bluuebunny/crossref_metadata_2025 huggingface dataset:
A Coagulation-Related Gene-Based Prognostic Model for Invasive Ductal Carcinoma
Authors: Li Jing , Du Jiajia , Wang Yanhong , Jia Hongyan
Published: September 2021

Background: Invasive ductal carcinoma (IDC) is the most common type of metastatic breast cancer. Due to the lack of valuable molecular biomarkers, the diagnosis and prognosis of IDC remain a challenge. A large number of studies have confirmed that coagulation is positively correlated with angiogenesis-related factors in metastatic breast cancer. Therefore, the purpose of this study was to construct a COAGULATION-related genes signature for IDC using the bioinformatics approaches.

Methods: The 50 hallmark gene sets were obtained from the molecular signature database (MsigDB) to conduct Gene Set Variation Analysis (GSVA). Gene Set Enrichment Analysis (GSEA) was applied to analyze the enrichment of HALLMARK_COAGULATION. The COAGULATION-related genes were extracted from the gene set. Then, Limma Package was used to identify the differentially expressed COAGULATION-related genes (DECGs) between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) samples in GSE26340 data set. A total of 740 IDC samples from The Cancer Genome Atlas (TCGA) database were divided into a training set and a validation set (7:3). The univariate and multivariate Cox regression analyses were performed to construct a risk signature, which divided the IDC samples into the high- and low-risk groups. The overall survival (OS) curve and receiver operating characteristic (ROC) curve were drawn in both training set and validation set. Finally, a nomogram was constructed to predict the 1-, 2-, 3-, 4-, and 5-year survival rates of IDC patients. Quantitative real-time fluorescence PCR (qRT-PCR) was performed to verify the expression levels of the prognostic genes.

Results: The “HALLMARK_COAGULATION” was significantly activated in IDC. There was a significant difference in the clinicopathological parameters between the DCIS and IDC patients. Twenty-four DECGs were identified, of which five genes (SERPINA1, CAPN2, HMGCS2, MMP7, and PLAT) were screened to construct the prognostic model. The high-risk group showed a significantly lower survival rate than the low-risk group both in the training set and validation set (p=3.5943e-06 and p=0.014243). The risk score was demonstrated to be an independent predictor of IDC prognosis. A nomogram including risk score, pathological_stage, and pathological_N provided a quantitative method to predict the survival probability of 1-, 2-, 3-, 4-, and 5-year in IDC patients. The results of decision curve analysis (DCA) further demonstrated that the nomogram had a high potential for clinical utility.

Conclusion: This study established a COAGULATION-related gene signature and showed its prognostic value in IDC through a comprehensive bioinformatics analysis, which may provide a potential new prognostic mean for patients with IDC.
Transcriptome Responses of Atlantic Salmon (Salmo salar L.) to Viral and Bacterial Pathogens, Inflammation, and Stress
Authors: Krasnov Aleksei , Johansen Lill-Heidi , Karlsen Christian , Sveen Lene , Ytteborg Elisabeth , Timmerhaus Gerrit , Lazado Carlo C. , Afanasyev Sergey
Published: September 2021

Transcriptomics provides valuable data for functional annotations of genes, the discovery of biomarkers, and quantitative assessment of responses to challenges. Meta-analysis of Nofima’s Atlantic salmon microarray database was performed for the selection of genes that have shown strong and reproducible expression changes. Using data from 127 experiments including 6440 microarrays, four transcription modules (TM) were identified with a total of 902 annotated genes: 161 virus responsive genes – VRG (activated with five viruses and poly I:C), genes that responded to three pathogenic bacteria (523 up and 33 down-regulated genes), inflammation not caused by infections – wounds, melanized foci in skeletal muscle and exposure to PAMP (180 up and 72 down-regulated genes), and stress by exercise, crowding and cortisol implants (33 genes). To assist the selection of gene markers, genes in each TM were ranked according to the scale of expression changes. In terms of functional annotations, association with diseases and stress was unknown or not reflected in public databases for a large part of genes, including several genes with the highest ranks. A set of multifunctional genes was discovered. Cholesterol 25-hydroxylase was present in all TM and 22 genes, including most differentially expressed matrix metalloproteinases 9 and 13 were assigned to three TMs. The meta-analysis has improved understanding of the defense strategies in Atlantic salmon. VRG have demonstrated equal or similar responses to RNA (SAV, IPNV, PRV, and ISAV), and DNA (gill pox) viruses, injection of bacterial DNA (plasmid) and exposure of cells to PAMP (CpG and gardiquimod) and relatively low sensitivity to inflammation and bacteria. Genes of the highest rank show preferential expression in erythrocytes. This group includes multigene families (gig and several trim families) and many paralogs. Of pathogen recognition receptors, only RNA helicases have shown strong expression changes. Most VRG (82%) are effectors with a preponderance of ubiquitin-related genes, GTPases, and genes of nucleotide metabolism. Many VRG have unknown roles. The identification of TMs makes possible quantification of responses and assessment of their interactions. Based on this, we are able to separate pathogen-specific responses from general inflammation and stress.
Changes in B Cell Pool of Patients With Multibacillary Leprosy: Diminished Memory B Cell and Enhanced Mature B in Peripheral Blood
Authors: Nogueira Otto Castro , Gandini Mariana , Cabral Natasha , de Figueiredo Vilma , Rodrigues-da-Silva Rodrigo Nunes , Lima-Junior Josué da Costa , Pinheiro Roberta Olmo , Pereira Geraldo Moura Batista , Pessolani Maria Cristina Vidal , de Macedo Cristiana Santos
Published: September 2021

Despite being treatable, leprosy still represents a major public health problem, and many mechanisms that drive leprosy immunopathogenesis still need to be elucidated. B cells play important roles in immune defense, being classified in different subgroups that present distinct roles in the immune response. Here, the profile of B cell subpopulations in peripheral blood of patients with paucibacillary (TT/BT), multibacillary (LL/BL) and erythema nodosum leprosum was analyzed. B cell subpopulations (memory, transition, plasmablasts, and mature B cells) and levels of IgG were analyzed by flow cytometry and ELISA, respectively. It was observed that Mycobacterium leprae infection can alter the proportions of B cell subpopulations (increase of mature and decrease of memory B cells) in patients affected by leprosy. This modulation is associated with an increase in total IgG and the patient’s clinical condition. Circulating B cells may be acting in the modulation of the immune response in patients with various forms of leprosy, which may reflect the patient’s ability to respond to M. leprae.
Risk Stratification Model for Predicting the Overall Survival of Elderly Triple-Negative Breast Cancer Patients: A Population-Based Study
Authors: Liu Xiaozhu , Yue Song , Huang Haodong , Duan Minjie , Zhao Binyi , Liu Jin , Xiang Tianyu
Published: September 2021

Background: The objective of this study was to evaluate the prognostic value of clinical characteristics in elderly patients with triple-negative breast cancer (TNBC).

Methods: The cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) program dating from 2010 to 2015. Univariate and multivariate analyses were performed using a Cox proportional risk regression model, and a nomogram was constructed to predict the 1-, 3-, and 5-year prognoses of elderly patients with TNBC. A concordance index (C-index), calibration curve, and decision curve analysis (DCA) were used to verify the nomogram.

Results: The results of the study identified a total of 5,677 patients who were randomly divided 6:4 into a training set (n = 3,422) and a validation set (n = 2,255). The multivariate analysis showed that age, race, grade, TN stage, chemotherapy status, radiotherapy status, and tumor size at diagnosis were independent factors affecting the prognosis of elderly patients with TNBC. Together, the 1 -, 3 -, and 5-year nomograms were made up of 8 variables. For the verification of these results, the C-index of the training set and validation set were 0.757 (95% CI 0.743–0.772) and 0.750 (95% CI 0.742–0.768), respectively. The calibration curve also showed that the actual observation of overall survival (OS) was in good agreement with the prediction of the nomograms. Additionally, the DCA showed that the nomogram had good clinical application value. According to the score of each patient, the risk stratification system of elderly patients with TNBC was further established by perfectly dividing these patients into three groups, namely, low risk, medium risk, and high risk, in all queues. In addition, the results showed that radiotherapy could improve prognosis in the low-risk group (P = 0.00056), but had no significant effect in the medium-risk (P < 0.4) and high-risk groups (P < 0.71). An online web app was built based on the proposed nomogram for convenient clinical use.

Conclusion: This study was the first to construct a nomogram and risk stratification system for elderly patients with TNBC. The well-established nomogram and the important findings from our study could guide follow-up management strategies for elderly patients with TNBC and help clinicians improve individual treatment.
A Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans – A Promising Future Therapy?
Authors: White Hayden , Heffernan Aaron J. , Worrall Simon , Grunsfeld Alexander , Thomas Matt
Published: September 2021

Therapeutic ketosis is traditionally induced with dietary modification. However, owing to the time delay involved, this is not a practical approach for treatment of acute conditions such as traumatic brain injury. Intravenous administration of ketones would obviate this problem by rapidly inducing ketosis. This has been confirmed in a number of small animal and human studies. Currently no such commercially available product exists. The aim of this systematic review is to review the safety and efficacy of intravenous beta-hydroxybutyrate. The Web of Science, PubMed and EMBASE databases were searched, and a systematic review undertaken. Thirty-five studies were included. The total beta-hydroxybutyrate dose ranged from 30 to 101 g administered over multiple doses as a short infusion, with most studies using the racemic form. Such dosing achieves a beta-hydroxybutyrate concentration >1 mmol/L within 15 min. Infusions were well tolerated with few adverse events. Blood glucose concentrations occasionally were reduced but remained within the normal reference range for all study participants. Few studies have examined the effect of intravenous beta-hydroxybutyrate in disease states. In patients with heart failure, intravenous beta-hydroxybutyrate increased cardiac output by up to 40%. No studies were conducted in patients with neurological disease. Intravenous beta-hydroxybutyrate has been shown to increase cerebral blood flow and reduce cerebral glucose oxidation. Moreover, beta-hydroxybutyrate reduces protein catabolism and attenuates the production of counter-regulatory hormones during induced hypoglycemia. An intravenous beta-hydroxybutyrate formulation is well tolerated and may provide an alternative treatment option worthy of further research in disease states.
Distinct Endophytic Bacterial Communities Inhabiting Seagrass Seeds
Authors: Tarquinio Flavia , Attlan Océane , Vanderklift Mathew A. , Berry Oliver , Bissett Andrew
Published: September 2021

Seagrasses are marine angiosperms that can live completely or partially submerged in water and perform a variety of significant ecosystem services. Like terrestrial angiosperms, seagrasses can reproduce sexually and, the pollinated female flower develop into fruits and seeds, which represent a critical stage in the life of plants. Seed microbiomes include endophytic microorganisms that in terrestrial plants can affect seed germination and seedling health through phytohormone production, enhanced nutrient availability and defence against pathogens. However, the characteristics and origins of the seagrass seed microbiomes is unknown. Here, we examined the endophytic bacterial community of six microenvironments (flowers, fruits, and seeds, together with leaves, roots, and rhizospheric sediment) of the seagrass Halophila ovalis collected from the Swan Estuary, in southwestern Australia. An amplicon sequencing approach (16S rRNA) was used to characterize the diversity and composition of H. ovalis bacterial microbiomes and identify core microbiome bacteria that were conserved across microenvironments. Distinct communities of bacteria were observed within specific seagrass microenvironments, including the reproductive tissues (flowers, fruits, and seeds). In particular, bacteria previously associated with plant growth promoting characteristics were mainly found within reproductive tissues. Seagrass seed-borne bacteria that exhibit growth promoting traits, the ability to fix nitrogen and anti-pathogenic potential activity, may play a pivotal role in seed survival, as is common for terrestrial plants. We present the endophytic community of the seagrass seeds as foundation for the identification of potential beneficial bacteria and their selection in order to improve seagrass restoration.
A Review of Using Mathematical Modeling to Improve Our Understanding of Bacteriophage, Bacteria, and Eukaryotic Interactions
Authors: Styles Kathryn M. , Brown Aidan T. , Sagona Antonia P.
Published: September 2021

Phage therapy, the therapeutic usage of viruses to treat bacterial infections, has many theoretical benefits in the ‘post antibiotic era.’ Nevertheless, there are currently no approved mainstream phage therapies. One reason for this is a lack of understanding of the complex interactions between bacteriophage, bacteria and eukaryotic hosts. These three-component interactions are complex, with non-linear or synergistic relationships, anatomical barriers and genetic or phenotypic heterogeneity all leading to disparity between performance and efficacy in in vivo versus in vitro environments. Realistic computer or mathematical models of these complex environments are a potential route to improve the predictive power of in vitro studies for the in vivo environment, and to streamline lab work. Here, we introduce and review the current status of mathematical modeling and highlight that data on genetic heterogeneity and mutational stochasticity, time delays and population densities could be critical in the development of realistic phage therapy models in the future. With this in mind, we aim to inform and encourage the collaboration and sharing of knowledge and expertise between microbiologists and theoretical modelers, synergising skills and smoothing the road to regulatory approval and widespread use of phage therapy.
Functional Characterization of a L-2-Haloacid Dehalogenase From Zobellia galactanivorans DsijT Suggests a Role in Haloacetic Acid Catabolism and a Wide Distribution in Marine Environments
Authors: Grigorian Eugénie , Groisillier Agnès , Thomas François , Leblanc Catherine , Delage Ludovic
Published: September 2021

L-2-halocid dehalogenases (L-2-HADs) have been mainly characterized from terrestrial polluted environments. By contrast, knowledge is still scarce about their role in detoxification of predominant halocarbons in marine environments. Here, phylogenetic analyses showed a wide diversity of homologous L-2-HADs, especially among those belonging to marine bacteria. Previously characterized terrestrial L-2-HADs were part of a monophyletic group (named group A) including proteins of terrestrial and marine origin. Another branch (named group B) contained mostly marine L-2-HADs, with two distinct clades of Bacteroidetes homologs, closely linked to Proteobacteria ones. This study further focused on the characterization of the only L-2-HAD from the flavobacterium Zobellia galactanivorans DsijT (ZgHAD), belonging to one of these Group B clades. The recombinant ZgHAD was shown to dehalogenate bromo- and iodoacetic acids, and gene knockout in Z. galactanivorans revealed a direct role of ZgHAD in tolerance against both haloacetic acids. Analyses of metagenomic and metatranscriptomic datasets confirmed that L-2-HADs from group A were well-represented in terrestrial and marine bacteria, whereas ZgHAD homologs (group B L-2-HADs) were mainly present in marine bacteria, and particularly in host-associated species. Our results suggest that ZgHAD homologs could be key enzymes for marine Bacteroidetes, by conferring selective advantage for the recycling of toxic halogen compounds produced in particular marine habitats, and especially during interactions with macroalgae.
Quantitative Proteomic Analysis for High- and Low-Aflatoxin-Yield Aspergillus flavus Strains Isolated From Natural Environments
Authors: Li Tao , Zhang Zhaowei , Wang Yu , Li Ying , Zhu Jiang , Hu Rui , Yang Yunhuang , Liu Maili
Published: September 2021

The molecular mechanisms underlying aflatoxin production have been well-studied in strains of the fungus Aspergillus flavus (A. flavus) under artificial conditions. However, aflatoxin biosynthesis has rarely been studied in A. flavus strains isolated from field conditions with different aflatoxin-producing ability. In the present study, tandem mass tag (TMT) labeling and high-performance liquid chromatography (HPLC) coupled with tandem-mass spectrometry analysis were used for proteomic quantification in natural isolates of high- and low-aflatoxin-yield A. flavus strains. Additionally, findings obtained using the TMT-labeling method were validated using the high-resolution multiple reaction monitoring (MRM-HR) method. In total, 4,363 proteins were quantified, among which 1,045 proteins were differentially expressed between the high- and low-aflatoxin-yield A. flavus strains. Bioinformatics analysis showed that the up-regulated proteins were significantly enriched in carbon-related metabolism and the biosynthesis of secondary metabolites, whereas the down-regulated proteins were enriched in oxidative phosphorylation. Moreover, GST proteins were found to be significantly down-regulated in high-yield A. flavus strains; this result contradicted previous findings obtained from A. flavus strains grown under artificial conditions. In summary, our study provides novel insights into aflatoxin regulation in A. flavus under field conditions and could facilitate the development of various strategies for the effective control of aflatoxin contamination in food crops.
Rapid Real-Time Polymerase Chain Reaction for Salmonella Serotyping Based on Novel Unique Gene Markers by Pangenome Analysis
Authors: Yang Seung-Min , Kim Eiseul , Kim Dayoung , Kim Hyeon-Be , Baek Jiwon , Ko Seyoung , Kim Donghyuk , Yoon Hyunjin , Kim Hae-Yeong
Published: September 2021

An accurate diagnostic method for Salmonella serovars is fundamental to preventing the spread of associated diseases. A diagnostic polymerase chain reaction (PCR)-based method has proven to be an effective tool for detecting pathogenic bacteria. However, the gene markers currently used in real-time PCR to detect Salmonella serovars have low specificity and are developed for only a few serovars. Therefore, in this study, we explored the novel unique gene markers for 60 serovars that share similar antigenic formulas and show high prevalence using pangenome analysis and developed a real-time PCR to detect them. Before exploring gene markers, the 535 Salmonella genomes were evaluated, and some genomes had serovars different from the designated serovar information. Based on these analyses, serovar-specific gene markers were explored. These markers were identified as genes present in all strains of target serovar genomes but absent in strains of other serovar genomes. Serovar-specific primer pairs were designed from the gene markers, and a real-time PCR method that can distinguish between 60 of the most common Salmonella serovars in a single 96-well plate assay was developed. As a result, real-time PCR showed 100% specificity for 199 Salmonella and 29 non-Salmonella strains. Subsequently, the method developed was applied successfully to both strains with identified serovars and an unknown strain, demonstrating that real-time PCR can accurately detect serovars of strains compared with traditional serotyping methods, such as antisera agglutination. Therefore, our method enables rapid and economical Salmonella serotyping compared with the traditional serotyping method.
Modeling the Performance of Full-Scale Anaerobic Biochemical System Treating Deinking Pulp Wastewater Based on Modified Anaerobic Digestion Model No. 1
Authors: Huang Yifeng , Ma Yongwen , Wan Jinquan , Wang Yan
Published: September 2021

The deinking pulp (DIP) is a main resource for paper making, and the wastewater from DIP process needs to be treated. Anaerobic biochemical technique has been widely applied in DIP wastewater treatment, due to the remarkable capability in reducing high chemical oxygen demand (COD). In this study, a mathematical simulation model was established to investigate the performance of a full-scale anaerobic biochemical system for treating DIP wastewater. The model was based on Anaerobic Digestion Model No. 1 (ADM1), which was modified according to the specific anaerobic digestion process for DIP wastewater treatment. The hydrodynamic behavior of a full-scale anaerobic biochemical system was considered in this model. The characteristics of the influent DIP wastewater were assessed, and then, the substrate COD proportion was divided successfully for the necessity of ADM1 applying. The Monte Carlo technique was implemented to distinguish the most sensitive parameters that influenced the model output indicators comprising effluent COD and biogas production. The sensitive parameters were estimated and optimized. The optimized value of k_m_pro is 12.02, K_S_pro is 0.35, k_m_ac is 4.26, K_S_ac is 0.26, k_m_h2 is 16.62, and K_S_h2 is 3.21 × 10–5. The model was calibrated with 150 days operation values measured in the field. The subsequent 100 days on-site values were used to validate the model, and the results obtained by the simulations were in good agreement. This study provides a meaningful and theoretical model guidance for full-scale wastewater anaerobic biochemical treatment simulation.
Magnetic Resonance Imaging as a Biomarker in Diabetic and HIV-Associated Peripheral Neuropathy: A Systematic Review-Based Narrative
Authors: Evans Matthew C. , Wade Charles , Hohenschurz-Schmidt David , Lally Pete , Ugwudike Albert , Shah Kamal , Bangerter Neal , Sharp David J. , Rice Andrew S. C.
Published: September 2021

Background: Peripheral neuropathy can be caused by diabetes mellitus and HIV infection, and often leaves patients with treatment-resistant neuropathic pain. To better treat this condition, we need greater understanding of the pathogenesis, as well as objective biomarkers to predict treatment response. Magnetic resonance imaging (MRI) has a firm place as a biomarker for diseases of the central nervous system (CNS), but until recently has had little role for disease of the peripheral nervous system.

Objectives: To review the current state-of-the-art of peripheral nerve MRI in diabetic and HIV symmetrical polyneuropathy. We used systematic literature search methods to identify all studies currently published, using this as a basis for a narrative review to discuss major findings in the literature. We also assessed risk of bias, as well as technical aspects of MRI and statistical analysis.

Methods: Protocol was pre-registered on NIHR PROSPERO database. MEDLINE, Web of Science and EMBASE databases were searched from 1946 to 15th August 2020 for all studies investigating either diabetic or HIV neuropathy and MRI, focusing exclusively on studies investigating symmetrical polyneuropathy. The NIH quality assessment tool for observational and cross-sectional cohort studies was used for risk of bias assessment.

Results: The search resulted in 18 papers eligible for review, 18 for diabetic neuropathy and 0 for HIV neuropathy. Risk of bias assessment demonstrated that studies generally lacked explicit sample size justifications, and some may be underpowered. Whilst most studies made efforts to balance groups for confounding variables (age, gender, BMI, disease duration), there was lack of consistency between studies. Overall, the literature provides convincing evidence that DPN is associated with larger nerve cross sectional area, T2-weighted hyperintense and hypointense lesions, evidence of nerve oedema on Dixon imaging, decreased fractional anisotropy and increased apparent diffusion coefficient compared with controls. Analysis to date is largely restricted to the sciatic nerve or its branches.

Conclusions: There is emerging evidence that various structural MR metrics may be useful as biomarkers in diabetic polyneuropathy, and areas for future direction are discussed. Expanding this technique to other forms of peripheral neuropathy, including HIV neuropathy, would be of value.

Systematic Review Registration: (identifier: CRD 42020167322) https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=167322.
Intracellular Properties of Deep-Layer Pyramidal Neurons in Frontal Eye Field of Macaque Monkeys
Authors: Piette Charlotte , Vandecasteele Marie , Bosch-Bouju Clémentine , Goubard Valérie , Paillé Vincent , Cui Yihui , Mendes Alexandre , Perez Sylvie , Valtcheva Silvana , Xu Hao , Pouget Pierre , Venance Laurent
Published: September 2021

Although many details remain unknown, several positive statements can be made about the laminar distribution of primate frontal eye field (FEF) neurons with different physiological properties. Most certainly, pyramidal neurons in the deep layer of FEF that project to the brainstem carry movement and fixation signals but clear evidence also support that at least some deep-layer pyramidal neurons projecting to the superior colliculus carry visual responses. Thus, deep-layer neurons in FEF are functionally heterogeneous. Despite the useful functional distinctions between neuronal responses in vivo, the underlying existence of distinct cell types remain uncertain, mostly due to methodological limitations of extracellular recordings in awake behaving primates. To substantiate the functionally defined cell types encountered in the deep layer of FEF, we measured the biophysical properties of pyramidal neurons recorded intracellularly in brain slices issued from macaque monkey biopsies. Here, we found that biophysical properties recorded in vitro permit us to distinguish two main subtypes of regular-spiking neurons, with, respectively, low-resistance and low excitability vs. high-resistance and strong excitability. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that at least two distinct populations of deep-layer neurons exist.
The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation
Authors: Morales-Valencia Jorge , David Gregory
Published: September 2021

Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells’ properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.
A Narrative Review of Circular RNAs in Brain Development and Diseases of Preterm Infants
Authors: Gu Qianying , Liu Heng , Ma Jingjing , Yuan Jiaming , Li Xinger , Qiao Lixing
Published: September 2021

Circular RNAs (circRNAs) generated by back-splicing are the vital class of non-coding RNAs (ncRNAs). Circular RNAs are highly abundant and stable in eukaryotes, and many of them are evolutionarily conserved. They are blessed with higher expression in mammalian brains and could take part in the regulation of physiological and pathophysiological processes. In addition, premature birth is important in neurodevelopmental diseases. Brain damage in preterm infants may represent the main cause of long-term neurodevelopmental disorders in surviving babies. Until recently, more and more researches have been evidenced that circRNAs are involved in the pathogenesis of encephalopathy of premature. We aim at explaining neuroinflammation promoting the brain damage. In this review, we summarize the current findings of circRNAs properties, expression, and functions, as well as their significances in the neurodevelopmental impairments, white matter damage (WMD) and hypoxic-ischemic encephalopathy (HIE). So we think that circRNAs have a direct impact on neurodevelopment and brain injury, and will be a powerful tool in the repair of the injured immature brain. Even though their exact roles and mechanisms of gene regulation remain elusive, circRNAs have potential applications as diagnostic biomarkers for brain damage and the target for neuroprotective intervention.
Atractyloside Protect Mice Against Liver Steatosis by Activation of Autophagy via ANT-AMPK-mTORC1 Signaling Pathway
Authors: Zhang Pengfei , Cheng Xinyu , Sun Huimin , Li Yajing , Mei Wuxuan , Zeng Changchun
Published: September 2021

Objective: Adenine nucleotide translocase (ANT) can transport ADP from cytoplasm to mitochondrial matrix and provide raw materials for ATP synthesis by oxidative phosphorylation. Dysfunction of ANT leads to limitation of ADP transport and decrease of ATP production. Atractyloside (ATR) is considered as a cytotoxic competitive inhibitor binding to ANT, making ANT vulnerable to transport ADP, and reduces ATP synthesis. Moreover, the blockage of ANT by ATR may increase ADP/ATP ratio, activate AMPK-mTORC1-autophagy signaling pathway, and promote lipid degradation in steatosis hepatocytes. The present study was conducted to investigate the mechanism of ATR, regulate ANT-AMPK-mTORC1 signaling pathway to activate autophagy, and promote the degradation of lipid droplets in high-fat diet (HFD) induced liver steatosis.

Methods: ICR mice were fed with HFD for 8 weeks to induce liver steatosis, and ATR solution was given by intraperitoneal injection. Intracellular triglyceride level and oil red O staining-lipid droplets (LDs) were assessed, the expression of proteins related to ANT-AMPK-mTORC1 signaling pathway and autophagy were determined, and the colocalization of LC3B and Perilipin 2 was performed.

Results: ATR treatment decreased the serum AST level, relative weight of liver and epididymal fat, and body weight of HFD mice. The LDs in HFD mice livers were reduced in the presence of ATR, and the TG level in serum and liver of HFD mice was significantly reduced by ATR. In addition, ATR inhibited ANT2 expression, promoted the activation of AMPK, then increased Raptor expression, and finally decreased the mTOR activity. Furthermore, ATR increased the protein level of LC3A/B and ATG7, and a strong colocalization of LC3B and PLIN2 was observed.

Conclusion: ATR treatment blocks ANT2 expression, promotes the activation of AMPK, then decreases the mTOR activity, and finally promotes autophagosomes formation, thus accelerating the degradation of HFD-induced accumulated lipids in the liver. This will provide new therapeutic ideas and experimental data for clinical prevention and treatment of non-alcoholic fatty liver disease.
Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells
Authors: Buoso Erica , Kenda Maša , Masi Mirco , Linciano Pasquale , Galbiati Valentina , Racchi Marco , Dolenc Marija Sollner , Corsini Emanuela
Published: September 2021

Receptor for activated C kinase 1 (RACK1) has an important role in immune activation, and is regulated through a balance between glucocorticoid and androgen levels. We have previously demonstrated that RACK1 expression can serve as a marker for evaluation of immunotoxic profiles of hormone-active substances, such as endocrine-disrupting chemicals (EDCs). In this study, we investigated the effects of three bisphenols (BPA, BPAF, BPS) on RACK1 expression and on the innate immune responses in the THP-1 human promyelocytic cell line, a validated model for this investigation. BPA and BPAF reduced RACK1 promoter transcriptional activity, mRNA expression, and protein levels. However, BPS had the opposite effect. As expected, these results on RACK1 were paralleled by lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and tumor necrosis factor-α (TNFα) production. Since BPA and BPAF induced RACK1 expression in the presence of glucocorticoid receptor (GR) antagonist mifepristone, a role of G-protein-coupled estrogen receptor (GPER) has been considered due to their known estrogenic profile. Therefore, additional molecular effects of BPA and BPAF were unmasked after treatment with different inhibitors of well-known pivotal players of GPER-mediated signaling. BPA exerted its effects on RACK1viaNF-κB, as shown using the NF-κB inhibitor BAY11-7085 and NF-κB-specific luciferase reporter assay. Conversely, BPAF induced RACK1 up-regulationviaandrogen receptor (AR) activation, as confirmed by treatment with AR antagonist flutamide. Indeed, a biased agonism profile for BPA and BPAF for GPER was suggested based on their different binding modes revealed by our molecular docking. Altogether, our data suggest that RACK1 could represent an important target of EDCs and serves as a screening tool for their immunotoxic potential. Furthermore, RACK1 can be exploited to unmask multiple molecular interactions of hormone-active substances to better dissect out their mechanisms of action.
Real-World Effectiveness of Inhalation Therapy Among Patients With Symptomatic COPD in China: A Multicenter Prospective Study
Authors: Cheng Wei , Duan Jiaxi , Zhou Aiyuan , Zhao Yiyang , Yi Rong , Liu Yi , Deng Dingding , Li Xin , Zeng Yuqin , Peng Yating , Song Qing , Lin Ling , Yang Min , Chen Ping
Published: September 2021

Purpose: This real-world study evaluated the effectiveness of different inhalation therapies in patients with symptomatic chronic obstructive pulmonary disease (COPD) in China and also explored the relevant factors that influence the effectiveness of inhalation therapy.

Patients and Methods: We conducted a multicenter prospective longitudinal study that was carried out in 12 hospitals in China from December 2016 to June 2021. A face-to-face interview was conducted to collect data. Baseline data were collected at the first visit. Minimum clinically important difference (MCID) was defined as attaining a COPD assessment test (CAT) decrease ≥2. We mainly assessed the MCID and the incidence of exacerbations at the 6 months follow-up.

Results: In 695 patients, the mean age was 62.5 ± 8.2 years, with a mean CAT score of 15.1 ± 6.0. Overall, 341 (49.1%) patients attained the MCID of CAT and the incidence of exacerbation during follow-up was 22.3%. Females were significantly more likely to attain MCID than male in COPD patients (adjusted odd ratio (aOR) = 1.93, adjusted 95% confidence interval (a95%CI) = 1.09–3.42, p = 0.024). Patients treated with LABA/LAMA or ICS/LABA/LAMA (ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist) were more likely to attain MCID than patients treated with LAMA (aOR = 3.97, a95%CI = 2.48–6.35, p < 0.001; aOR = 3.17, a95%CI = 2.09–4.80, p < 0.001, respectively). Patients treated with LABA/LAMA had a higher incidence of severe exacerbation than patients treated with ICS/LABA/LAMA (aOR = 1.95, a95%CI = 1.04–3.66, p = 0.038).

Conclusion: The incidence of MCID in symptomatic COPD patients treated with inhalation therapy was nearly 50%. Patients treated with LABA/LAMA or ICS/LABA/LAMA were more likely to attain MCID than patients treated with LAMA. Patients treated with LABA/LAMA had a higher incidence of severe exacerbations than with ICS/LABA/LAMA.
Phillygenin Attenuates Carbon Tetrachloride-Induced Liver Fibrosis via Modulating Inflammation and Gut Microbiota
Authors: Wang Cheng , Ma Cheng , Fu Ke , Gong Li-Hong , Zhang Ya-Fang , Zhou Hong-Lin , Li Yun-Xia
Published: September 2021

Liver fibrosis is a chronic pathological process that various pathogenic factors lead to abnormal hyperplasia of hepatic connective tissue, and its main feature is the excessive deposition of extracellular matrix. However, there are currently no drugs approved for the treatment of liver fibrosis. Phillygenin (PHI), a lignan isolated from Forsythiae Fructus, showed potential anti-inflammatory and anti-fibrosis effects but the mechanisms remain unknown. In view of the vital role of gut microbiota in the development of liver fibrosis, this study aimed to explore whether PHI could protect intestinal epithelial barrier and attenuate liver fibrosis by maintaining the homeostasis of intestinal microbiota. Therefore, the liver fibrosis model was induced by intraperitoneal injection of olive oil containing 10% carbon tetrachloride (CCl4) for 4 weeks in C57BL/6J mice. Histological analysis including Hematoxylin-Eosin, Masson, Sirius red, and immunohistochemistry staining were carried out to detect the histopathology and collagen deposition of mice liver tissues. The biochemical indexes related to liver function (ALT, AST, AKP, γ-GT), fibrosis (HYP, HAase, LN, PC III, IV-C) and inflammation (TNF-α, MIP-1, LPS) were determined by specific commercial assay kits. In vivo experimental results showed that PHI could improve liver histopathological injury, abnormal liver function, collagen deposition, inflammation and fibrosis caused by CCl4. Moreover, PHI restored the intestinal epithelial barrier by promoting the expression of intestinal barrier markers, including ZO-1, Occludin and Claudin-1. More importantly, the corrective effect of PHI on the imbalance of gut microbiota was confirmed by sequencing of the 16 S rRNA gene. In particular, PHI treatment enriches the relative abundance of Lactobacillus, which is reported to alleviate inflammation and fibrosis of damaged liver. Collectively, PHI attenuates CCl4-induced liver fibrosis partly via modulating inflammation and gut microbiota.
VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes
Authors: Jannaway Melanie , Scallan Joshua P.
Published: September 2021

Lymphatic vascular permeability prevents lymph leakage that is associated with lymphedema, lymphatic malformations, obesity, and inflammation. However, the molecular control of lymphatic permeability remains poorly understood. Recent studies have suggested that adherens junctions and vesicle transport may be involved in regulating lymphatic vessel permeability. To determine the contribution of each transport pathway, we utilized an ex vivo permeability assay to directly measure the solute flux of various molecular weight solutes across a range of pressures in intact murine collecting lymphatic vessels. Pharmacological and biological tools were used to probe the relative contributions of vesicles and junction proteins in the lymphatic vasculature. We show that the permeability of collecting lymphatic vessels is inversely related to the solute molecular weight. Further, our data reveal that vesicles selectively transport BSA, as an inhibitor of vesicle formation significantly decreased the permeability to BSA (∼60% decrease, n = 8, P = 0.02), but not to 3 kDa dextran (n = 7, P = 0.41), α-lactalbumin (n = 5, P = 0.26) or 70 kDa dextran (n = 8, P = 0.13). In contrast, disruption of VE-cadherin binding with a function blocking antibody significantly increased lymphatic vessel permeability to both 3 kDa dextran (5.7-fold increase, n = 5, P < 0.0001) and BSA (5.8-fold increase, n = 5, P < 0.0001). Thus, in the lymphatic vasculature, adherens junctions did not exhibit selectivity for any of the solutes tested here, whereas vesicles specifically transport BSA. Overall, the findings suggest that disease states that disrupt VE-cadherin localization or expression will cause significant leakage of solutes and fluid from the lymphatic vasculature.
Effects of a Short-Term Left Ventricular Assist Device on Hemodynamics in a Heart Failure Patient-Specific Aorta Model: A CFD Study
Authors: Wang Yu , Wang Junwei , Peng Jing , Huo Mingming , Yang Zhiqiang , Giridharan Guruprasad A. , Luan Yong , Qin Kairong
Published: September 2021

Patients with heart failure (HF) or undergoing cardiogenic shock and percutaneous coronary intervention require short-term cardiac support. Short-term cardiac support using a left ventricular assist device (LVAD) alters the pressure and flows of the vasculature by enhancing perfusion and improving the hemodynamic performance for the HF patients. However, due to the position of the inflow and outflow of the LVAD, the local hemodynamics within the aorta is altered with the LVAD support. Specifically, blood velocity, wall shear stress, and pressure difference are altered within the aorta. In this study, computational fluid dynamics (CFD) was used to elucidate the effects of a short-term LVAD for hemodynamic performance in a patient-specific aorta model. The three-dimensional (3D) geometric models of a patient-specific aorta and a short-term LVAD, Impella CP, were created. Velocity, wall shear stress, and pressure difference in the patient-specific aorta model with the Impella CP assistance were calculated and compared with the baseline values of the aorta without Impella CP support. Impella CP support augmented cardiac output, blood velocity, wall shear stress, and pressure difference in the aorta. The proposed CFD study could analyze the quantitative changes in the important hemodynamic parameters while considering the effects of Impella CP, and provide a scientific basis for further predicting and assessing the effects of these hemodynamic signals on the aorta.
Irisin, Energy Homeostasis and Male Reproduction
Authors: Sengupta Pallav , Dutta Sulagna , Karkada Ivan Rolland , Akhigbe Roland Eghoghosoa , Chinni Suresh V.
Published: September 2021

Irisin is a novel skeletal muscle- and adipose tissue-secreted peptide. It is conventionally regarded as an adipomyokine and is a cleaved fragment of Fibronectin type III domain-containing protein 5 (FNDC5). It is involved in the browning of white adipose tissue, glucose tolerance, and reversing of metabolic disruptions. Fertility is closely linked to energy metabolism and the endocrine function of the adipose tissue. Moreover, there is established association between obesity and male infertility. Irisin bears strong therapeutic promise in obesity and its associated disorders, as well as shown to improve male reproductive functions. Thus, irisin is a molecule of great interest in exploring the amelioration of metabolic syndrome or obesity-induced male infertility. In this review we aim to enumerate the most significant aspects of irisin actions and discuss its involvement in energy homeostasis and male reproduction. Though current and future research on irisin is very promiscuous, a number of clarifications are still needed to reveal its full potential as a significant medicinal target in several human diseases including male infertility.
Untargeted Metabolomics and Targeted Quantitative Analysis of Temporal and Spatial Variations in Specialized Metabolites Accumulation in Poria cocos (Schw.) Wolf (Fushen)
Authors: Yang Mei , Zhao Yujiao , Qin Yuejian , Xu Rui , Yang Zhengyang , Peng Huasheng
Published: September 2021

Poria cocos (Schw.) Wolf is a saprophytic fungus that grows around the roots of old, dead pine trees. Fushen, derived from the sclerotium of P. cocos but also containing a young host pine root, has been widely used as a medicine and food in China, Japan, Korea, Southeast Asian countries, and some European countries. However, the compound variations at the different growth periods and in the different parts of Fushen have not previously been investigated. In this study, an untargeted metabolomics approach based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) and targeted quantitative analysis was utilized to characterize the temporal and spatial variations in the accumulation of specialized metabolites in Fushen. There were 119 specialized metabolites tentatively identified using the UPLC-Q/TOF-MS. The nine growth periods of Fushen were divided into four groups using partial least squares discrimination analysis (PLS-DA). Four different parts of the Fushen [fulingpi (FP), the outside of baifuling (BO), the inside of baifuling (BI), and fushenmu (FM)] were clearly discriminated using a PLS-DA and orthogonal partial least squares discrimination analysis (OPLS-DA). Markers for the different growth periods and parts of Fushen were also screened. In addition, the quantitative method was successfully applied to simultaneously determine 13 major triterpenoid acids in the nine growth periods and four parts. The quantitative results indicated that the samples in January, March, and April, i.e., the late growth period, had the highest content levels for the 13 triterpenoid acids. The pachymic acid, dehydropachymic acid, and dehydrotumulosic acid contents in the FM were higher than those in other three parts in March, whereas the poricoic acid B, poricoic acid A, polyporenic acid C, dehydrotratrametenolic acid, dehydroeburicoic acid, and eburicoic acid in FP were higher beginning in October. These findings reveal characteristics in temporal and spatial distribution of specialized metabolites in Fushen and provide guidance for the identification of harvesting times and for further quality evaluations.