bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Liver Inflammation and Fibrosis by Interleukin-37
Authors: Mountford Steffeni , Effenberger Maria , Noll-Puchta Heidi , Griessmair Lucas , Ringleb Andrea , Haas Sonja , Denk Gerald , Reiter Florian P. , Mayr Doris , Dinarello Charles A. , Tilg Herbert , Bufler Philip
Published: March 2021

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis.

Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity.

Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis.

Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.
Diet, Immunity, and Microbiota Interactions: An Integrative Analysis of the Intestine Transcriptional Response and Microbiota Modulation in Gilthead Seabream (Sparus aurata) Fed an Essential Oils-Based Functional Diet
Authors: Firmino Joana P. , Vallejos-Vidal Eva , Balebona M. Carmen , Ramayo-Caldas Yuliaxis , Cerezo Isabel M. , Salomón Ricardo , Tort Lluis , Estevez Alicia , Moriñigo Miguel Ángel , Reyes-López Felipe E. , Gisbert Enric
Published: March 2021

Essential oils (EOs) are promising alternatives to chemotherapeutics in animal production due to their immunostimulant, antimicrobial, and antioxidant properties, without associated environmental or hazardous side effects. In the present study, the modulation of the transcriptional immune response (microarray analysis) and microbiota [16S Ribosomal RNA (rRNA) sequencing] in the intestine of the euryhaline fish gilthead seabream (Sparus aurata) fed a dietary supplementation of garlic, carvacrol, and thymol EOs was evaluated. The transcriptomic functional analysis showed the regulation of genes related to processes of proteolysis and inflammatory modulation, immunity, transport and secretion, response to cyclic compounds, symbiosis, and RNA metabolism in fish fed the EOs-supplemented diet. Particularly, the activation of leukocytes, such as acidophilic granulocytes, was suggested to be the primary actors of the innate immune response promoted by the tested functional feed additive in the gut. Fish growth performance and gut microbiota alpha diversity indices were not affected, while dietary EOs promoted alterations in bacterial abundances in terms of phylum, class, and genus. Subtle, but significant alterations in microbiota composition, such as the decrease in Bacteroidia and Clostridia classes, were suggested to participate in the modulation of the intestine transcriptional immune profile observed in fish fed the EOs diet. Moreover, regarding microbiota functionality, increased bacterial sequences associated with glutathione and lipid metabolisms, among others, detected in fish fed the EOs supported the metabolic alterations suggested to potentially affect the observed immune-related transcriptional response. The overall results indicated that the tested dietary EOs may promote intestinal local immunity through the impact of the EOs on the host-microbial co-metabolism and consequent regulation of significant biological processes, evidencing the crosstalk between gut and microbiota in the inflammatory regulation upon administration of immunostimulant feed additives.
Complement and Chlamydia psittaci: Non-Myeloid-Derived C3 Predominantly Induces Protective Adaptive Immune Responses in Mouse Lung Infection
Authors: Kohn Martin , Lanfermann Christian , Laudeley Robert , Glage Silke , Rheinheimer Claudia , Klos Andreas
Published: March 2021

Recent advances in complement research have revolutionized our understanding of its role in immune responses. The immunomodulatory features of complement in infections by intracellular pathogens, e.g., viruses, are attracting increasing attention. Thereby, local production and activation of complement by myeloid-derived cells seem to be crucial. We could recently show that C3, a key player of the complement cascade, is required for effective defense against the intracellular bacteriumChlamydia psittaci. Avian zoonotic strains of this pathogen cause life-threatening pneumonia with systemic spread in humans; closely related non-avian strains are responsible for less severe diseases of domestic animals with economic loss. To clarify how far myeloid- and non-myeloid cell-derived complement contributes to immune response and resulting protection againstC. psittaci, adoptive bone marrow transfer experiments focusing on C3 were combined with challenge experiments using a non-avian (BSL 2) strain of this intracellular bacterium. Surprisingly, our data prove that forC. psittaci-induced pneumonia in mice, non-myeloid-derived, circulating/systemic C3 has a leading role in protection, in particular on the development of pathogen-specific T- and B- cell responses. In contrast, myeloid-derived and most likely locally produced C3 plays only a minor, mainly fine-tuning role. The work we present here describes authentic, although less pronounced, antigen directed immune responses.
The Characterization of Disease Severity Associated IgG Subclasses Response in COVID-19 Patients
Authors: Luo Huanle , Jia Tingting , Chen Jiamin , Zeng Shike , Qiu Zengzhao , Wu Shu , Li Xu , Lei Yuxuan , Wang Xin , Wu Weihua , Zhang Renli , Zou Xuan , Feng Tiejian , Ding Ruxia , Zhang Yue , Chen Yao-Qing , Sun Caijun , Wang Tian , Fang Shisong , Shu Yuelong
Published: March 2021

Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1β was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.
Variation in Seagrass-Associated Macroinvertebrate Communities Along the Gulf Coast of Peninsular Florida: An Exploration of Patterns and Ecological Consequences
Authors: Barry Savanna C. , Hyman A. Challen , Jacoby Charles A. , Reynolds Laura K. , Kowalewski Michal , Frazer Thomas K.
Published: March 2021

Seagrasses form vast meadows of structurally complex habitat that support faunal communities with greater numbers of species and individuals than nearby unstructured habitats. The Gulf coast of peninsular Florida represents a natural laboratory ideally suited to the study of processes that shape seagrass-associated invertebrate and fish communities within meadows of a single species of seagrass, Thalassia testudinum. This suitability arises from a pronounced structural and chemical gradient that exists over ecologically relevant spatial and temporal scales, as revealed by extensive monitoring of water quality and seagrass. We hypothesized that seagrass-associated invertebrate communities would vary across five estuarine systems spread along a spatial gradient in phosphorus concentration, an important driver of seagrass and phytoplankton growth in this region. The quantitative results based on data acquired at 25 stations (75 samples, 52,086 specimens, and 161 taxa) indicated that each of the five estuarine systems were distinct with regard to species composition and differences among systems were driven by abundant or relatively common species. In addition, we found evidence to indicate food webs in seagrass meadows along this gradient may differ, especially in the relative dominance of algal grazers and predatory invertebrates. These changes in species composition and trophic roles could be driven by phosphorus directly, through increases in rates of primary production with higher concentrations of phosphorus, or indirectly, through nutrient-mediated changes in the physical structure of the seagrass canopy. Our results suggest that differences in the habitat created by T. testudinum under differing phosphorus supplies lead to ecologically significant shifts in macroinvertebrate communities.
Using Gaming Technology to Explore and Visualize Management Impacts on Marine Ecosystems
Authors: Steenbeek Jeroen , Felinto Dalai , Pan Mike , Buszowski Joe , Christensen Villy
Published: March 2021

We have developed an approach that connects a complex and widely used scientific ecosystem modeling approach with a game engine for real-time communication and visualization of scientific results. The approach, OceanViz, focuses on communicating scientific data to non-scientific audiences to foster dialogue, offering experimental, immersive approaches to visualizing complex ecosystems whilst avoiding information overload. Within the context of ecosystem-based fisheries management, OceanViz can engage decision makers into the implicit operation of scientific software as an aid during the decision process, and it can be of direct use for public communication through appealing and informative visualizations. Beside a server-client architecture to centralize decision making around an ecosystem model, OceanViz includes an extensive visualization toolkit capable of accurately reflecting marine ecosystem changes through a simulated three-dimensional (3D) underwater environment. Here we outline the ideas and concepts that went into OceanViz, its implementation and its related challenges. We reflect on challenges to scientific visualization and communication as food-for-thought for the marine ecosystem modeling community and beyond.
Convolutional Neural Network for Skin Lesion Classification: Understanding the Fundamentals Through Hands-On Learning
Authors: Cullell-Dalmau Marta , Noé Sergio , Otero-Viñas Marta , Meić Ivan , Manzo Carlo
Published: March 2021

Deep learning architectures for the classification of images have shown outstanding results in a variety of disciplines, including dermatology. The expectations generated by deep learning for, e.g., image-based diagnosis have created the need for non-experts to become familiar with the working principles of these algorithms. In our opinion, getting hands-on experience with these tools through a simplified but accurate model can facilitate their understanding in an intuitive way. The visualization of the results of the operations performed by deep learning algorithms on dermatological images can help students to grasp concepts like convolution, even without an advanced mathematical background. In addition, the possibility to tune hyperparameters and even to tweak computer code further empower the reach of an intuitive comprehension of these processes, without requiring advanced computational and theoretical skills. This is nowadays possible thanks to recent advances that have helped to lower technical and technological barriers associated with the use of these tools, making them accessible to a broader community. Therefore, we propose a hands-on pedagogical activity that dissects the procedures to train a convolutional neural network on a dataset containing images of skin lesions associated with different skin cancer categories. The activity is available open-source and its execution does not require the installation of software. We further provide a step-by-step description of the algorithm and of its functions, following the development of the building blocks of the computer code, guiding the reader through the execution of a realistic example, including the visualization and the evaluation of the results.
The Transcriptomic and Bioinformatic Characterizations of Iron Acquisition and Heme Utilization in Avibacterium paragallinarum in Response to Iron-Starvation
Authors: Huo Caiyun , Zeng Ximin , Xu Fuzhou , Li Fangbing , Li Donghai , Li Guiping , Hu Zhenguo , Hu Yanxin , Lin Jun , Sun Huiling
Published: March 2021

Avibacterium paragallinarum is the pathogen of infectious coryza, which is a highly contagious respiratory disease of chickens that brings a potentially serious threat to poultry husbandry. Iron is an important nutrient for bacteria and can be obtained from surroundings such as siderophores and hemophores. To date, the mechanisms of iron acquisition and heme utilization as well as detailed regulation in A. paragallinarum have been poorly understood. In this study, we investigated the transcriptomic profiles in detail and the changes of transcriptomes induced by iron restriction in A. paragallinarum using RNA-seq. Compared with the iron-sufficiency control group, many more differentially expressed genes (DEGs) and cellular functions as well as signaling pathways were verified in the iron-restriction group. Among these DEGs, the majority of genes showed decreased expression and some were found to be uniquely present in the iron-restriction group. With an in-depth study of bioinformatic analyses, we demonstrated the crucial roles of the Hut protein and DUF domain-containing proteins, which were preferentially activated in bacteria following iron restriction and contributed to the iron acquisition and heme utilization. Consequently, RT-qPCR results further verified the iron-related DEGs and were consistent with the RNA-seq data. In addition, several novel sRNAs were present in A. paragallinarum and had potential regulatory roles in iron homeostasis, especially in the regulation of Fic protein to ensure stable expression. This is the first report of the molecular mechanism of iron acquisition and heme utilization in A. paragallinarum from the perspective of transcriptomic profiles. The study will contribute to a better understanding of the transcriptomic response of A. paragallinarum to iron starvation and also provide novel insight into the development of new antigens for potential vaccines against infectious coryza by focusing on these iron-related genes.
Nile Red Incubation Time Before Reading Fluorescence Greatly Influences the Yeast Neutral Lipids Quantification
Authors: Ramírez-Castrillón Mauricio , Jaramillo-Garcia Victoria P. , Lopes Barros Helio , Pegas Henriques João A. , Stefani Valter , Valente Patricia
Published: March 2021

High-throughput screening methodologies to estimate lipid content in oleaginous yeasts use Nile red fluorescence in a given solvent and optimized excitation/emission wavelengths. However, Nile red fluorescence stabilization has been poorly analyzed, and high variability occurs when relative fluorescence is measured immediately or a few minutes after dye addition. The aim of this work was to analyze the fluorescence of Nile red at different incubation times using a variety of solvents and oleaginous/non-oleaginous yeast strains. We showed that fluorescence stabilization occurs between 20 and 30 min, depending on the strain and solvent. Therefore, we suggest that fluorescence measurements should be followed until stabilization, where Relative Fluorescence Units should be considered after stabilization for lipid content estimation.
Predictive Metagenomic Analysis of Autoimmune Disease Identifies Robust Autoimmunity and Disease Specific Microbial Signatures
Authors: Volkova Angelina , Ruggles Kelly V.
Published: March 2021

Within the last decade, numerous studies have demonstrated changes in the gut microbiome associated with specific autoimmune diseases. Due to differences in study design, data quality control, analysis and statistical methods, many results of these studies are inconsistent and incomparable. To better understand the relationship between the intestinal microbiome and autoimmunity, we have completed a comprehensive re-analysis of 42 studies focusing on the gut microbiome in 12 autoimmune diseases to identify a microbial signature predictive of multiple sclerosis (MS), inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and general autoimmune disease using both 16S rRNA sequencing data and shotgun metagenomics data. To do this, we used four machine learning algorithms, random forest, eXtreme Gradient Boosting (XGBoost), ridge regression, and support vector machine with radial kernel and recursive feature elimination to rank disease predictive taxa comparing disease vs. healthy participants and pairwise comparisons of each disease. Comparing the performance of these models, we found the two tree-based methods, XGBoost and random forest, most capable of handling sparse multidimensional data, to consistently produce the best results. Through this modeling, we identified a number of taxa consistently identified as dysregulated in a general autoimmune disease model includingOdoribacter, Lachnospiraceae Clostridium, andMogibacteriaceaeimplicating all as potential factors connecting the gut microbiome to autoimmune response. Further, we computed pairwise comparison models to identify disease specific taxa signatures highlighting a role forPeptostreptococcaceaeandRuminococcaceae Gemmigerin IBD andAkkermansia, Butyricicoccus, and Mogibacteriaceaein MS. We then connected a subset of these taxa with potential metabolic alterations based on metagenomic/metabolomic correlation analysis, identifying 215 metabolites associated with autoimmunity-predictive taxa.
Elevated β-Carotene Production Using Codon-Adapted CarRA&B and Metabolic Balance in Engineered Yarrowia lipolytica
Authors: Liu Liang , Qu Yu Ling , Dong Gui Ru , Wang Jing , Hu Ching Yuan , Meng Yong Hong
Published: March 2021

β-carotene is a precursor of vitamin A and has multiple physiological functions. Producing β-carotene by microbial fermentation has attracted much attention to consumers’ preference for natural products. This study focused on improving β-carotene production by constructing codon-adapted genes and minimizing intermediate accumulation. The codon-adapted CarRA and CarB genes from the industrial strain of Blakeslea trispora were integrated into the genome of the Yarrowia lipolytica to construct YL-C0, the baseline strain for producing β-carotene. Thereafter, the β-carotene biosynthetic pathway’s metabolic balance was accurately regulated to reduce the intermediates’ accumulation. Notably, the β-carotene content increased by 21 times to reach 12.5 dry cell weight (DCW) mg/g when minimizing HMG-CoA and FPP accumulation. Further, we improved the expression levels of the CarRA and CarB genes to minimize the accumulation of phytoene and lycopene. Total production of β-carotene of 1.7 g/L and 21.6 mg/g DCW was achieved. These results reveal that the rate-limiting enzymes CarRA and CarB of B. trispora exhibited higher catalytic activity than the same enzymes from other microorganisms. Promoting metabolic balance by minimizing the accumulation of intermediates is a very effective strategy for increasing β-carotene. The β-carotene-producing strain constructed in this study has established the foundation for its potential use in industrial production. These successful engineering strategies also provide a foundation for large-scale production of other terpenoids.
Quercetin Inhibits Biofilm Formation by Decreasing the Production of EPS and Altering the Composition of EPS in Staphylococcus epidermidis
Authors: Mu Yongqi , Zeng Hong , Chen Wei
Published: March 2021

Staphylococcus epidermidis is an opportunistic pathogen, and its biofilm formation ability is an important virulent factor. Quercetin, a typical flavonoid ubiquitously used in dietary supplementation, is known for its antioxidant property, but its anti-biofilm activity against S. epidermidis remains unknown. In this study, the anti-biofilm activity of quercetin was investigated using S. epidermidis ATCC35984, a strong biofilm-positive strain. An attempt was made to disclose the mechanisms of the anti-biofilm activity of quercetin. S. epidermidis exhibited a less cell surface hydrophobicity after quercetin treatment. Also, quercetin effectively inhibited S. epidermidis cells from adhering to the glass slides. Quercetin downregulated the intercellular adhesion (ica) locus and then polysaccharide intercellular adhesin (PIA) production was reduced. Therefore, S. epidermidis cells became less hydrophobic, which supported quercetin’s anti-biofilm effect. Our study suggests that quercetin from plants be given further attention as a potential anti-biofilm agent against the biofilm formation of S. epidermidis, even biofilm infections of other bacteria.
The Surge of Hypervirulent ST398 MRSA Lineage With Higher Biofilm-Forming Ability Is a Critical Threat to Clinics
Authors: Lu Huiying , Zhao Lin , Si Yuanguo , Jian Ying , Wang Yanan , Li Tianming , Dai Yingxin , Huang Qian , Ma Xiaowei , He Lei , Li Min
Published: March 2021

The global increase of community-associated (CA) infections with methicillin-resistant Staphylococcus aureus (MRSA) is a major healthcare problem. Although sequence type (ST) 398 MRSA was first described as a livestock-associated (LA) lineage, human-adapted MRSA (HO-MRSA) ST398 without livestock contact has subsequently been reported from China in our previous study and other later research. The proportion of ST398 HO-MRSA has also remarkably increased in recent years in China. Based on 3878 S. aureus isolates that were collected in a general hospital between 2008 and 2018, we identified 56 ST398 HO-MRSA isolates. The four early appearing isolates of them have been sequenced by whole-genome sequencing (WGS) in our previous study. Here, by usage of WGS on the later-appearing 52 isolates and analyzing the phylogenetic dynamics of the linage, we found that 50 isolates clustered together with the former 4 isolates, making it a main clade out of MSSA clones and other MRSA clones, although ST398 HO-MRSA evolved with multiple origins. Drug resistance and virulence gene analysis based on the WGS data demonstrated that ST398 HO-MRSA main clade exhibited a similar pattern in both parts. Furthermore, they all carried a conserved variant of prophage 3 to guarantee virulence and a short SCCmec type V element of class D to maintain considerable lower methicillin resistance. Further phenotypical research verified that the epidemic HO-MRSA ST398 displayed enhanced biofilm formation ability when keeping high virulence. The dual advantages of virulence and biofilm formation in the HO-MRSA ST398 subtype promote their fitness in the community and even in the healthcare environment, which poses a serious threat in clinical S. aureus infections. Therefore, further surveillance is required to prevent and control the problematic public health impact of HO-MRSA ST398 in the future.
Assessment of the Concordance and Diagnostic Accuracy Between Elecsys and Lumipulse Fully Automated Platforms and Innotest
Authors: Dakterzada Farida , López-Ortega Ricard , Arias Alfonso , Riba-Llena Iolanda , Ruiz-Julián Maria , Huerto Raquel , Tahan Nuria , Piñol-Ripoll Gerard
Published: March 2021

Manual ELISA assays are the most commonly used methods for quantification of biomarkers; however, they often show inter- and intra-laboratory variability that limits their wide use. Here, we compared the Innotest ELISA method with two fully automated platforms (Lumipulse and Elecsys) to determine whether these new methods can provide effective substitutes for ELISA assays. We included 149 patients with AD (n = 34), MCI (n = 94) and non-AD dementias (n = 21). Aβ42, T-tau, and P-tau were quantified using the ELISA method (Innotest, Fujirebio Europe), CLEIA method on a Lumipulse G600II (Fujirebio Diagnostics), and ECLIA method on a Cobas e 601 (Roche Diagnostics) instrument. We found a high correlation between the three methods, although there were systematic differences between biomarker values measured by each method. Both Lumipulse and Elecsys methods were highly concordant with clinical diagnoses, and the combination of Lumipulse Aβ42 and P-tau had the highest discriminating power (AUC 0.915, 95% CI 0.822–1.000). We also assessed the agreement of AT(N) classification for each method with AD diagnosis. Although differences were not significant, the use of Aβ42/Aβ40 ratio instead of Aβ42 alone in AT(N) classification enhanced the diagnostic accuracy (AUC 0.798, 95% CI 0.649–0.947 vs. AUC 0.778, 95% CI 0.617–0.939). We determined the cut-offs for the Lumipulse and Elecsys assays based on the Aβ42/Aβ40 ratio ± status as a marker of amyloid pathology, and these cut-offs were consistent with those recommended by manufacturers, which had been determined based on visual amyloid PET imaging or diagnostic accuracy. Finally, the biomarker ratios (P-tau/Aβ42 and T-tau/Aβ42) were more consistent with the Aβ42/Aβ40 ratio for both Lumipulse and Elecsys methods, and Elecsys P-tau/Aβ42 had the highest consistency with amyloid pathology (AUC 0.994, 95% CI 0.986–1.000 and OPA 96.4%) at the ≥0.024 cut-off. The Lumipulse and Elecsys cerebrospinal fluid (CSF) AD assays showed high analytical and clinical performances. As both automated platforms were standardized for reference samples, their use is recommended for the measurement of CSF AD biomarkers compared with unstandardized manual methods, such as Innotest ELISA, that have demonstrated a high inter and intra-laboratory variability.
The Membrane Interaction of Alpha-Synuclein
Authors: Liu Cencen , Zhao Yunfei , Xi Huan , Jiang Jie , Yu Yang , Dong Wei
Published: March 2021

A presynaptic protein closely related to Parkinson's disease (PD), α-synuclein (α-Syn), has been studied extensively regarding its pathogenic mechanisms. As a physiological protein in presynapses, however, α-Syn's physiological function remains unclear. Its location in nerve terminals and effects on membrane fusion also imply its functional role in synaptic transmission, including its possible interaction with high-curvature membranes via its N-terminus and amorphous C-terminus. PD-related mutants that disrupt the membrane interaction (e.g., A30P and G51D) additionally suggest a relationship between α-Syn's pathogenic mechanisms and physiological roles through the membrane binding. Here, we summarize recent research on how α-Syn and its variants interact with membranes and influence synaptic transmission. We list several membrane-related connections between the protein's physiological function and the pathological mechanisms that stand to expand current understandings of α-Syn.
Effects of a 4-Step Standard Operating Procedure for the Treatment of Fever in Patients With Acute Stroke
Authors: Lee Hanna , Hedtmann Günter , Schwab Stefan , Kollmar Rainer
Published: March 2021

Background and Purpose: Fever in the acute phase of stroke leads to an unfavorable clinical outcome and increased mortality. However, no specific form of effective fever treatment has been established, so far. We analyzed the effectiveness of our in-house standard operating procedure (SOP) of fever treatment.

Methods: This SOP was analyzed for a period of 33 weeks. Patients with cerebral ischemia (ischemic stroke, transient ischemic attack) or cerebral hemorrhage (intracerebral, subarachnoid) and body temperature elevation of ≥ 37.5°C within the first 6 days after admission were eligible for inclusion in the analysis. The results of SOP group, who's data have been collected prospectively were then compared with a historical control group that had been treated conventionally 1 year earlier in the same period. The data of control group have been collected in retrospect. The primary endpoint was the total duration of the fever for the first 6 days after admission to the stroke unit.

Results: A total of 130 patients (mean age of 78 ± 12) received 370 antipyretic interventions. Sequential application of paracetamol (n = 245), metamizole (n = 53) and calf compress (n = 15) led to significant reduction in body temperature. In patients who did not respond to these applications, normothermia could be achieved after infusion of the cooled saline solution. Normothermia could be achieved within 120 min in more than 90% of the cases treated by the SOP. The SOP reduced the fever duration in the 6 days significantly, from 12.2 ± 2.7 h [95% confidence interval (CI) for mean] in the control group to 3.9 ± 1.0 h (95% CI) in the SOP group (p < 0.001). The SOP was rated to be reasonable and effective.

Conclusion: Our in-house SOP is cost-efficient and effective for fever treatment in stroke patients, that can be implemented by local health care professionals.
Neuroimaging Markers of Mal de Débarquement Syndrome
Authors: Cha Yoon Hee , Ding Lei , Yuan Han
Published: March 2021

Mal de débarquement syndrome (MdDS) is a motion-induced disorder of oscillating vertigo that persists after the motion has ceased. The neuroimaging characteristics of the MdDS brain state have been investigated with studies on brain metabolism, structure, functional connectivity, and measurements of synchronicity. Baseline metabolism and resting-state functional connectivity studies indicate that a limbic focus in the left entorhinal cortex and amygdala may be important in the pathology of MdDS, as these structures are hypermetabolic in MdDS and exhibit increased functional connectivity to posterior sensory processing areas and reduced connectivity to the frontal and temporal cortices. Both structures are tunable with periodic stimulation, with neurons in the entorhinal cortex required for spatial navigation, acting as a critical efferent pathway to the hippocampus, and sending and receiving projections from much of the neocortex. Voxel-based morphometry measurements have revealed volume differences between MdDS and healthy controls in hubs of multiple resting-state networks including the default mode, salience, and executive control networks. In particular, volume in the bilateral anterior cingulate cortices decreases and volume in the bilateral inferior frontal gyri/anterior insulas increases with longer duration of illness. Paired with noninvasive neuromodulation interventions, functional neuroimaging with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and simultaneous fMRI-EEG have shown changes in resting-state functional connectivity that correlate with symptom modulation, particularly in the posterior default mode network. Reduced parieto-occipital connectivity with the entorhinal cortex and reduced long-range fronto-parieto-occipital connectivity correlate with symptom improvement. Though there is a general theme of desynchronization correlating with reduced MdDS symptoms, the prediction of optimal stimulation parameters for noninvasive brain stimulation in individuals with MdDS remains a challenge due to the large parameter space. However, the pairing of functional neuroimaging and noninvasive brain stimulation can serve as a probe into the biological underpinnings of MdDS and iteratively lead to optimal parameter space identification.
Handgrip Based Action Information Modulates Attentional Selection: An ERP Study
Authors: Kumar Sanjay , Riddoch M. Jane , Humphreys Glyn W.
Published: March 2021

Prior work shows that the possibility of action to an object (visual affordance) facilitates attentional deployment. We sought to investigate the neural mechanisms underlying this modulation of attention by examining ERPs to target objects that were either congruently or incongruently gripped for their use in the presence of a congruently or incongruently gripped distractor. Participants responded to the presence or absence of a target object matching a preceding action word with a distractor object presented in the opposite location. Participants were faster in responding to congruently gripped targets compared to incongruently gripped targets. There was a reduced N2pc potential when the target was congruently gripped, and the distractor was incongruently gripped compared to the conditions where targets were incongruently gripped or when the distractor, as well as target, was congruently gripped. The N2pc results indicate that target selection is easier when action information is congruent with an object’s use.
The Impacts of Age and Sex in a Mouse Model of Childhood Narcolepsy
Authors: Coffey Alissa A. , Joyal Adam A. , Yamanaka Akihiro , Scammell Thomas E.
Published: March 2021

Narcolepsy is a sleep disorder caused by selective death of the orexin neurons that often begins in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, episodes of paralysis during wakefulness. Cataplexy is often worse when narcolepsy develops in children compared to adults, but the reason for this difference remains unknown. We usedorexin-tTA; TetO DTAmice to model narcolepsy at different ages. When doxycycline is removed from the diet, the orexin neurons of these mice express diphtheria toxin A and die within 2–3 weeks. We removed doxycycline at 4 weeks (young-onset) or 14 weeks (adult-onset) of age in male and female mice. We implanted electroencephalography (EEG) and electromyography (EMG) electrodes for sleep recordings two weeks later and then recorded EEG/EMG/video for 24 h at 3 and 13 weeks after removal of doxycycline. Age-matched controls had access to doxycycline diet for the entire experiment. Three weeks after doxycycline removal, both young-onset and adult-onset mice developed severe cataplexy and the sleep-wake fragmentation characteristic of narcolepsy. Cataplexy and maintenance of wake were no worse in young-onset compared to adult-onset mice, but female mice had more bouts of cataplexy than males. Orexin neuron loss was similarly rapid in both young- and adult-onset mice. As age of orexin neuron loss does not impact the severity of narcolepsy symptoms in mice, the worse symptoms in children with narcolepsy may be due to more rapid orexin neuron loss than in adults.
The Altered Functional Connectivity With Pain Features Integration and Interaction in Migraine Without Aura
Authors: Tian Zilei , Yin Tao , Xiao Qingqing , Dong Xiaohui , Yang Yunhong , Wang Menglin , Ha Guodong , Chen Jiyao , Liang Fanrong , Zeng Fang , Lan Lei
Published: March 2021

Introduction

Migraine without aura (MwoA) is a primary type of migraine, a common disabling disorder, and a disabling neurological condition. The headache is a complex experience, a common form of pain, in which multiple sensory information dimensions are combined to provide a unified conscious event. Migraine ictal have unique neuroimage biomarkers, but the brain is also affected during the inter-ictal phase. According to the current studies, a hypothesis was constructed that the altered integration of pain spatial and intensity information impacts headache intensity in the inter-ictal period.

Methods

In this study, we applied theory-based region-to-region functional connectivity (FC) analyses to compare the differences in resting-state FC between MwoA participants and healthy controls with the pain integration hypothesis. After the correlation matrices between FC edges and clinical symptoms were constructed, the moderating effect and simple slope tests were investigated to explain whether and how the dysfunction of pain features discrimination affects the clinical symptoms.

Results

Functional connectivity analyses showed significantly decreased FC edges between the left dorsolateral superior frontal gyrus (SFGdor) and left insula, and an increased FC edge between the left SFGdor and bilateral angular gyrus. The correlation matrix showed no significant correlation between significantly altered FC edge and headache duration, frequency, Zung self-rating anxiety scale, and Zung self-rating depression scale. Only one significantly altered edge in the MwoA condition was significantly correlated with headache intensity. Moderating Module 1 and 2 manifested the moderator variable (altered rs-FC edge) moderated the link between the normal edges and headache intensity.

Conclusion

The pain features integration processes in migraineurs vary from HCs, related to the clinical symptoms during a migraine attack. Moreover, the clinical symptoms will be affected by one or more discrimination modules. And the spatial or intensity discrimination modules have a higher impact when combined with another module on clinical symptoms than the single module.
Circulating MicroRNAs and Long Non-coding RNAs as Potential Diagnostic Biomarkers for Parkinson’s Disease
Authors: Yang Yimin , Li Yanhua , Yang Hongmei , Guo Jianxing , Li Nan
Published: March 2021

Parkinson’s disease (PD) is the world’s second most common neurodegenerative disease that is associated with age. With the aging of the population, patients with PD are increasing in number year by year. Most such patients lose their ability to self-care with disease progression, which brings an incalculable burden to individual families and society. The pathogenesis of PD is complex, and its clinical manifestations are diverse. Therefore, it is of great significance to screen for circulating biomarkers associated with PD to reveal its pathogenesis and develop objective diagnostic methods so as to prevent, control, and treat the disease. In recent years, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are considered to be effective biomarkers for various diseases due to their stability, and resistance to RNAase digestion and extreme conditions in circulating fluids. Here, we review recent advances in the detection of abnormally expressed miRNAs and lncRNAs in PD circulating fluids, and discuss the function and molecular mechanisms of plasma or serum miR-124, miR-132, miR-29, miR-221, miR-7, miR-433, and miR-153 in the regulation and progression of PD. Additionally, application of the differential expression of lncRNAs in circulating fluid in the pathological progression and diagnosis of PD is also reviewed. In short, the determination of abnormally expressed circulating miRNAs and lncRNAs will be valuable for the future diagnosis and treatment of PD.
Case Report: Intercostal Lymph Node Metastasis: A Case Report and Review of the Literature
Authors: Zhou Yurong , Hou Jinxuan , Meng Ning , Daniel Staiculescu , Chen Jiang , Xu Liying
Published: March 2021

The axillary lymph nodes are the primary group responsible for lymphatic drainage in the breast and, consequently, are the most common location for breast cancer metastasis. However, lymphatic pathways running from the breast, via intercostal spaces, to parasternal lymph vessels have also been identified. According to the American Joint Committee on Cancer eighth edition manual, regional lymph node metastasis normally travels to the ipsilateral axillary, supraclavicular, subclavicular, and internal mammary lymph nodes. The presence of intercostal metastasis is out the range of these regional lymph nodes. It is very rare for intercostal lymph nodes to be the extra-axillary site of metastasis in breast cancer, and it has been little reported on in the literature. Despite its rarity, it has the capacity to adversely affect the prognosis of breast cancer and drastically influence treatment choice. Here, we analyze such a case, with a patient receiving a radical mastectomy and metastatic intercostal lymph node dissection due to the presence of intercostal lymph node metastasis indicated via MRI. Furthermore, the potential application of preoperative 3-dimensional (3D) visualization and surgical planning is also discussed.
Baseline Serum C-Reactive Protein and Plasma Fibrinogen-Based Score in the Prediction of Survival in Glioblastoma
Authors: Wach Johannes , Apallas Stefanos , Schneider Matthias , Güresir Agi , Schuss Patrick , Herrlinger Ulrich , Vatter Hartmut , Güresir Erdem
Published: March 2021

Objective: The present study investigates a score based on baseline C-reactive protein (CRP) and fibrinogen values (FC score) in 173 consecutive glioblastoma (GBM) patients.

Methods: The optimal cut-off value for fibrinogen and CRP was defined as 3.5 g/dl and 3.0 mg/L, respectively, according to previous reports. Patients with elevated CRP and fibrinogen were classified with a score of 2, those with an elevation of only one of these parameters were allocated a score of 1, and those without any abnormalities were assigned a score of 0.

Results: No significant differences in age, gender, tumor area, molecular pathology, physical status, or extent of resection were identified among the three groups defined by this score. Univariate survival analysis demonstrated that a high baseline FC score (≥1) is significantly associated with a shortened overall survival (OS) (HR: 1.52, 95% CI: 1.05–2.20, p = 0.027). A multivariate Cox regression analysis considering age (>65/≤65), extent of resection (GTR/STR), MGMT promoter status (hypermethylated/non-hypermethylated), and FC score (0/≥1) confirmed that an elevated FC score (≥1) is an independent predictor of shortened OS (HR: 1.71, 95% CI: 1.16–2.51, p = 0.006).

Conclusions: The baseline fibrinogen and CRP score thus serves as an independent predictor of OS in GBM. Further investigations of the role of inflammation in the prediction of a prognosis are needed.
Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity
Authors: Olorundare Olufunke Esan , Adeneye Adejuwon Adewale , Akinsola Akinyele Olubiyi , Ajayi Abayomi Mayowa , Agede Olalekan Ayodele , Soyemi Sunday Sokunle , Mgbehoma Alban Ikenna , Okoye Ikechukwu Innocent , Albrecht Ralph M. , Ntambi James Mukasa , Crooks Peter Anthony
Published: March 2021

Trastuzumab (TZM) is useful in the clinical management of HER2-positive metastatic breast, gastric, and colorectal carcinoma but has been limited by its off-target cardiotoxicity. This study investigates the therapeutic potentials of 0.25 mg/kg/day amlodipine, 0.035 mg/kg/day lisinopril, 5 mg/kg/day valsartan, and their fixed-dose combinations in TZM-intoxicated Wistar rats that were randomly allotted into 10 groups of 6 rats for each group. Group I rats were treated with 10 ml/kg/day sterile water orally and 1 ml/kg/day sterile water intraperitoneally; Groups II, III, and IV rats were orally gavaged with 5 mg/kg/day valsartan and 1 ml/kg/day sterile water intraperitoneally, 0.25 mg/kg/day amlodipine and 1 ml/kg/day sterile water via the intraperitoneal route, 0.035 mg/kg/day lisinopril and 1 ml/kg/day sterile water administered intraperitoneally, respectively. Group V rats were orally treated with 10 ml/kg/day of sterile water prior to intraperitoneal administration of 2.25 mg/kg/day of TZM. Groups VI–VIII rats were equally pretreated with 5 mg/kg/day valsartan, 0.25 mg/kg/day amlodipine, and 0.035 mg/kg/day lisinopril before intraperitoneal 2.25 mg/kg/day TZM treatment, respectively; Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day amlodipine +0.035 mg/kg/day lisinopril and 5 mg/kg/day valsartan +0.035 mg/kg/day lisinopril, respectively, before TZM treatment. Cardiac injury and tissue oxidative stress markers, complete lipids profile, histopathological, and immunohistochemical assays were the evaluating endpoints. Results showed that repeated TZM treatments caused profound increases in the serum TG and VLDL-c levels, serum cTnI and LDH levels, and cardiac tissue caspase-3 and -9 levels but decreased BCL-2 expression. TZM also profoundly attenuated CAT, SOD, GST and GPx activities, and increased MDA levels in the treated tissues. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, the altered biochemical, histopathological, and immunohistochemical changes were reversed with amlodipine, lisinopril, valsartan, and fixed-dose combinations, although fixed-dose valsartan/lisinopril combination was further associated with hyperlipidemia and increased AI and CRI values and coronary artery cartilaginous metaplasia. Thus, the promising therapeutic potentials of amlodipine, lisinopril, valsartan and their fixed-dose combinations in the management of TZM cardiotoxicity, majorly mediated via antiapoptotic and oxidative stress inhibition mechanisms were unveiled through this study.
Kaempferol Alleviates Oxidative Stress and Apoptosis Through Mitochondria-dependent Pathway During Lung Ischemia-Reperfusion Injury
Authors: Yang Chunli , Yang Wenkai , He Zhaohui , Guo Jinghua , Yang Xiaogang , Wang Rongsheng , Li Hongbo
Published: March 2021

In previous study, we reported that kaempferol ameliorates significantly lung ischemia-reperfusion injury (LIRI), and may be achieved by targeting the SIRT 1 pathway. This study further explored the anti-LIRI mechanism of kaempferol. In vitro, the rat alveolar epithelial cells L2 was cultured and subjected to anoxia/reoxygenation (A/R) insult. In vivo, SD rats were operated to establish LIRI model. The related indicators of oxidative stress and apoptosis in L2 cells and rats lung tissues were detected. Results showed that kaempferol pre-treatment significantly increased the cell viability, improved mitochondrial membrane potential, inhibited the opening of mitochondrial permeability transition pores, reduced the levels of oxidative stress and apoptosis, increased the expressions of Bcl-2 and mitochondrial cytochrome c, and decreased the expressions of Bax and cytoplasmic cytochrome c in L2 cells after A/R insult. In vivo, kaempferol improved the pathological injury, inhibited the levels of oxidative stress and apoptosis, increased the expressions of Bcl-2 and mitochondrial cytochrome c, and decreased the expressions of Bax and cytoplasmic cytochrome c in rats lung tissues after I/R. However, the aforementioned effects of kaempferol were significantly attenuated by the SIRT 1 inhibitor EX527 or the PGC-1α inhibitor SR-18292. What’s more, SR-18292 has not reversed the effect of kaempferol on increasing the protein activity of SIRT 1. Above results suggest that kaempferol ameliorates LIRI by improving mitochondrial function, reducing oxidative stress and inhibiting cell apoptosis. Its molecular mechanism of action includes the SIRT 1/PGC-1α/mitochondria signaling pathway.