) has been constructed and validated. Samples with increased IFNGrGS scores were characterized by increased neutrophil and macrophage infiltration and exuberant innate immune responses, while the activated adaptive immune response may be frustrated by multiple immunosuppressive mechanisms. Notably, the IFNG pathway as well as its antagonistic pathways including IL4, IL10, TGF-beta, and VEGF converged on the expression of immune checkpoints. Besides, gene mutations involved in the microenvironment were associated with the IFNGrGS-based stratification, where the heterogeneous prognostic significance of EGFR mutation may be related to the different degrees of IFNG response. Moreover, the IFNGrGS score had solid prognostic value and the potential to screen ICB and radiotherapy sensitive populations. Collectively, our study provided insights into the role of IFNG on the GBM immune microenvironment and offered feasible information for optimizing the treatment of GBM.
GITR Promotes the Polarization of TFH-Like Cells in Helicobacter pylori-Positive Gastritis
Authors: Ming Siqi , Yin Huan , Li Xingyu , Gong Sitang , Zhang Guoliang , Wu Yongjian
Published: September 2021

Gastric CD4+T cells contribute to Helicobacter pylori (H. pylori)-induced gastritis by amplifying mucosal inflammation and exacerbating mucosal injuries. However, the pathogenic CD4+ T cell subset involved in gastritis and the potential regulators are still unclear. Here we identified an IL-21-producing gastric CD4+T cell subset, which exhibited tissue-resident CXCR5−BTLA−PD-1hi TFH-like phenotype in H. pylori-positive gastritis patients. Meanwhile, we identified glucocorticoid-induced tumor necrosis factor receptor (GITR) as an important regulator to facilitate IL-21 production by CD4+T cells and accelerate mucosal inflammation in gastritis patients with H. pylori infection. Moreover, GITR expression was increased in gastric CD4+T cells of gastritis patients compared to healthy controls, along with the upregulated expression of its ligand GITRL in mucosal macrophages (Mϕ) of gastritis patients. Further observations showed that the activation of GITR/GITRL signal promoted the IL-21 production of CD4+T cells via the STAT3 pathway. Besides this, IL-21 from CD4+T cells induced the proliferation of B cell and promoted the production of inflammatory cytokines IL-1β and IL-6 and chemokines MIP-3α and CCL-25 as well as matrix metalloproteinase (MMP)-3 and MMP-9 by human gastric epithelial cells, suggesting the facilitating effect of IL-21-producing CD4+T cells on mucosal inflammation and injuries. Taking these data together, we revealed that GITR/GITRL signal promoted the polarization of mucosal IL-21-producing CD4+T cells in H. pylori-positive gastritis, which may provide therapeutic strategies for the clinical treatment of H. pylori-induced gastritis.
Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease
Authors: Yánez Diana C. , Papaioannou Eleftheria , Chawda Mira M. , Rowell Jasmine , Ross Susan , Lau Ching-In , Crompton Tessa
Published: September 2021

Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.
Anti-Desmocollin Autoantibodies in Autoimmune Blistering Diseases
Authors: Bosch-Amate Xavier , Iranzo Pilar , Ivars Marta , Mascaró Galy José Manuel , España Agustín
Published: September 2021

The presence of anti-desmocollin (Dsc) antibodies is rarely described in autoimmune blistering diseases patients. Moreover, several clinical phenotypes of pemphigus may be associated with these antibodies. In this review we analyze clinicopathological, immunologic and outcome features of anti-Dsc autoimmune blistering diseases patients, to improve their diagnosis and management. We conducted a systematic search of PubMed and Embase (1990-present) for studies reporting cases of autoimmune blistering diseases with anti-Dsc antibodies. We classified the selected patients as patients with exclusively anti-Dsc autoantibodies, and patients with anti-Dsc and other autoantibodies. Of 93 cases with anti-Dsc autoantibodies included, 38 (41%) had exclusively these antibodies. Only 18% of patients presented with the typical clinicopathological phenotype of pemphigus vulgaris or pemphigus foliaceous. Mucosal involvement was seen in approximately half of the patients. Up to 18% of cases were associated with neoplasms. Acantholysis was described in 54% of cases with histopathological information. Treatments and outcomes vary in the different clinical phenotypes. The presence of anti-Dsc antibodies must be suspected mainly in those patients with either atypical pemphigus, in special with clinical pustules, or in cases showing intraepithelial or dermal neutrophilic/eosinophilic infiltrate on histological examination and dual pattern by direct immunofluorescence examination.
Investigating Spinner Dolphin (Stenella longirostris) Occurrence and Acoustic Activity in the Maui Nui Region
Authors: McElligott Megan M. , Lammers Marc O.
Published: September 2021

Hawaiian spinner dolphins (Stenella longirostris) rest during the day in the islands’ coastal waters where they are susceptible to human disturbance. Due to concerns over the negative impacts of human activity, the Pacific Islands Regional Office of the National Oceanic and Atmospheric Administration (NOAA) has proposed a 50-yard approach rule for spinner dolphins and is also considering time-area closures of certain important spinner dolphin resting areas. However, gaps still persist in the understanding of how spinner dolphin populations on different Hawaiian Islands use coastal waters, raising questions about the efficacy of the proposed rules. To better understand how spinner dolphins use the waters in the Maui Nui region (Maui, Moloka‘i, Lāna‘i, and the ‘Au‘au channel), a study was conducted using a combination of passive acoustic monitoring and vessel surveys to document spinner dolphin occurrence and movements. Bottom-moored acoustic recorders were deployed at eight locations in Maui Nui, and at one previously established resting bay off west O‘ahu for comparison. The amount of whistles, clicks, and burst pulses at each location was quantified and averaged by the hour of the day. Acoustic activity was greater at the O‘ahu site than at any of the Maui Nui sites, and was greatest between sunrise and noon. Acoustic activity and vessel surveys both reveal that spinner dolphins occur and exhibit resting behaviors in the ‘Au‘au channel between Maui and Lāna‘i, and also along west Maui and southeast Lāna‘i. Spinner dolphins resting in a channel between islands appears to be unique to Maui Nui and differs from resting patterns described along Hawai‘i Island and O‘ahu. Because spinner dolphins appear to use both the coastlines and the channel to rest in Maui Nui, the 50-yard approach rule appears to be a more suitable management option for the region than time-area closures.
Influence of Antibiotic Management on Microbial Selection and Infectious Complications After Trauma
Authors: Schindler Cora Rebecca , Woschek Mathias , Franz Jan-Niklas , Störmann Philipp , Henrich Dirk , Marzi Ingo
Published: September 2021

Background: The inflammatory response and post-traumatic complications like infections play an important role in the pathophysiology of severe injuries. This study examines the microbiological aspects in anti-infective treatment of trauma patients and their inflammatory response in post-traumatic infections complications.

Patients and Methods: A retrospective analysis of prospectively collected data in trauma patients (ISS ≥ 16) over a 1-year period (01/2018 to 12/2018) is provided. Patient population was stratified into severely injured patients without post-traumatic infection (inf-PT), and severely injured patients who developed an infection (inf+PT).

Results: Of 114 trauma patients, 45 suffered from post-traumatic infection during the first 10 days of hospitalization. Severely injured patients with concomitant traumatic brain injury (PT+TBI) showed the highest rate of post-traumatic infection. Pro-inflammatory reaction was tracked by levels of Interleukin (IL-)6 (day 3: inf+T 190.8 ± 359.4 pg/dL > inf-PT 56.2 ± 57.7 pg/mL (mean ± SD); p = 0.008) and C-Reactive-Protein (CRP, day 3: inf+PT 15.3 mg/dL > inf-PT 6.7 mg/dL, p = 0.001) which were significantly higher in trauma patients who develop an infectious complication and showed a significant positive correlation with the occurrence of infection. The leading entity of infection was pneumonia followed by infections of the urinary tract mainly caused by gram-negative Enterobacteriaceae. 67.5% of all trauma patients received single-shot antibiosis during initial care in trauma bay. The development of secondary colonization was not relevant positively correlated with single-shot antibiosis (r = 0.013, p = 0.895) and prophylactically calculated antibiotic administration (r = 0.066, p = 0.500).

Conclusion: Severely injured trauma patients have an increased risk for development of infectious complications, which mainly is pneumonia followed by infection of the urinary tract mainly caused by gram-negative Enterobacteriaceae. Based on the data in this study, the one-time antibiotic and prophylactic calculated use of antibiotics, like Cephalosporins must be critically discussed in terms of their role in the development of post-traumatic infections and microbial selection.
The Global Prevalence of Daptomycin, Tigecycline, and Linezolid-Resistant Enterococcus faecalis and Enterococcus faecium Strains From Human Clinical Samples: A Systematic Review and Meta-Analysis
Authors: Dadashi Masoud , Sharifian Parastoo , Bostanshirin Nazila , Hajikhani Bahareh , Bostanghadiri Narjess , Khosravi-Dehaghi Nafiseh , van Belkum Alex , Darban-Sarokhalil Davood
Published: September 2021

Background and Aim: The predominant species of the Enterococcus, Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) cause great variety of infections. Therefore, the expansion of antimicrobial resistance in the Enterococcus is one of the most important global concerns. This study was conducted to investigate the prevalence of resistance to linezolid, tigecycline, and daptomycin among enterococcal strains isolated from human clinical specimens worldwide.

Methods: Several databases including Web of Science, EMBASE, and Medline (via PubMed), were carefully searched and reviewed for original research articles available in databases and published between 2000 and 2020. A total of 114 studies worldwide that address E. faecalis and E. faecium resistance to linezolid, tigecycline, and daptomycin were analyzed by STATA software.

Results: The overall prevalence of antibiotic-resistant E. faecalis and E. faecium was reported to be 0.9 and 0.6%, respectively. E. faecalis and E. faecium were more resistant to the linezolid (2.2%) and daptomycin (9%), respectively. The prevalence of tigecyline-resistant E. facium (1%) strains was higher than E. faecalis strains (0.3%). Accordingly, the prevalence of linezolid-resistant E. faecalis was higher in Asia (2.8%), while linezolid-resistant E. faecium was higher in the America (3.4%). Regarding tigecycline-resistance, a higher prevalence of E. faecalis (0.4%) and E. faecium (3.9%) was reported in Europe.

Conclusion: In conclusion, this meta-analysis shows that there is an emerging resistance in Enterococcus strains. Despite the rising resistance of enterococci to antibiotics, our results demonstrate that tigecycline, daptomycin, and linezolid can still be used for the treatment of enterococcal infections worldwide.
Description, Taxonomy, and Comparative Genomics of a Novel species, Thermoleptolyngbya sichuanensis sp. nov., Isolated From Hot Springs of Ganzi, Sichuan, China
Authors: Tang Jie , Li Liheng , Li Meijin , Du Lianming , Shah Md Mahfuzur R. , Waleron Michal M. , Waleron Malgorzata , Waleron Krzysztof F. , Daroch Maurycy
Published: September 2021

Thermoleptolyngbya is a newly proposed genus of thermophilic cyanobacteria that are often abundant in thermal environments. However, a vast majority ofThermoleptolyngbyastrains were not systematically identified, and genomic features of this genus are also sparse. Here, polyphasic approaches were employed to identify a thermophilic strain, PKUAC-SCTA183 (A183 hereafter), isolated from hot spring Erdaoqiao, Ganzi prefecture, China. Whole-genome sequencing of the strain revealed its allocation toThermoleptolyngbyasp. and genetic adaptations to the hot spring environment. While the results of 16S rRNA were deemed inconclusive, the more comprehensive polyphasic approach encompassing phenetic, chemotaxic, and genomic approaches strongly suggest that a new taxon,Thermoleptolyngbya sichuanensissp. nov., should be delineated around the A183 strain. The genome-scale phylogeny and average nucleotide/amino-acid identity confirmed the genetic divergence of the A183 strain from other strains ofThermoleptolyngbyaalong with traditional methods such as 16S-23S ITS and its secondary structure analyses. Comparative genomic and phylogenomic analyses revealed inconsistent genome structures betweenThermoleptolyngbyaA183 and O-77 strains. Further gene ontology analysis showed that the unique genes of the two strains were distributed in a wide range of functional categories. In addition, analysis of genes related to thermotolerance, signal transduction, and carbon/nitrogen/sulfur assimilation revealed the ability of this strain to adapt to inhospitable niches in hot springs, and these findings were preliminarily confirmed using experimental, cultivation-based approaches.
Breeding Strategy Shapes the Composition of Bacterial Communities in Female Nile Tilapia Reared in a Recirculating Aquaculture System
Authors: Abdelhafiz Yousri , Fernandes Jorge M. O. , Larger Simone , Albanese Davide , Donati Claudio , Jafari Omid , Nedoluzhko Artem V. , Kiron Viswanath
Published: September 2021

In industrial animal production, breeding strategies are essential to produce offspring of better quality and vitality. It is also known that host microbiome has a bearing on its health. Here, we report for the first time the influence of crossbreeding strategy, inbreeding or outbreeding, on the buccal and intestinal bacterial communities in female Nile tilapia (Oreochromis niloticus). Crossbreeding was performed within a family and between different fish families to obtain the inbred and outbred study groups, respectively. The genetic relationship and structure analysis revealed significant genetic differentiation between the inbred and outbred groups. We also employed a 16S rRNA gene sequencing technique to understand the significant differences between the diversities of the bacterial communities of the inbred and outbred groups. The core microbiota composition in the mouth and the intestine was not affected by the crossbreeding strategy but their abundance varied between the two groups. Furthermore, opportunistic bacteria were abundant in the buccal cavity and intestine of the outbred group, whereas beneficial bacteria were abundant in the intestine of the inbred group. The present study indicates that crossbreeding can influence the abundance of beneficial bacteria, core microbiome and the inter-individual variation in the microbiome.
Flavonoids as Molecules With Anti-Zika virus Activity
Authors: Cataneo Allan Henrique Depieri , Ávila Eloah Pereira , Mendes Larissa Albuquerque de Oliveira , de Oliveira Viviane Guedes , Ferraz Camila Rodrigues , de Almeida Mauro Vieira , Frabasile Sandra , Duarte dos Santos Claudia Nunes , Verri Waldiceu Aparecido , Bordignon Juliano , Wowk Pryscilla Fanini
Published: September 2021

Zika virus (ZIKV) is an arthropod-born virus that is mainly transmitted to humans by mosquitoes of the genus Aedes spp. Since its first isolation in 1947, only a few human cases had been described until large outbreaks occurred on Yap Island (2007), French Polynesia (2013), and Brazil (2015). Most ZIKV-infected individuals are asymptomatic or present with a self-limiting disease and nonspecific symptoms such as fever, myalgia, and headache. However, in French Polynesia and Brazil, ZIKV outbreaks led to the diagnosis of congenital malformations and microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. These new clinical presentations raised concern from public health authorities and highlighted the need for anti-Zika treatments and vaccines to control the neurological damage caused by the virus. Despite many efforts in the search for an effective treatment, neither vaccines nor antiviral drugs have become available to control ZIKV infection and/or replication. Flavonoids, a class of natural compounds that are well-known for possessing several biological properties, have shown activity against different viruses. Additionally, the use of flavonoids in some countries as food supplements indicates that these molecules are nontoxic to humans. Thus, here, we summarize knowledge on the use of flavonoids as a source of anti-ZIKV molecules and discuss the gaps and challenges in this area before these compounds can be considered for further preclinical and clinical trials.
Ratio of Electron Donor to Acceptor Influences Metabolic Specialization and Denitrification Dynamics in Pseudomonas aeruginosa in a Mixed Carbon Medium
Authors: Zhang Irene H. , Mullen Susan , Ciccarese Davide , Dumit Diana , Martocello Donald E. , Toyofuku Masanori , Nomura Nobuhiko , Smriga Steven , Babbin Andrew R.
Published: September 2021

Denitrifying microbes sequentially reduce nitrate (NO3–) to nitrite (NO2–), NO, N2O, and N2 through enzymes encoded by nar, nir, nor, and nos. Some denitrifiers maintain the whole four-gene pathway, but others possess partial pathways. Partial denitrifiers may evolve through metabolic specialization whereas complete denitrifiers may adapt toward greater metabolic flexibility in nitrogen oxide (NOx–) utilization. Both exist within natural environments, but we lack an understanding of selective pressures driving the evolution toward each lifestyle. Here we investigate differences in growth rate, growth yield, denitrification dynamics, and the extent of intermediate metabolite accumulation under varying nutrient conditions between the model complete denitrifier Pseudomonas aeruginosa and a community of engineered specialists with deletions in the denitrification genes nar or nir. Our results in a mixed carbon medium indicate a growth rate vs. yield tradeoff between complete and partial denitrifiers, which varies with total nutrient availability and ratios of organic carbon to NOx–. We found that the cultures of both complete and partial denitrifiers accumulated nitrite and that the metabolic lifestyle coupled with nutrient conditions are responsible for the extent of nitrite accumulation.
Comparative Genome Sequence Analysis of Actinobacillus pleuropneumoniae Serovar 8 Isolates From Norway, Denmark, and the United Kingdom Indicates Distinct Phylogenetic Lineages and Differences in Distribution of Antimicrobial Resistance Genes
Authors: Cohen Liza Miriam , Bossé Janine T. , Stegger Marc , Li Yanwen , Langford Paul R. , Kielland Camilla , Klem Thea Blystad , Gulliksen Stine Margrethe , Ranheim Birgit , Grøntvedt Carl Andreas , Angen Øystein
Published: September 2021

Actinobacillus pleuropneumoniae is the etiological agent of porcine pleuropneumonia, a disease of major impact on pig health, welfare, and productivity globally. Serovar 8 (APP) is the predominant clinical serovar in Norway and the United Kingdom (UK), and has been isolated from clinical cases in Denmark. The primary objective of this study was to characterize the genetic variability of isolates of A. pleuropneumoniae APP8 in the Norwegian population. The secondary objectives were to determine the within-host variability of APP8; to compare the APP8 bacterial populations in Norway, Denmark, and the UK, including antimicrobial resistance (AMR) gene profiles and to assess the effect of national differences in antimicrobial drug use and restricted animal movement on the occurrence of resistance. Isolates of APP8 from the UK (n=67), Denmark (n=22), and Norway (n=123) collected between 1983 and 2020 were compared using whole genome sequencing. To investigate genetic variability within individual hosts, an additional 104 APP8 isolates from the lungs of six Norwegian pigs were compared. Very low within-host variation was observed (≤ 2 single nucleotide polymorphisms). The phylogeny of 123 Norwegian APP8 isolates from 76 herds revealed some within-herd genetic variation, but substantial geographical clustering. When inferring the relatedness of the three international APP8 collections, the topology highlighted the existence of two distinct monophyletic branches characterized by the Norwegian and UK isolates, respectively. Three Danish isolates were scattered across the UK branch, whereas the remaining 19 Danish isolates clustered in two monophyletic groups nested in the Norwegian branch. Coalescence analysis, performed to estimate the divergences from a common ancestor, indicated a last common ancestor several centuries ago. The phylogenetic analyses also revealed striking differences in occurrence of AMR genes, as these were 23-times more prevalent among the UK isolates than among the Norwegian isolates. An increased understanding of the effects of population strategies is helpful in surveillance and control of infectious diseases.
Bacterial Transformation of Aromatic Monomers in Softwood Black Liquor
Authors: Navas Laura E. , Dexter Gara , Liu Jie , Levy-Booth David , Cho MiJung , Jang Soo-Kyeong , Mansfield Shawn D. , Renneckar Scott , Mohn William W. , Eltis Lindsay D.
Published: September 2021

The valorization of lignin, a major component of plant-derived biomass, is essential to sustainable biorefining. We identified the major monoaromatic compounds present in black liquor, a lignin-rich stream generated in the kraft pulping process, and investigated their bacterial transformation. Among tested solvents, acetone extracted the greatest amount of monoaromatic compounds from softwood black liquor, with guaiacol, vanillin, and acetovanillone, in an approximately 4:3:2 ratio, constituting ~90% of the total extracted monoaromatic content. 4-Ethanol guaiacol, vanillate, and 4-propanol guaiacol were also present. Bacterial strains that grew on minimal media supplemented with the BL extracts at 1mM total aromatic compounds included Pseudomonas putida KT2442, Sphingobium sp. SYK-6, and Rhodococcus rhodochrous EP4. By contrast, the extracts inhibited the growth of Rhodococcus jostii RHA1 and Rhodococcus opacus PD630, strains extensively studied for lignin valorization. Of the strains that grew on the extracts, only R. rhodochrous GD01 and GD02, isolated for their ability to grow on acetovanillone, depleted the major extracted monoaromatics. Genomic analyses revealed that EP4, GD01, and GD02 share an average nucleotide identity (ANI) of 98% and that GD01 and GD02 harbor a predicted three-component carboxylase not present in EP4. A representative carboxylase gene was upregulated ~100-fold during growth of GD02 on a mixture of the BL monoaromatics, consistent with the involvement of the enzyme in acetovanillone catabolism. More generally, quantitative RT-PCR indicated that GD02 catabolizes the BL compounds in a convergent manner via the β-ketoadipate pathway. Overall, these studies help define the catabolic capabilities of potential biocatalytic strains, describe new isolates able to catabolize the major monoaromatic components of BL, including acetovanillone, and facilitate the design of biocatalysts to valorize under-utilized components of industrial lignin streams.
Hydroxychloroquine Induces Apoptosis in Cholangiocarcinoma via Reactive Oxygen Species Accumulation Induced by Autophagy Inhibition
Authors: Chen Jiaqi , Pan Qiaoya , Bai Yang , Chen Xuepeng , Zhou Yi
Published: September 2021

Purpose: Despite considerable efforts to improve treatment modalities for cholangiocarcinoma, a common form of malignant tumor, its long-term survival rate remains poor. Hydroxychloroquine (HCQ) is a 4-aminoquinoline derivative antimalarial drug that has antimalarial and autophagy inhibition effects and exhibits comprehensive therapeutic effects on various cancers. In this study, we aimed to explore the anticancer potential and the underlying molecular mechanism of HCQ in cholangiocarcinoma treatment in vitro and in vivo.

Methods: Autophagy-related genes (ARGs) were obtained from the Human Autophagy Database and Molecular Signatures Database, and the expression profiles of ARGs were downloaded from the database of The Cancer Genome Atlas. Different expression gene sets were performed using R software. The Gene Ontology and KEGG enrichment analyses were performed to reveal significantly enriched signaling pathways and to identify differentially expressed genes in cholangiocarcinoma tissues. HuCCT-1 and CCLP-1 cells were exposed to different concentrations of HCQ. Cell proliferation was detected by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were detected by the Live/Dead cell assay and flow cytometry (FCM). The inhibition of autophagy was observed using fluorescence microscopy. The reactive oxygen species levels were assessed by fluorescence microscopy and flow cytometry. The protein levels were determined by western blot. A cholangiocarcinoma cell line xenograft model was used to evaluate the antitumor activity of HCQ in vivo.

Results: Compared with normal tissues, there were 141 ARGs with an aberrant expression in cholangiocarcinoma tissues which were mainly enriched in autophagy-related processes. Inhibition of autophagy by HCQ effectively suppressed cholangiocarcinoma in vitro and in vivo. HCQ inhibited cell proliferation and induced apoptosis and cycle arrest in vitro by increasing ROS accumulation, which was involved in autophagy inhibition. The ROS scavenger reduced l-glutathione distinctly weakened HCQ-induced cell apoptosis and viability inhibition in cholangiocarcinoma cells. In addition, HCQ inhibited growth of cholangiocarcinoma cell line xenograft tumors.

Conclusion: HCQ could inhibit cell proliferation and induce apoptosis in cholangiocarcinoma by triggering ROS accumulation via autophagy inhibition, which makes HCQ a potential antitumor drug candidate for cholangiocarcinoma treatment.
Prenatal Maternal Stress From a Natural Disaster and Hippocampal Volumes: Gene-by-Environment Interactions in Young Adolescents From Project Ice Storm
Authors: Cao-Lei Lei , Yogendran Sandra , Dufoix Romane , Elgbeili Guillaume , Laplante David P. , King Suzanne
Published: September 2021

Gene-by-environment interactions influence brain development from conception to adulthood. In particular, the prenatal period is a window of vulnerability for the interplay between environmental and genetic factors to influence brain development. Rodent and human research demonstrates that prenatal maternal stress (PNMS) alters hippocampal volumes. Although PNMS affects hippocampal size on average, similar degrees of PNMS lead to different effects in different individuals. This differential susceptibility to the effects of PNMS may be due to genetic variants. Hence, we investigated the role of genetic variants of two SNPs that are candidates to moderate the effects of PNMS on hippocampal volume: COMT (rs4680) and BDNF (rs6265). To investigate this, we assessed 53 children who were in utero during the January 1998 Quebec ice storm. In June 1998 their mothers responded to questionnaires about their objective, cognitive, and subjective levels of stress from the ice storm. When children were 11 1/2 years old, T1-weighted structural magnetic resonance imaging (MRI) scans were obtained using a 3T scanner and analyzed to determine hippocampal volumes. We collected and genotyped the children’s saliva DNA. Moderation analyses were conducted to determine whether either or both of the SNPs moderate the effect of PNMS on hippocampal volumes. We found that objective hardship was associated with right hippocampal volume in girls, and that the BDNF and COMT genotypes were associated with left hippocampal volume in boys and girls. In addition, SNPs located on COMT moderated the effect of maternal objective distress in boys, and subjective distress in girls, on both right hippocampal volume. Thus, we conclude that an individual’s genotype alters their susceptibility to the effects of PNMS.
RETRACTED: Cerebral Microbleed Detection via Convolutional Neural Network and Extreme Learning Machine
Authors: Lu Siyuan , Liu Shuaiqi , Wang Shui-Hua , Zhang Yu-Dong
Published: September 2021

Aim: Cerebral microbleeds (CMBs) are small round dots distributed over the brain which contribute to stroke, dementia, and death. The early diagnosis is significant for the treatment.

Method: In this paper, a new CMB detection approach was put forward for brain magnetic resonance images. We leveraged a sliding window to obtain training and testing samples from input brain images. Then, a 13-layer convolutional neural network (CNN) was designed and trained. Finally, we proposed to utilize an extreme learning machine (ELM) to substitute the last several layers in the CNN for detection. We carried out an experiment to decide the optimal number of layers to be substituted. The parameters in ELM were optimized by a heuristic algorithm named bat algorithm. The evaluation of our approach was based on hold-out validation, and the final predictions were generated by averaging the performance of five runs.

Results: Through the experiments, we found replacing the last five layers with ELM can get the optimal results.

Conclusion: We offered a comparison with state-of-the-art algorithms, and it can be revealed that our method was accurate in CMB detection.
Intestinal Decontamination Therapy for Dyskinesia and Motor Fluctuations in Parkinson's Disease
Authors: Baizabal-Carvallo José Fidel , Alonso-Juarez Marlene , Fekete Robert
Published: September 2021

Parkinson's disease is neurodegenerative disorder with an initial robust response to levodopa. As the disease progresses, patients frequently develop dyskinesia and motor fluctuations, which are sometimes resistant to pharmacological therapy. In recent years, abnormalities in gut microbiota have been identified in these patients with a possible role in motor manifestations. Dysbiosis may reduce levodopa absorption leading to delayed “On” or “no-On” states. Among 84 consecutive patients with PD, we selected 14 with levodopa-induced dyskinesia and motor fluctuations with a Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV ≥ 8 points following a trial of pharmacological adjustment 2–3 months prior to study enrollment or adjustments in deep brain stimulation therapy. Patients received treatment with sodium phosphate enema followed by oral rifaximin and polyethylene glycol for 7 and 10 days, respectively. Evaluations between 14 to 21 days after starting treatment showed improvement in MDS-UPDRS-IV (P = 0.001), including duration (P = 0.001) and severity of dyskinesia (P = 0.003); duration of medication “Off”-state (P = 0.004); functional impact of motor fluctuations (P = 0.047) and complexity of motor fluctuations (P = 0.031); no statistical improvement was observed in “Off” dystonia (P = 0.109) and total motor scores (P = 0.430). Marked to moderate improvement in dyskinesia was observed in 57% of cases with blinded evaluation of videos. About 80% of patients perceived moderate to robust improvement at follow-up. A therapeutic strategy aimed at decontamination of intestines showed benefit in motor fluctuations and dyskinesia. Further studies should confirm and clarify the mechanism of improvement observed in these patients.
Serum Cystatin C as a Potential Predictor of the Severity of Multiple System Atrophy With Predominant Cerebellar Ataxia: A Case-Control Study in Chinese Population
Authors: Ye Fei , Wang Tianzhu , Li Huan , Liang Jie , Wu Xiaoxin , Sheng Wenli
Published: September 2021

Objective:Multiple system atrophy (MSA) is a serious neurodegenerative disease that is charactered by progressive neurological disability. The aim of this study was to investigate the correlation of serum oxidant factors with the severity of MSA.

Methods:A total of 52 MSA patients and 52 age- and gender- matched healthy subjects were retrospectively enrolled in this study. Enzymatic colorimetric methods were used to assay the concentrations of uric acid (UA), serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C (Cys-C). Disease severity was evaluated by the Unified Multiple System Atrophy Rating Scale (UMSARS). The disease progression rate was defined by the change in UMSARS-IV (global disability score, GDS) over a 1-year period.

Results:Comparisons between the two groups revealed that there were no significant differences in terms of serum Scr (70.81 ± 13.88 vs. 70.92 ± 14.19 μmol/L,p= 0.967). However, the serum levels of the other three biomarkers were significantly higher in the MSA patients (UA: 325.31 ± 84.92 vs. 291.19 ± 64.14 μmol/L,p= 0.023; BUN: 5.68 ± 1.67 vs. 4.60 ± 1.24 mmol/L,p< 0.001; Cys-C: 0.96 ± 0.15 vs. 0.89 ± 0.14 mg/L,p= 0.024). In addition, Pearson correlation analyses revealed that only serum Cys-C was significantly correlated to GDS (r= 0.281,p= 0.044). Subgroup analysis further demonstrated that serum Cys-C was the only factor that was positively associated with the disease severity in patients with MSA and predominant cerebellar ataxia (MSA-C) (r= 0.444,p= 0.018); there was no significant association in MSA patients with predominant Parkinsonism (MSA-P) (r= 0.118,p= 0.582). MSA-C patients with severe disability were shown to express higher serum levels of Cys-C than patients with mild disability (1.03 ± 0.13 vs. 0.88 ± 0.12 mg/L,p= 0.009). Finally, Kaplan-Meier plots revealed a significant difference in the 5-year probability of survival from severe disability between MSA-C patients with high- and low-concentrations of serum Cys-C (Log-rank test: X2= 4.154,p= 0.042). ROC curve analysis confirmed that serum Cys-C exhibits good performance as a biomarker (AUC = 0.847).

Conclusion:Our research indicated that oxidative stress plays a vital role in MSA. Serum Cys-C represents a potential prognostic biomarker to evaluate the severity of disease in patients with MSA-C.
Enhancement of Oxytocin in the Medial Prefrontal Cortex Reverses Behavioral Deficits Induced by Repeated Ketamine Administration in Mice
Authors: Zhu Weili , Ding Zengbo , Zhang Zhihui , Wu Xiao , Liu Xiaoya , Zhang Ya , Li Suxia , Zhou Liping , Tian Geng , Qin Jing
Published: September 2021

Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.
The Role of Mfsd2a in Nervous System Diseases
Authors: Huang Bei , Li Xihong
Published: September 2021

Major facilitator superfamily (MFS) is the maximum and most diversified membrane transporter, acting as uniporters, symporters and antiporters. MFS is considered to have a good development potential in the transport of drugs for the treatment of brain diseases. The major facilitator superfamily domain containing protein 2a (Mfsd2a) is a member of MFS. Mfsd2a-knockout mice have shown a marked decrease of docosahexaenoic acid (DHA) level in brain, exhibiting neuron loss, microcephaly and cognitive deficits, as DHA acts essentially in brain growth and integrity. Mfsd2a has attracted more and more attention in the study of nervous system diseases because of its critical role in maintaining the integrity of the blood-brain barrier (BBB) and transporting DHA, including inhibiting cell transport in central nervous system endothelial cells, alleviating BBB injury, avoiding BBB injury in cerebral hemorrhage model, acting as a carrier etc. Up to now, the clinical research of Mfsd2a in nervous system diseases is rare. This article reviewed the current research progress of Mfsd2a in nervous system diseases. It summarized the physiological functions of Mfsd2a in the occurrence and development of intracranial hemorrhage (ICH), Alzheimer’s disease (AD), sepsis-associated encephalopathy (SAE), autosomal recessive primary microcephaly (MCPH) and intracranial tumor, aiming to provide ideas for the basic research and clinical application of Mfsd2a.
Experience-Specific Dimensions of Consciousness (Observable in Flexible and Spontaneous Action Planning Among Animals)
Authors: Kaufmann Angelica
Published: September 2021

The multidimensional framework to the study of consciousness, which comes as an alternative to a single sliding scale model, offers a set of experimental paradigms for investigating dimensions of animal consciousness, acknowledging the compelling urge for a novel approach. One of these dimensions investigates whether non-human animals can flexibly and spontaneously plan for a future event, and for future desires, without relying on reinforcement learning. This is a critical question since different intentional structures for action in non-human animals are described as served by different neural mechanisms underpinning the capacity to represent temporal properties. And a lack of appreciation of this variety of intentional structures and neural correlates has led many experts to doubt that animals have access to temporal reasoning and to not recognize temporality as a mark of consciousness, and as a psychological resource for their life. With respect to this, there is a significant body of ethological evidence for planning abilities in non-human animals, too often overlooked, and that instead should be taken into serious account. This could contribute to assigning consciousness profiles, across and within species, that should be tailored according to an implemented and expansive use of the multidimensional framework. This cannot be fully operational in the absence of an additional tag to its dimensions of variations: theexperience-specificityof consciousness.
Maintenance Therapy in First-Line Gastric and Gastroesophageal Junction Adenocarcinoma: A Retrospective Analysis
Authors: Walden Daniel , Sonbol Mohamad Bassam , Buckner Petty Skye , Yoon Harry H. , Borad Mitesh , Bekaii-Saab Tanios S. , Ahn Daniel H.
Published: September 2021

Background

Fluoropyrimidine with platinum-based chemotherapy has become the standard of care for advanced gastric and gastroesophageal (GEJ) cancer. Trials in colon cancer show that induction chemotherapy followed by maintenance chemotherapy is an efficacious strategy to maximize clinical response while minimizing toxicity. The current retrospective study aims to evaluate the efficacy and tolerability of maintenance versus continuous treatment in advanced GEJ malignancy.

Methods

A retrospective analysis of patients with metastatic gastric/GEJ adenocarcinoma treated with fluoropyrimidine and platinum chemotherapy between 2007-2017 was performed. Patients who achieved at least stable disease after initial induction treatment were included. After 16 weeks of induction chemotherapy, patients were categorized into the continuous group if induction chemotherapy was continued and the maintenance group if chemotherapy was switched to maintenance fluoropyrimidine monotherapy or observed off treatment. Endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.

Results

In total, 90 patients met the criteria, 48 received continuous therapy, and 42 received maintenance. Baseline characteristics were comparable. No difference in PFS (9.9 vs 8.4 months p = .28) or in OS (16.1 vs 21.3 months p = .75) was observed, including after controlling for the best response on induction therapy and other variables. In patients on continuous induction therapy, there was a higher prevalence of grade three neuropathy (42.6% vs 9.8% p = .001) and neutropenic fever (13% vs 0% p =.03).

Conclusions

Maintenance therapy following induction fluoropyrimidine and platinum-based therapy is associated with an improved toxicity profile and appears to have comparable efficacy to continuous treatment in metastatic gastric/GEJ cancer.