bluuebunny/crossref_metadata_2025 huggingface dataset:
Subgingival Microbiome and Specialized Pro-Resolving Lipid Mediator Pathway Profiles Are Correlated in Periodontal Inflammation
Authors: Lee Chun-Teh , Li Ruoxing , Zhu Lisha , Tribble Gena D. , Zheng W. Jim , Ferguson Brittney , Maddipati Krishna Rao , Angelov Nikola , Van Dyke Thomas E.
Published: June 2021

Failure of resolution pathways in periodontitis is reflected in levels of specialized pro-resolving lipid mediators (SPMs) and SPM pathway markers but their relationship with the subgingival microbiome is unclear. This study aimed to analyze and integrate lipid mediator level, SPM receptor gene expression and subgingival microbiome data in subjects with periodontitis vs. healthy controls. The study included 13 periodontally healthy and 15 periodontitis subjects that were evaluated prior to or after non-surgical periodontal therapy. Samples of gingival tissue and subgingival plaque were collected prior to and 8 weeks after non-surgical treatment; only once in the healthy group. Metabololipidomic analysis was performed to measure levels of SPMs and other relevant lipid mediators in gingiva. qRT-PCR assessed relative gene expression (2-ΔΔCT) of known SPM receptors. 16S rRNA sequencing evaluated the relative abundance of bacterial species in subgingival plaque. Correlations between lipid mediator levels, receptor gene expression and bacterial abundance were analyzed using the Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) and Sparse Partial Least Squares (SPLS) methods. Profiles of lipid mediators, receptor genes and the subgingival microbiome were distinct in the three groups. The strongest correlation existed between lipid mediator profile and subgingival microbiome profile. Multiple lipid mediators and bacterial species were highly correlated (correlation coefficient ≥0.6) in different periodontal conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to healthy controls revealed that one bacterial species, Corynebacterium durum, and five lipid mediators, 5(S)6(R)-DiHETE, 15(S)-HEPE, 7-HDHA, 13-HDHA and 14-HDHA, were identified in both conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to after treatment revealed that one bacterial species, Anaeroglobus geminatus, and four lipid mediators, 5(S)12(S)-DiHETE, RvD1, Maresin 1 and LTB4, were identified in both conditions. Four Selenomonas species were highly correlated with RvD1, RvE3, 5(S)12(S)-DiHETE and proinflammatory mediators in the periodontitis after treatment group. Profiles of lipid mediators, receptor gene and subgingival microbiome are associated with periodontal inflammation and correlated with each other, suggesting inflammation mediated by lipid mediators influences microbial composition in periodontitis. The role of correlated individual lipid mediators and bacterial species in periodontal inflammation have to be further studied.
Taurine Reprograms Mammary-Gland Metabolism and Alleviates Inflammation Induced by Streptococcus uberis in Mice
Authors: Lan Riguo , Wan Zhixin , Xu Yuanyuan , Wang Zhenglei , Fu Shaodong , Zhou Yuanyuan , Lin Xinguang , Han Xiangan , Luo Zhenhua , Miao Jinfeng , Yin Yulong
Published: June 2021

Streptococcus uberis (S. uberis) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK–mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis.
Structure of Blood Coagulation Factor VIII in Complex With an Anti-C2 Domain Non-Classical, Pathogenic Antibody Inhibitor
Authors: Ronayne Estelle K. , Peters Shaun C. , Gish Joseph S. , Wilson Celena , Spencer H. Trent , Doering Christopher B. , Lollar Pete , Spiegel P. Clint , Childers Kenneth C.
Published: June 2021

Factor VIII (fVIII) is a procoagulant protein that binds to activated factor IX (fIXa) on platelet surfaces to form the intrinsic tenase complex. Due to the high immunogenicity of fVIII, generation of antibody inhibitors is a common occurrence in patients during hemophilia A treatment and spontaneously occurs in acquired hemophilia A patients. Non-classical antibody inhibitors, which block fVIII activation by thrombin and formation of the tenase complex, are the most common anti-C2 domain pathogenic inhibitors in hemophilia A murine models and have been identified in patient plasmas. In this study, we report on the X-ray crystal structure of a B domain-deleted bioengineered fVIII bound to the non-classical antibody inhibitor, G99. While binding to G99 does not disrupt the overall domain architecture of fVIII, the C2 domain undergoes an ~8 Å translocation that is concomitant with breaking multiple domain-domain interactions. Analysis of normalized B-factor values revealed several solvent-exposed loops in the C1 and C2 domains which experience a decrease in thermal motion in the presence of inhibitory antibodies. These results enhance our understanding on the structural nature of binding non-classical inhibitors and provide a structural dynamics-based rationale for cooperativity between anti-C1 and anti-C2 domain inhibitors.
Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment
Authors: Scott Ellen N. , Gocher Angela M. , Workman Creg J. , Vignali Dario A. A.
Published: June 2021

Regulatory T cells (Tregs) are key immunosuppressive cells that promote tumor growth by hindering the effector immune response. Tregsutilize multiple suppressive mechanisms to inhibit pro-inflammatory responses within the tumor microenvironment (TME) by inhibition of effector function and immune cell migration, secretion of inhibitory cytokines, metabolic disruption and promotion of metastasis. In turn, Tregsare being targeted in the clinic either alone or in combination with other immunotherapies, in efforts to overcome the immunosuppressive TME and increase anti-tumor effects. However, it is now appreciated that Tregsnot only suppress cells intratumorallyviadirect engagement, but also serve as key interactors in the peritumor, stroma, vasculature and lymphatics to limit anti-tumor immune responses prior to tumor infiltration. We will review the suppressive mechanisms that Tregsutilize to alter immune and non-immune cells outside and within the TME and discuss how these mechanisms collectively allow Tregsto create and promote a physical and biological barrier, resulting in an immune-excluded or limited tumor microenvironment.
Rainfall Erosion Damage of Residual Soil Slope in Intermittently Frozen Area Based on Discrete Element Method
Authors: Ke Yunbin , Chen Yanyu , Jiang Zhenliang , Qiu Yonghui
Published: June 2021

This study developed a discrete element simulation model based on the 2D particle flow code (PFC2D), of which the mesoscopic parameters were calibrated by the indoor experiments, to investigate the rainfall erosion damage of residual soil slope in the intermittently frozen area. It is to be noted that the runoff scouring action was simulated according to the equivalent rainfall method, the soil particles on the slope were given initial velocity, and the water absorption was considered by increasing the unit weight. The results indicated that the scouring action only caused superficial erosion with the main damage region at the foot, regardless of the FT effect. A splitting phenomenon was observed in the lower part of the steeper slope under the FT effect. Moreover, regardless of the FT effect, the gentler slope tended to incur spalling rather than a splitting phenomenon, where the soil particles slid along the structural plane with strong anti-scouring ability. Besides, the gentler slope maintained higher stability and shorter scouring time. Finally, the scouring velocity increased the erosion damage to a large extent.
A Holistic Approach Towards Surface Topography Analyses for Ice Tribology Applications
Authors: Lungevics Janis , Jansons Ernests , Boiko Irina , Velkavrh Igor , Voyer Joël , Wright Thomas
Published: June 2021

A surface texture can be subdivided into three categories based on the magnitude of its wavelengths, i.e., macro-geometrical form, waviness, and roughness (from largest to smallest). Together, these components define how a surface will interact with the opposing surface. In most ice tribology studies, <2% of the entire sample surface is topographically analyzed. Although such a small percentage of the entire surface area generally provides statistically relevant information, the missing information about the texture complexity on a larger scale might reduce the possibility of accurately explaining the resulting tribological behavior. The purpose of this study was to review the existing surface measurement methods related to ice tribology and to present a holistic approach towards surface topography measurements for ice tribology applications. With the holistic surface measurement approach, the entire sample surfaces are scanned, and the measured data is analyzed on different magnitude levels. The discussed approach was applied to sandblasted steel samples which were afterward tested on two different ice tribometers. The experimental results showed that additional information about the sample surface topography enabled a better understanding of the ice friction mechanisms and allowed for a more straightforward correlation between the sample surface topography and its ice friction response.
Application of CRISPR/Cas9 System for Plasmid Elimination and Bacterial Killing of Bacillus cereus Group Strains
Authors: Wang Xiaojing , Lyu Yufei , Wang Siya , Zheng Qingfang , Feng Erling , Zhu Li , Pan Chao , Wang Shenghou , Wang Dongshu , Liu Xiankai , Wang Hengliang
Published: June 2021

The CRISPR-Cas system has been widely applied in prokaryotic genome editing with its high efficiency and easy operation. We constructed some “scissors plasmids” via using the temperature-sensitive pJOE8999 shuttle plasmid, which carry the different 20nt (N20) guiding the Cas9 nuclease as a scissors to break the target DNA. We successfully used scissors plasmids to eliminate native plasmids from Bacillus anthracis and Bacillus cereus, and specifically killed B. anthracis. When curing pXO1 and pXO2 virulence plasmids from B. anthracis A16PI2 and A16Q1, respectively, we found that the plasmid elimination percentage was slightly higher when the sgRNA targeted the replication initiation region (96–100%), rather than the non-replication initiation region (88–92%). We also tried using a mixture of two scissors plasmids to simultaneously eliminate pXO1 and pXO2 plasmids from B. anthracis, and the single and double plasmid-cured rates were 29 and 14%, respectively. To our surprise, when we used the scissor plasmid containing two tandem sgRNAs to cure the target plasmids pXO1 and pXO2 from wild strain B. anthracis A16 simultaneously, only the second sgRNA could guide Cas9 to cleave the target plasmid with high efficiency, while the first sgRNA didn't work in all the experiments we designed. When we used the CRISPR/cas9 system to eliminate the pCE1 mega-virulence plasmid from B. cereus BC307 by simply changing the sgRNA, we also obtained a plasmid-cured isogenic strain at a very high elimination rate (69%). The sterilization efficiency of B. anthracis was about 93%, which is similar to the efficiency of plasmid curing, and there was no significant difference in the efficiency of among the scissors plasmids containing single sgRNA, targeting multi-sites, or single-site targeting and the two tandem sgRNA. This simple and effective curing method, which is applicable to B. cereus group strains, provides a new way to study these bacteria and their virulence profiles.
Biofilm Formation, Production of Matrix Compounds and Biosorption of Copper, Nickel and Lead by Different Bacterial Strains
Authors: Haque Md. Manjurul , Mosharaf Md Khaled , Haque Md. Amdadul , Tanvir Md. Zahid Hasan , Alam Md. Khairul
Published: June 2021

Bacterial biofilms play a key role in metal biosorption from wastewater. Recently, Enterobacter asburiae ENSD102, Enterobacter ludwigii ENSH201, Vitreoscilla sp. ENSG301, Acinetobacter lwoffii ENSG302, and Bacillus thuringiensis ENSW401 were shown to form air–liquid (AL) and solid–air–liquid (SAL) biofilms in a static condition at 28 and 37°C, respectively. However, how environmental and nutritional conditions affect biofilm formation; production of curli and cellulose; and biosorption of copper (Cu), nickel (Ni), and lead (Pb) by these bacteria have not been studied yet. In this study, E. asburiae ENSD102, E. ludwigii ENSH201, and B. thuringiensis ENSW401 developed the SAL biofilms at pH 8, while E. asburiae ENSD102 and Vitreoscilla sp. ENSG301 constructed the SAL biofilms at pH 4. However, all these strains produced AL biofilms at pH 7. In high osmolarity and ½-strength media, all these bacteria built fragile AL biofilms, while none of these strains generated the biofilms in anaerobic conditions. Congo red binding results showed that both environmental cues and bacterial strains played a vital role in curli and cellulose production. Calcofluor binding and spectrophotometric results revealed that all these bacterial strains produced significantly lesser amounts of cellulose at 37°C, pH 8, and in high osmotic conditions as compared to the regular media, at 28°C, and pH 7. Metal biosorption was drastically reduced in these bacteria at 37°C than at 28°C. Only Vitreoscilla sp. ENSG301 and B. thuringiensis ENSW401 completely removed (100%) Cu and Ni at an initial concentration of 12.5 mg l–1, while all these bacteria totally removed (100%) Pb at concentrations of 12.5 and 25 mg l–1 at pH 7 and 28°C. At an initial concentration of 100 mg l–1, the removal of Cu (92.5 to 97.8%) and Pb (89.3 to 98.3%) was the highest at pH 6, while it was higher (84.7 to 93.9%) for Ni at pH 7. Fourier transform infrared spectroscopy results showed metal-unloaded biomass biofilms contained amino, hydroxyl, carboxyl, carbonyl, and phosphate groups. The peak positions of these groups were shifted responding to Cu, Ni, and Pb, suggesting biosorption of metals. Thus, these bacterial strains could be utilized to remove Cu, Ni, and Pb from aquatic environment.
Phycobilins as Potent Food Bioactive Broad-Spectrum Inhibitors Against Proteases of SARS-CoV-2 and Other Coronaviruses: A Preliminary Study
Authors: Pendyala Brahmaiah , Patras Ankit , Dash Chandravanu
Published: June 2021

In the 21st century, we have witnessed three coronavirus outbreaks: SARS in 2003, MERS in 2012, and the ongoing pandemic coronavirus disease 2019 (COVID-19). The search for efficient vaccines and development and repurposing of therapeutic drugs are the major approaches in the COVID-19 pandemic research area. There are concerns about the evolution of mutant strains (e.g., VUI – 202012/01, a mutant coronavirus in the United Kingdom), which can potentially reduce the impact of the current vaccine and therapeutic drug development trials. One promising approach to counter the mutant strains is the “development of effective broad-spectrum antiviral drugs” against coronaviruses. This study scientifically investigates potent food bioactive broad-spectrum antiviral compounds by targeting main protease (Mpro) and papain-like protease (PLpro) proteases of coronaviruses (CoVs) usingin silicoandin vitroapproaches. The results reveal that phycocyanobilin (PCB) shows potential inhibitor activity against both proteases. PCB had the best binding affinity to Mpro and PLpro with IC50values of 71 and 62 μm, respectively. Also,in silicostudies with Mproand PLproenzymes of other human and animal CoVs indicate broad-spectrum inhibitor activity of the PCB. As with PCB, other phycobilins, such as phycourobilin (PUB), phycoerythrobilin (PEB), and phycoviolobilin (PVB) show similar binding affinity to SARS-CoV-2 Mproand PLpro.
Prevalence and Distribution of Listeria monocytogenes in Three Commercial Tree Fruit Packinghouses
Authors: Simonetti Tobin , Peter Kari , Chen Yi , Jin Qing , Zhang Guodong , LaBorde Luke F. , Macarisin Dumitru
Published: June 2021

A 2-year longitudinal study of three tree fruit packinghouses was conducted to determine the prevalence and distribution of Listeria monocytogenes. Samples were collected from 40 standardized non-food-contact surface locations six different times over two 11-month production seasons. Of the 1,437 samples collected, the overall prevalence of L. monocytogenes over the course of the study was 17.5%. Overall prevalence did not differ significantly (p > 0.05) between each year. However, values varied significantly (p ≤ 0.05) within each production season following packing activity levels; increasing in the fall, peaking in early winter, and then decreasing through spring. L. monocytogenes was most often found in the packing line areas, where moisture and fruit debris were commonly observed and less often in dry cold storage and packaging areas. Persistent contamination was attributed to the inability of water drainage systems to prevent moisture accumulation on floors and equipment during peak production times and uncontrolled employee and equipment traffic throughout the facility. This is the first multiyear longitudinal surveillance study to compare L. monocytogenes prevalence at standardized sample sites common to multiple tree fruit packinghouses. Recommendations based on our results will help packinghouse operators to identify critical areas for inclusion in their L. monocytogenes environmental monitoring programs.
Bacteria Isolated From the Antarctic Sponge Iophon sp. Reveals Mechanisms of Symbiosis in Sporosarcina, Cellulophaga, and Nesterenkonia
Authors: Moreno-Pino Mario , Ugalde Juan A. , Valdés Jorge H. , Rodríguez-Marconi Susana , Parada-Pozo Génesis , Trefault Nicole
Published: June 2021

Antarctic sponges harbor a diverse range of microorganisms that perform unique metabolic functions for nutrient cycles. Understanding how microorganisms establish functional sponge–microbe interactions in the Antarctic marine ecosystem provides clues about the success of these ancient animals in this realm. Here, we use a culture-dependent approach and genome sequencing to investigate the molecular determinants that promote a dual lifestyle in three bacterial genera Sporosarcina, Cellulophaga, and Nesterenkonia. Phylogenomic analyses showed that four sponge-associated isolates represent putative novel bacterial species within the Sporosarcina and Nesterenkonia genera and that the fifth bacterial isolate corresponds to Cellulophaga algicola. We inferred that isolated sponge-associated bacteria inhabit similarly marine sponges and also seawater. Comparative genomics revealed that these sponge-associated bacteria are enriched in symbiotic lifestyle-related genes. Specific adaptations related to the cold Antarctic environment are features of the bacterial strains isolated here. Furthermore, we showed evidence that the vitamin B5 synthesis-related gene, panE from Nesterenkonia E16_7 and E16_10, was laterally transferred within Actinobacteria members. Together, these findings indicate that the genomes of sponge-associated strains differ from other related genomes based on mechanisms that may contribute to the life in association with sponges and the extreme conditions of the Antarctic environment.
Characterization of Non-selected Intermolecular Gene Conversion in the Polyploid Haloarchaeon Haloferax volcanii
Authors: Wasser Daniel , Borst Andreas , Hammelmann Mathias , Ludt Katharina , Soppa Jörg
Published: June 2021

Gene conversion is defined as the non-reciprocal transfer of genetic information from one site to a homologous, but not identical site of the genome. In prokaryotes, gene conversion can increase the variance of sequences, like in antigenic variation, but can also lead to a homogenization of sequences, like in the concerted evolution of multigene families. In contrast to these intramolecular mechanisms, the intermolecular gene conversion in polyploid prokaryotes, which leads to the equalization of the multiple genome copies, has hardly been studied. We have previously shown the intermolecular gene conversion in halophilic and methanogenic archaea is so efficient that it can be studied without selecting for conversion events. Here, we have established an approach to characterize unselected intermolecular gene conversion in Haloferax volcanii making use of two genes that encode enzymes involved in carotenoid biosynthesis. Heterozygous strains were generated by protoplast fusion, and gene conversion was quantified by phenotype analysis or/and PCR. It was verified that unselected gene conversion is extremely efficient and it was shown that gene conversion tracts are much longer than in antigenic variation or concerted evolution in bacteria. Two sites were nearly always co-converted when they were 600 bp apart, and more than 30% co-conversion even occurred when two sites were 5 kbp apart. The gene conversion frequency was independent from the extent of genome differences, and even a one nucleotide difference triggered conversion.
What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile
Authors: Brauer Madita , Lassek Christian , Hinze Christian , Hoyer Juliane , Becher Dörte , Jahn Dieter , Sievers Susanne , Riedel Katharina
Published: June 2021

The anaerobic pathogen Clostridioides difficile is perfectly equipped to survive and persist inside the mammalian intestine. When facing unfavorable conditions C. difficile is able to form highly resistant endospores. Likewise, biofilms are currently discussed as form of persistence. Here a comprehensive proteomics approach was applied to investigate the molecular processes of C. difficile strain 630Δerm underlying biofilm formation. The comparison of the proteome from two different forms of biofilm-like growth, namely aggregate biofilms and colonies on agar plates, revealed major differences in the formation of cell surface proteins, as well as enzymes of its energy and stress metabolism. For instance, while the obtained data suggest that aggregate biofilm cells express both flagella, type IV pili and enzymes required for biosynthesis of cell-surface polysaccharides, the S-layer protein SlpA and most cell wall proteins (CWPs) encoded adjacent to SlpA were detected in significantly lower amounts in aggregate biofilm cells than in colony biofilms. Moreover, the obtained data suggested that aggregate biofilm cells are rather actively growing cells while colony biofilm cells most likely severely suffer from a lack of reductive equivalents what requires induction of the Wood-Ljungdahl pathway and C. difficile’s V-type ATPase to maintain cell homeostasis. In agreement with this, aggregate biofilm cells, in contrast to colony biofilm cells, neither induced toxin nor spore production. Finally, the data revealed that the sigma factor SigL/RpoN and its dependent regulators are noticeably induced in aggregate biofilms suggesting an important role of SigL/RpoN in aggregate biofilm formation.
Thermodynamic Analysis for Binding of 4-O-β-tri-N-acetylchitotriosyl Moranoline, a Transition State Analogue Inhibitor for Hen Egg White Lysozyme
Authors: Ogata Makoto , Fukamizo Tamo , Ohnuma Takayuki
Published: June 2021

4-O-β-tri-N-acetylchitotriosyl moranoline (GN3M) is a transition-state analogue for hen egg white lysozyme (HEWL) and identified as the most potent inhibitor till date. Isothermal titration calorimetry experiments provided the thermodynamic parameters for binding of GN3M to HEWL and revealed that the binding is driven by a favorable enthalpy change (ΔH° = −11.0 kcal/mol) with an entropic penalty (−TΔS° = 2.6 kcal/mol), resulting in a free energy change (ΔG°) of −8.4 kcal/mol [Ogata et al. (2013) 288, 6,072–6,082]. Dissection of the entropic term showed that a favorable solvation entropy change (−TΔSsolv° = −9.2 kcal/mol) is its sole contributor. The change in heat capacity (ΔCp°) for the binding of GN3M was determined to be −120.2 cal/K·mol. These results indicate that the bound water molecules play a crucial role in the tight interaction between GN3M and HEWL.
Treatment of Unruptured Vertebral Artery Aneurysm Involving Posterior Inferior Cerebellar Artery With Pipeline Embolization Device
Authors: Fu Weiqi , Ge Huijian , Luo Gang , Meng Xiangyu , Wang Jiejun , Jin Hengwei , Li Youxiang
Published: June 2021

Background: Treatment of unruptured vertebral artery aneurysm involving posterior inferior cerebellar artery (PICA) is challenging. The experience of pipeline embolization device (PED) therapy for these lesions is still limited.

Objective: To evaluate the safety and efficacy of the PED for unruptured vertebral artery aneurysm involving PICA.

Methods: Thirty-two patients with unruptured vertebral artery aneurysm involving PICA underwent treatment with PED were retrospectively identified. Procedure-related complications, PICA patency, clinical, and angiographic outcomes were analyzed.

Results: Thirty-two aneurysms were successfully treated without any procedure-related complications. Images were available in 30 patients (93.8%) during a period of 3–26 months follow-up (average 8.4 months), which confirmed complete occlusion in 17 patients (56.5%), near-complete occlusion in 9 patients (30%), and incomplete occlusion in one patient (3.3%). Parent artery occlusion (PAO) was occurred in 3 patients (10%). Twenty-eight of 30 PICA remained patent. The two occlusions of PICA were secondary to PAO. At a mean of 20.7 months (range 7–50 months) clinical follow-up, all the patients achieved a favorable outcome without any new neurological deficit.

Conclusion: PED seems to be a safe and effective alternative endovascular option for patients with unruptured vertebral artery aneurysm involving PICA.
Contribution of CT-Scan Analysis by Artificial Intelligence to the Clinical Care of TBI Patients
Authors: Brossard Clément , Lemasson Benjamin , Attyé Arnaud , de Busschère Jules-Arnaud , Payen Jean-François , Barbier Emmanuel L. , Grèze Jules , Bouzat Pierre
Published: June 2021

The gold standard to diagnose intracerebral lesions after traumatic brain injury (TBI) is computed tomography (CT) scan, and due to its accessibility and improved quality of images, the global burden of CT scan for TBI patients is increasing. The recent developments of automated determination of traumatic brain lesions and medical-decision process using artificial intelligence (AI) represent opportunities to help clinicians in screening more patients, identifying the nature and volume of lesions and estimating the patient outcome. This short review will summarize what is ongoing with the use of AI and CT scan for patients with TBI.
The Effect of Prior Knowledge of Color on Behavioral Responses and Event-Related Potentials During Go/No-go Task
Authors: Kubo Nami , Watanabe Tatsunori , Chen Xiaoxiao , Matsumoto Takuya , Yunoki Keisuke , Kuwabara Takayuki , Kirimoto Hikari
Published: June 2021

In daily life, the meaning of color plays an important role in execution and inhibition of a motor response. For example, the symbolism of traffic light can help pedestrians and drivers to control their behavior, with the color green/blue meaning go and red meaning stop. However, we don’t always stop with a red light and sometimes start a movement with it in such a situation as drivers start pressing the brake pedal when a traffic light turns red. In this regard, we investigated how the prior knowledge of traffic light signals impacts reaction times (RTs) and event-related potentials (ERPs) in a Go/No-go task. We set up Blue Go/Red No-go and Red Go/Blue No-go tasks with three different go signal (Go) probabilities (30, 50, and 70%), resulting in six different conditions. The participants were told which color to respond (Blue or Red) just before each condition session but didn’t know the Go probability. Neural responses to Go and No-go signals were recorded at Fz, Cz, and Oz (international 10–20 system). We computed RTs for Go signal and N2 and P3 amplitudes from the ERP data. We found that RT was faster when responding to blue than red light signal and also was slower with lower Go probability. Overall, N2 amplitude was larger in Red Go than Blue Go trial and in Red No-go than Blue No-go trial. Furthermore, P3 amplitude was larger in Red No-go than Blue No-go trial. Our findings of RT and N2 amplitude for Go ERPs could indicate the presence of Stroop-like interference, that is a conflict between prior knowledge about traffic light signals and the meaning of presented signal. Meanwhile, the larger N2 and P3 amplitudes in Red No-go trial as compared to Blue No-go trial may be due to years of experience in stopping an action in response to a red signal and/or attention. This study provides the better understanding of the effect of prior knowledge of color on behavioral responses and its underlying neural mechanisms.
Characterizing Network Search Algorithms Developed for Dynamic Causal Modeling
Authors: Aranyi Sándor Csaba , Nagy Marianna , Opposits Gábor , Berényi Ervin , Emri Miklós
Published: June 2021

Dynamic causal modeling (DCM) is a widely used tool to estimate the effective connectivity of specified models of a brain network. Finding the model explaining measured data is one of the most important outstanding problems in Bayesian modeling. Using heuristic model search algorithms enables us to find an optimal model without having to define a model set a priori. However, the development of such methods is cumbersome in the case of large model-spaces. We aimed to utilize commonly used graph theoretical search algorithms for DCM to create a framework for characterizing them, and to investigate relevance of such methods for single-subject and group-level studies. Because of the enormous computational demand of DCM calculations, we separated the model estimation procedure from the search algorithm by providing a database containing the parameters of all models in a full model-space. For test data a publicly available fMRI dataset of 60 subjects was used. First, we reimplemented the deterministic bilinear DCM algorithm in the ReDCM R package, increasing computational speed during model estimation. Then, three network search algorithms have been adapted for DCM, and we demonstrated how modifications to these methods, based on DCM posterior parameter estimates, can enhance search performance. Comparison of the results are based on model evidence, structural similarities and the number of model estimations needed during search. An analytical approach using Bayesian model reduction (BMR) for efficient network discovery is already available for DCM. Comparing model search methods we found that topological algorithms often outperform analytical methods for single-subject analysis and achieve similar results for recovering common network properties of the winning model family, or set of models, obtained by multi-subject family-wise analysis. However, network search methods show their limitations in higher level statistical analysis of parametric empirical Bayes. Optimizing such linear modeling schemes the BMR methods are still considered the recommended approach. We envision the freely available database of estimated model-spaces to help further studies of the DCM model-space, and the ReDCM package to be a useful contribution for Bayesian inference within and beyond the field of neuroscience.
Self-Referential Processing Effects of Non-invasive Brain Stimulation: A Systematic Review
Authors: Bao Zhongjie , Howidi Belal , Burhan Amer M. , Frewen Paul
Published: June 2021

Systematic reviews of neuroimaging studies confirm stimulus-induced activity in response to verbal and non-verbal self-referential processing (SRP) in cortical midline structures, temporoparietal cortex and insula. Whether SRP can be causally modulated by way of non-invasive brain stimulation (NIBS) has also been investigated in several studies. Here we summarize the NIBS literature including 27 studies of task-based SRP comparing response between verbal and non-verbal SRP tasks. The studies differed in design, experimental tasks and stimulation parameters. Results support the role of left inferior parietal lobule (left IPL) in verbal SRP and for the medial prefrontal cortex when valenced stimuli were used. Further, results support roles for the bilateral parietal lobe (IPL, posterior cingulate cortex), the sensorimotor areas (the primary sensory and motor cortex, the premotor cortex, and the extrastriate body area) and the insula in non-verbal SRP (bodily self-consciousness). We conclude that NIBS may differentially modulate verbal and non-verbal SRP by targeting the corresponding brain areas.
A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population
Authors: Swart Patricia C. , van den Heuvel Leigh L. , Lewis Cathryn M. , Seedat Soraya , Hemmings Sian M. J.
Published: June 2021

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10–6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke’s pseudo R2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R2 = 0.00856, p = 0.0367) and PCL-5 score (R2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke’s pseudo R2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.
Cannabinoid Modulation of Dopamine Release During Motivation, Periodic Reinforcement, Exploratory Behavior, Habit Formation, and Attention
Authors: Oleson Erik B. , Hamilton Lindsey R. , Gomez Devan M.
Published: June 2021

Motivational and attentional processes energize action sequences to facilitate evolutionary competition and promote behavioral fitness. Decades of neuropharmacology, electrophysiology and electrochemistry research indicate that the mesocorticolimbic DA pathway modulates both motivation and attention. More recently, it was realized that mesocorticolimbic DA function is tightly regulated by the brain’s endocannabinoid system and greatly influenced by exogenous cannabinoids—which have been harnessed by humanity for medicinal, ritualistic, and recreational uses for 12,000 years. Exogenous cannabinoids, like the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol, produce their effects by acting at binding sites for naturally occurring endocannabinoids. The brain’s endocannabinoid system consists of two G-protein coupled receptors, endogenous lipid ligands for these receptor targets, and several synthetic and metabolic enzymes involved in their production and degradation. Emerging evidence indicates that the endocannabinoid 2-arachidonoylglycerol is necessary to observe concurrent increases in DA release and motivated behavior. And the historical pharmacology literature indicates a role for cannabinoid signaling in both motivational and attentional processes. While both types of behaviors have been scrutinized under manipulation by either DA or cannabinoid agents, there is considerably less insight into prospective interactions between these two important signaling systems. This review attempts to summate the relevance of cannabinoid modulation of DA release during operant tasks designed to investigate either motivational or attentional control of behavior. We first describe how cannabinoids influence DA release and goal-directed action under a variety of reinforcement contingencies. Then we consider the role that endocannabinoids might play in switching an animal’s motivation from a goal-directed action to the search for an alternative outcome, in addition to the formation of long-term habits. Finally, dissociable features of attentional behavior using both the 5-choice serial reaction time task and the attentional set-shifting task are discussed along with their distinct influences by DA and cannabinoids. We end with discussing potential targets for further research regarding DA-cannabinoid interactions within key substrates involved in motivation and attention.
Interplay Between Exercise and Gut Microbiome in the Context of Human Health and Performance
Authors: Clauss Matthieu , Gérard Philippe , Mosca Alexis , Leclerc Marion
Published: June 2021

Gut microbiota and exercise have recently been shown to be interconnected. Both moderate and intense exercise are typically part of the training regimen of endurance athletes, but they exert different effects on health. Moderate exercise has positive effects on the health of average athletes, such as a reduction in inflammation and intestinal permeability and an improvement in body composition. It also induces positive changes in the gut microbiota composition and in the microbial metabolites produced in the gastrointestinal tract. Conversely, intense exercise can increase gastrointestinal epithelial wall permeability and diminish gut mucus thickness, potentially enabling pathogens to enter the bloodstream. This, in turn, may contribute to the increase in inflammation levels. However, elite athletes seem to have a higher gut microbial diversity, shifted toward bacterial species involved in amino acid biosynthesis and carbohydrate/fiber metabolism, consequently producing key metabolites such as short-chain fatty acids. Moreover, rodent studies have highlighted a bidirectional relationship, with exercise impacting the gut microbiota composition while the microbiota may influence performance. The present review focuses on gut microbiota and endurance sports and how this interconnection depends upon exercise intensity and training. After pointing out the limits of the studies so far available, we suggest that taking into account the microbiota composition and its metabolic contribution to human host health could help in monitoring and modulating athletes' health and performance. Such an integrated approach should help in the design of microbiome-based solutions for health or performance.
TRP Channels Interactome as a Novel Therapeutic Target in Breast Cancer
Authors: Saldías María Paz , Maureira Diego , Orellana-Serradell Octavio , Silva Ian , Lavanderos Boris , Cruz Pablo , Torres Camila , Cáceres Mónica , Cerda Oscar
Published: June 2021

Breast cancer is one of the most frequent cancer types worldwide and the first cause of cancer-related deaths in women. Although significant therapeutic advances have been achieved with drugs such as tamoxifen and trastuzumab, breast cancer still caused 627,000 deaths in 2018. Since cancer is a multifactorial disease, it has become necessary to develop new molecular therapies that can target several relevant cellular processes at once. Ion channels are versatile regulators of several physiological- and pathophysiological-related mechanisms, including cancer-relevant processes such as tumor progression, apoptosis inhibition, proliferation, migration, invasion, and chemoresistance. Ion channels are the main regulators of cellular functions, conducting ions selectively through a pore-forming structure located in the plasma membrane, protein–protein interactions one of their main regulatory mechanisms. Among the different ion channel families, the Transient Receptor Potential (TRP) family stands out in the context of breast cancer since several members have been proposed as prognostic markers in this pathology. However, only a few approaches exist to block their specific activity during tumoral progress. In this article, we describe several TRP channels that have been involved in breast cancer progress with a particular focus on their binding partners that have also been described as drivers of breast cancer progression. Here, we propose disrupting these interactions as attractive and potential new therapeutic targets for treating this neoplastic disease.
PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells
Authors: Bi Fangfang , An Yuanyuan , Sun Tianshui , You Yue , Yang Qing
Published: June 2021

Background

Platinum-based chemotherapy is the first line option for ovarian cancer. The development of resistance to such chemotherapy results in treatment failure, while the underlying mechanisms are poorly understood.

Methods

Clinical samples were collected from Shengjing Hospital of China Medical University. MTT assay was used to see the proliferation and chemoresistance of ovarian cancer cells. Transwell migration and Matrigel invasion assays was used to see the invasion ability of ovarian cancer cells. In addition, polysome profiling and tissue microarray and immunohistochemical staining were also used. The statistical significance of the difference was analyzed by ANOVA and post hoc Dunnett’s test.

Results

PHGDH is the first enzyme responsible for serine biosynthesis pathway. The current study demonstrated that PHGDH is upregulated in platin-resistant ovarian cancer cells and tissues at the protein level. Importantly, knockdown of PHGDH suppressed, while overexpression of PHGDH increased the survival upon cisplatin exposure, invasiveness and spheroid formation of ovarian cancer cells. The current study demonstrated that PHGDH translation was upregulated in platin-resistant ovarian cancer. In addition, our study provided evidence that LncRNA RMRP (RNA Component of Mitochondrial RNA Processing Endoribonuclease) was upregulated in platin-resistant ovarian cancer, which promoted enrichment of RNA binding protein DDX3X (DEAD-Box Helicase 3 X-Linked) on the PHGDH mRNA to promote its translation.

Conclusion

Collectively, the current study described that PHGDH was upregulated and conferred resistance of ovarian cancer cells to cisplatin, suggesting that cisplatin resistance could be overcome by targeting PHGDH. Our study also provided evidence that differential PHGDH protein expression was defined by its translation, and RNA binding protein DDX3X and LncRNA RMRP are regulators of its translation.
Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo
Authors: Shi Xiaodan , Zhang Yuanyuan , Xie Xiaomeng , Pang Mengjun , Laster Kyle , Li Jian , Ma Xinli , Liu Kangdong , Dong Zigang , Kim Dong Joon
Published: June 2021

Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used clinically for the treatment of osteoporosis. However, the anticancer activity of Ipriflavone and its molecular mechanisms in the context of esophageal squamous cell carcinoma (ESCC) have not been investigated. In this study, we report that Ipriflavone is a novel mammalian target of rapamycin (mTOR) inhibitor that suppresses cell proliferation and induces cell apoptosis in ESCC cells. Ipriflavone inhibited anchorage-dependent and -independent growth of ESCC cells. Ipriflavone induced G1 phase cell cycle arrest and intrinsic cell apoptosis by activating caspase 3 and increasing the expression of cytochrome c. Based on the results of in vitro screening and cell-based assays, Ipriflavone inhibited mTOR signaling pathway through directly targeting mTOR. Knockdown of mTOR strongly inhibited the growth of ESCC cells, and the cell growth inhibitory effect exerted by Ipriflavone was found to be dependent upon mTOR signaling pathway. Remarkably, Ipriflavone strongly inhibited ESCC patient-derived xenograft tumor growth in an in vivo mouse model. Our findings suggest that Ipriflavone is an mTOR inhibitor that could be potentially useful for treating ESCC.
Insights Into the Function and Clinical Application of HDAC5 in Cancer Management
Authors: Yang Jun , Gong Chaoju , Ke Qinjian , Fang Zejun , Chen Xiaowen , Ye Ming , Xu Xi
Published: June 2021

Histone deacetylase 5 (HDAC5) is a class II HDAC. Aberrant expression of HDAC5 has been observed in multiple cancer types, and its functions in cell proliferation and invasion, the immune response, and maintenance of stemness have been widely studied. HDAC5 is considered as a reliable therapeutic target for anticancer drugs. In light of recent findings regarding the role of epigenetic reprogramming in tumorigenesis, in this review, we provide an overview of the expression, biological functions, regulatory mechanisms, and clinical significance of HDAC5 in cancer.
Expression and Prognostic Significance of PD-L2 in Diffuse Large B-Cell Lymphoma
Authors: Gu Qianhui , Li Jing , Chen Zhuolin , Zhang Jie , Shen Hui , Miao Xiaobing , Zhou Ying , Xu Xiaohong , He Song
Published: June 2021

Recent studies suggest that programmed death ligand-2 (PD-L2) constitutes an important antitumor immune response. Here, we investigated the relationship between PD-L2 expression and clinicopathological features in diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry showed that positive expression of PD-L2 was observed in 45 of 181 newly diagnosed patients, including 14 cases with expression exclusively on tumor cells (TCs) and 31 cases with the expression on both TCs and immune cells (ICs) in the tumor microenvironment (TME). In 21 recurrent patients, positive expression of PD-L2 was present in six cases, including two cases with expression exclusively on TCs, and four cases with the expression on both TCs and ICs in the TME. Patients with PD-L2 tumor proportion score (TPS) ≥1% exhibited a better ECOG performance status (PS) (ECOG PS score <2, P = 0.041), lower international prognostic index (IPI) score (P < 0.001), and early Ann Arbor stage (Ann Arbor stage I or II, P = 0.010). Similarly, patients with PD-L2 immune proportion score (IPS) ≥1% also exhibited a better ECOG PS (ECOG PS score < 2, P = 0.006) and lower IPI score (P = 0.001). Survival analysis showed that patients with PD-L2 TPS ≥1% exhibited prolonged overall survival (OS) and progression-free survival (PFS). However, survival analysis showed no prognostic significance based on expression of PD-L2 on ICs in the TME. TC PD-L2 expression was significantly associated with OS (P = 0.041) and PFS (P = 0.001). In the multivariate analysis, TC PD-L2 expression was an independent prognostic risk factor for PFS (P = 0.013), but not for OS (P = 0.249). Furthermore, we found that higher TC and IC PD-L2 expression was associated with higher objective response rate (ORR). Moreover, we demonstrated that the expression level of PD-L2 was positively correlated with the expression status of M1 macrophage markers CD86. Our findings highlight PD-L2 as a promising therapeutic target in DLBCL.