bluuebunny/crossref_metadata_2025 huggingface dataset:
3D Poly(Lactic Acid) Scaffolds Promote Different Behaviors on Endothelial Progenitors and Adipose-Derived Stromal Cells in Comparison With Standard 2D Cultures
Authors: Biagini Giuliana , Senegaglia Alexandra Cristina , Pereira Tarciso , Berti Lucas Freitas , Marcon Bruna Hilzendeger , Stimamiglio Marco Augusto
Published: September 2021

Tissue engineering is a branch of regenerative medicine, which comprises the combination of biomaterials, cells and other bioactive molecules to regenerate tissues. Biomaterial scaffolds act as substrate and as physical support for cells and they can also reproduce the extracellular matrix cues. Although tissue engineering applications in cellular therapy tend to focus on the use of specialized cells from particular tissues or stem cells, little attention has been paid to endothelial progenitors, an important cell type in tissue regeneration. We combined 3D printed poly(lactic acid) scaffolds comprising two different pore sizes with human adipose-derived stromal cells (hASCs) and expanded CD133+ cells to evaluate how these two cell types respond to the different architectures. hASCs represent an ideal source of cells for tissue engineering applications due to their low immunogenicity, paracrine activity and ability to differentiate. Expanded CD133+ cells were isolated from umbilical cord blood and represent a source of endothelial-like cells with angiogenic potential. Fluorescence microscopy and scanning electron microscopy showed that both cell types were able to adhere to the scaffolds and maintain their characteristic morphologies. The porous PLA scaffolds stimulated cell cycle progression of hASCs but led to an arrest in the G1 phase and reduced proliferation of expanded CD133+ cells. Also, while hASCs maintained their undifferentiated profile after 7 days of culture on the scaffolds, expanded CD133+ cells presented a reduction of the von Willebrand factor (vWF), which affected the cells’ angiogenic potential. We did not observe changes in cell behavior for any of the parameters analyzed between the scaffolds with different pore sizes, but the 3D environment created by the scaffolds had different effects on the cell types tested. Unlike the extensively used mesenchymal stem cell types, the 3D PLA scaffolds led to opposite behaviors of the expanded CD133+ cells in terms of cytotoxicity, proliferation and immunophenotype. The results obtained reinforce the importance of studying how different cell types respond to 3D culture systems when considering the scaffold approach for tissue engineering.
Depletion of Demethylase KDM6 Enhances Early Neuroectoderm Commitment of Human PSCs
Authors: Meng Yajing , Zhang Tianzhe , Zheng Ran , Ding Song , Yang Jie , Liu Ran , Jiang Yingan , Jiang Wei
Published: September 2021

Epigenetic modifications play a crucial role in neurogenesis, learning, and memory, but the study of their role in early neuroectoderm commitment from pluripotent inner cell mass is relatively lacking. Here we utilized the system of directed neuroectoderm differentiation from human embryonic stem cells and identified that KDM6B, an enzyme responsible to erase H3K27me3, was the most upregulated enzyme of histone methylation during neuroectoderm differentiation by transcriptome analysis. We then constructed KDM6B-null embryonic stem cells and found strikingly that the pluripotent stem cells with KDM6B knockout exhibited much higher neuroectoderm induction efficiency. Furthermore, we constructed a series of embryonic stem cell lines knocking out the other H3K27 demethylase KDM6A, and depleting both KDM6A and KDM6B, respectively. These cell lines together confirmed that KDM6 impeded early neuroectoderm commitment. By RNA-seq, we found that the expression levels of a panel of WNT genes were significantly affected upon depletion of KDM6. Importantly, the result that WNT agonist and antagonist could abolish the differential neuroectoderm induction due to manipulating KDM6 further demonstrated that WNT was the major downstream of KDM6 during early neural induction. Moreover, we found that the chemical GSK-J1, an inhibitor of KDM6, could enhance neuroectoderm induction from both embryonic stem cells and induced pluripotent stem cells. Taken together, our findings not only illustrated the important role of the histone methylation modifier KDM6 in early neurogenesis, providing insights into the precise epigenetic regulation in cell fate determination, but also showed that the inhibitor of KDM6 could facilitate neuroectoderm differentiation from human pluripotent stem cells.
Dexmedetomidine Relieves Neuropathic Pain in Rats With Chronic Constriction Injury via the Keap1–Nrf2 Pathway
Authors: Liu Yatao , Liu Wei , Wang Xiao-Qing , Wan Zhan-Hai , Liu Yong-Qiang , Zhang Meng-Jie
Published: September 2021

This study aimed to determine the role of dexmedetomidine (Dex) in neuropathic pain (NP) after chronic constriction injury (CCI) in a rat model as well as its underlying mechanism. First, a CCI rat model was established. After treatment with Dex, the severity of NP was ascertained by monitoring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different time points. Immunohistochemical analysis was performed to determine the levels of Keap1 and Nrf2 in the spinal cord. Furthermore, the levels of Keap1–Nrf2–HO-1 pathway molecules, apoptotic proteins, and antioxidant genes in the spinal cord or isolated primary microglia were determined using quantitative polymerase chain reaction and western blotting. The release of proinflammatory cytokines was detected via enzyme-linked immunosorbent assay. To evaluate Dex-treated CCI-induced NP via the Keap1–Nrf2–HO-1 pathway, the rats were intrathecally injected with lentivirus to upregulate or downregulate the expression of Keap1. We found that Dex inhibited pathological changes and alleviated sciatic nerve pain as well as repressed inflammation, apoptosis, and redox disorders of the spinal cord in CCI rats. Keap1 protein expression was substantially downregulated, whereas Nrf2 and HO-1 expressions were significantly upregulated in the spinal cord after Dex administration. Additionally, Keap1 overexpression counteracted Dex-mediated inhibition of NP. Keap1 overexpression led to a decrease in Nrf2 and HO-1 levels as well as PWT and PWL but led to an aggravation of inflammation and antioxidant disorders and increased apoptosis. Keap1 silencing alleviated NP in rats with CCI, as evidenced by an increase in PWT and PWL. Keap1 depletion resulted in the alleviation of inflammation and spinal cord tissue injury in CCI rats. Collectively, these findings suggest that Dex inhibits the Keap1–Nrf2–HO-1-related antioxidant response, inflammation, and apoptosis, thereby alleviating NP in CCI rats.
Iodide Functionalized Paper-Based SERS Sensors for Improved Detection of Narcotics
Authors: Tay Li-Lin , Poirier Shawn , Ghaemi Ali , Hulse John , Wang Shiliang
Published: September 2021

An inkjet-printed paper-based Surface-enhanced Raman scattering (SERS) sensor is a robust and versatile device that provides trace sensing capabilities for the detection and analysis of narcotics and drugs. Such sensors generally work well for analytes with good binding affinity towards the Au or Ag plasmonic nanoparticles (NPs) resident in the sensors. In this report, we show that iodide functionalization of the printed sensors helps to remove adsorbed contaminants from AuNP surfaces enabling superior performance with improved detection of narcotics such as fentanyl, heroin and cocaine by SERS. SERS signals are easily doubled with the iodide-functionalized sensors which also showed orders of magnitude improvement in detection limit. In this report, we show that a short (90 s) iodide treatment of the sensors significantly improved the detection of heroin. We propose that iodide functionalization be integrated into field detection kits through the solvent that wets paper-based sensor prior to swabbing for narcotics. Alternatively, we have also demonstrated that iodide functionalized sensors can be stored in ambient for up to 1 week and retain the improved performance towards heroin detection. This report will help to significantly improve the performance of paper-based sensors for field detection of narcotic drugs.
Lysine Residues in the MK-Rich Region Are Not Required for Binding of the PbsP Protein From Group B Streptococci to Plasminogen
Authors: Coppolino Francesco , Romeo Letizia , Pietrocola Giampiero , Lentini Germana , De Gaetano Giuseppe Valerio , Teti Giuseppe , Galbo Roberta , Beninati Concetta
Published: September 2021

Binding to plasminogen (Plg) enables bacteria to associate with and invade host tissues. The cell wall protein PbsP significantly contributes to the ability of group B streptococci, a frequent cause of invasive infection, to bind Plg. Here we sought to identify the molecular regions involved in the interactions between Plg and PbsP. The K4 Kringle domain of the Plg molecule was required for binding of Plg to whole PbsP and to a PbsP fragment encompassing a region rich in methionine and lysine (MK-rich domain). These interactions were inhibited by free L-lysine, indicating the involvement of lysine binding sites in the Plg molecule. However, mutation to alanine of all lysine residues in the MK-rich domain did not decrease its ability to bind Plg. Collectively, our data identify a novel bacterial sequence that can interact with lysine binding sites in the Plg molecule. Notably, such binding did not require the presence of lysine or other positively charged amino acids in the bacterial receptor. These data may be useful for developing alternative therapeutic strategies aimed at blocking interactions between group B streptococci and Plg.
Progress and Challenges of Demand-Led Co-Produced Sub-Seasonal-to-Seasonal (S2S) Climate Forecasts in Nigeria
Authors: Lawal Kamoru A. , Olaniyan Eniola , Ishiyaku Ibrahim , Hirons Linda C. , Thompson Elisabeth , Talib Joshua , Boult Victoria L. , Ogungbenro Stephen Bunmi , Gbode Imoleayo Ezekiel , Ajayi Vincent Olanrewaju , Okogbue Emmanuel Chilekwu , Adefisan Elijah A. , Indasi Victor S. , Youds Lorraine , Nkiaka Elias , Stone Dáithí A. , Nzekwu Richard , Folorunso Olusegun , Oyedepo John A. , New Mark G. , Woolnough Steve J.
Published: September 2021

This paper identifies fundamental issues which prevent the effective uptake of climate information services in Nigeria. We propose solutions which involve the extension of short-range (1 to 5 days) forecasts beyond that of medium-range (7 to 15 days) timescales through the operational use of current forecast data as well as improve collaboration and communication with forecast users. Using newly available data to provide seamless operational forecasts from short-term to sub-seasonal timescales, we examine evidence to determine if effective demand-led sub-seasonal-to-seasonal (S2S) climate forecasts can be co-produced. This evidence involves: itemization of forecast products delivered to stakeholders, with their development methodology; enumeration of inferences of forecast products and their influences on decisions taken by stakeholders; user-focused discussions of improvements on co-produced products; and the methods of evaluating the performance of the forecast products.

We find that extending the production pipeline of short-range forecast timescales beyond the medium-range, such that the medium-range forecast timescales can be fed into existing tools for applying short-range forecasts, assisted in mitigating the risks of sub-seasonal climate variability on socio-economic activities in Nigeria. We also find that enhancing of collaboration and communication channels between the producers and the forecast product users helps to: enhance the development of user-tailored impact-based forecasts; increases users' trusts in the forecasts; and, seamlessly improves forecast evaluations. In general, these measures lead to more smooth delivery and increase in uptake of climate information services in Nigeria.
National Leaders’ Usage of Twitter in Response to COVID-19: A Sentiment Analysis
Authors: Wang Yuming , Croucher Stephen M , Pearson Erika
Published: September 2021

Twitter is a powerful tool for world leaders to disseminate public health information and to reach citizens. While Twitter, like other platforms, affords world leaders the opportunity to rapidly present information to citizens, the discourse is often politically framed. In this study, we analysed how leaders’ of the Five Eyes intelligence sharing group use Twitter to frame the COVID-19 virus. Specifically, four research questions were explored: 1) How frequently did each leader tweet about COVID-19 in 2020? 2) Which frames emerged from tweet content of each leader regarding COVID-19? 3) What was the overall tweet valence of each leader regarding COVID-19? and 4) To what extent can leaders’ future tweets be predicted by the data? We used natural language processing (NLP) and conducted sentiment analysis via Python to identify frames and to compare the leaders’ messaging. Results showed that of the leaders, President Trump tweeted the most, with Prime Minister Morrison posting the least number of tweets. The majority of each leaders’ tweets were positive, while President Trump had the most negative tweets. Predictive modelling of tweet behavior was highly accurate.
Dropout in Rural Higher Education: A Systematic Review
Authors: Guzmán Alfredo , Barragán Sandra , Cala Vitery Favio
Published: September 2021

Student dropout in higher education has been of great interest to the academic community, state and social actors over the last three decades, due to the various effects that this event has on the student, the family, higher education institutions, and the state itself. It is recognised that dropout at this level of education is extremely complex due to its multi-causality which is expressed in the existing relationship in its explanatory variables associated with the students, their socioeconomic and academic conditions, as well as the characteristics of the educational institutions. Thus, the aim of this article was to identify the individual, socioeconomic, academic, and institutional explanatory variables involved in student dropout in rural populations, based on a synthesis of the evidence available in the SCOPUS database. In order to achieve it, a mixed systematic review was defined under the PRISMA 2020 method. The analysis was approached in two stages; the first concerned the identification of the documents and the conformation of the sample, where 21 documents were distinguished for effectively dealing with dropout in rural higher education; and the second corresponded to the procedures defined for the development of the bibliometric analysis and synthesis of the information found in the documents. The results showed the distribution of studies by country, years of publication, the categorisation of the documents in SCOPUS, their classification by type and the methodologies used in the development of the studies analysed, as well as the variables that have been addressed in previous research. In this way, it is concluded that the results of the studies are not generalisable, either because of the size of the sample or because of the marked social asymmetries that exist in some countries, which can make the findings lack significance; on the other hand, the interest in research on variables associated with individual and academic determinants to explain rural student dropout is highlighted. In addition, some future research lines which can be addressed as a complement to the current view of the dropout event in rural higher education were identified.
Catecholaminergic Crisis After a Bleeding Complication of COVID-19 Infection: A Case Report
Authors: Rebollo-Román Angel , Alhambra-Expósito Maria R. , Herrera-Martínez Yiraldine , Leiva-Cepas F. , Alzas Carlos , Muñoz-Jiménez Concepcion , Ortega-Salas R. , Molina-Puertas María J. , Gálvez-Moreno Maria A. , Herrera-Martínez Aura D.
Published: September 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents in some cases with hemostatic and thrombotic complications. Pheochromocytomas are unusual, though potentially lethal tumors. Herein we describe the first case of hemorrhage in a pheochromocytoma related to SARS-CoV-2 infection. A 62-year-old man consulted for syncope, fever, and palpitations. He was diagnosed with SARS-CoV-2 pneumonia and presented with a hemorrhage in a previously unknown adrenal mass, which resulted in a catecholaminergic crisis. Medical treatment and surgery were required for symptom control and stabilization. We hereby alert clinicians to watch for additional/unreported clinical manifestations in COVID-19 infection.
Interferences and Matrix Effects on Iron Isotopic Composition Measurements by 57Fe-58Fe Double-Spike Multi-Collector Inductively Coupled Plasma Mass Spectrometry; the Importance of Calcium and Aluminum Interferences
Authors: Lacan F. , Artigue L. , Klar J. K. , Pradoux C. , Chmeleff J. , Freydier R.
Published: September 2021

Multi-collector inductively coupled plasma mass spectrometers (MC-ICPMS) are widely used for Fe isotope measurements. The latter may be perturbed by interferences (notably from Cr and Ni) and matrix effects (notably from major elements), caused by elements remaining in the samples after purification. We quantified some of these perturbations and our ability to correct them whenever possible, using Thermo Neptune and Neptune Plus MC-ICPMS with a 57-58Fe double-spike mass bias correction. 54Cr and 58Ni isobaric interference corrections were found to be extremely efficient up to Cr/Fe=0.12 and Ni/Fe=0.04 (g/g natural Fe). Matrix effects were found negligible up to at least Na/Fe=175, Mg/Fe=10, K/Fe=1.5, and Mo/Fe=75 (g/g natural Fe). 28Si2+ interference was found negligible up to Si/Fe=50. Finally, we found that calcium and aluminum could cause significant interferences (e.g., 40Ca16O and 27Al2+), for Ca/Fe ≥ 2.5 and Al/Fe ≥ 2.5. The perturbation intensity relative to the Ca/Fe ratio was found dependent on the measurement conditions (plateau width). While working with samples with potentially high calcium or aluminum contents (such as calcite minerals or tests, bones and teeth, or marine samples and crustal rocks), we recommend to carefully take into account Ca and Al while tuning the instrument and checking the measurement accuracy with isotopic standards (i.e., doping the isotopic standard with Ca and Al levels comparable to those of the samples).
Hormonal Regulation of Programmed Cell Death in Sea Urchin Metamorphosis
Authors: Wynen Hannah , Heyland Andreas
Published: September 2021

Programmed cell death (PCD) has been identified as a key process in the metamorphic transition of indirectly developing organisms such as frogs and insects. Many marine invertebrate species with indirect development and biphasic life cycles face the challenge of completing the metamorphic transition of the larval body into a juvenile when they settle into the benthic habitat. Some key characteristics stand out during this transition in comparison to frogs and insects: (1) the transition is often remarkably fast and (2) the larval body is largely abandoned and few structures transition into the juvenile stage. In sea urchins, a group with a drastic and fast metamorphosis, development and destruction of the larval body is regulated by endocrine signals. Here we provide a brief review of the basic regulatory mechanisms of PCD in animals. We then narrow our discussion to metamorphosis with a specific emphasis on sea urchins with indirect life histories and discuss the function of thyroid hormones and histamine in larval development, metamorphosis and settlement of the sea urchin Strongylocentrotus purpuratus. We were able to annotate the large majority of PCD related genes in the sea urchin S. purpuratus and ongoing studies on sea urchin metamorphosis will shed light on the regulatory architecture underlying this dramatic life history transition. While we find overwhelming evidence for hormonal regulation of PCD in animals, especially in the context of metamorphosis, the mechanisms in many marine invertebrate groups with indirect life histories requires more work. Hence, we propose that studies of PCD in animals requires functional studies in whole organisms rather than isolated cells. We predict that future work, targeting a broader array of organisms will not only help to reveal important new functions of PCD but provide a fundamentally new perspective on its use in a diversity of taxonomic, developmental, and ecological contexts.
An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease
Authors: Shi Yuchen , Liu Ruifei , Guo Ying , Li Qiwei , Zhou Haichun , Yu Shaolei , Liang Hua , Li Zeguang
Published: September 2021

It has been a long time that the relationship between serum calcium levels and Alzheimer’s disease (AD) remains unclear. Until recently, observational studies have evaluated the association between serum calcium levels and the risk of AD, however, reported inconsistent findings. Meanwhile, a Mendelian randomization (MR) study had been conducted to test the causal association between serum calcium levels and AD risk, however, only selected 6 serum calcium SNPs as the instrumental variables. Hence, these findings should be further verified using additional more genetic variants and large-scale genome-wide association study (GWAS) dataset to increase the statistical power. Here, we conduct an updated MR analysis of the causal association between serum calcium levels and the risk of AD using a two-stage design. In discovery stage, we conducted a MR analysis using 14 SNPs from serum calcium GWAS dataset (N= 61,079), and AD GWAS dataset (N= 63,926, 21,982 cases, 41,944 cognitively normal controls). All four MR methods including IVW, weighted median, MR-Egger, and MR-PRESSO showed a reduced trend of AD risk with the increased serum calcium levels. In the replication stage, we performed a MR analysis using 166 SNPs from serum calcium GWAS dataset (N= 305,349), and AD GWAS dataset (N= 63,926, 21,982 cases, 41,944 cognitively normal controls). Only the weighted median indicated that genetically increased serum calcium level was associated with the reduced risk of AD. Hence, additional studies are required to investigate these findings.
Profiling of MicroRNAs in Midguts of Plutella xylostella Provides Novel Insights Into the Bacillus thuringiensis Resistance
Authors: Yang Jie , Xu Xuejiao , Lin Sujie , Chen Shiyao , Lin Guifang , Song Qisheng , Bai Jianlin , You Minsheng , Xie Miao
Published: September 2021

The diamondback moth (DBM), Plutella xylostella, one of the most destructive lepidopteran pests worldwide, has developed field resistance to Bacillus thuringiensis (Bt) Cry toxins. Although miRNAs have been reported to be involved in insect resistance to multiple insecticides, our understanding of their roles in mediating Bt resistance is limited. In this study, we constructed small RNA libraries from midguts of the Cry1Ac-resistant (Cry1S1000) strain and the Cry1Ac-susceptible strain (G88) using a high-throughput sequencing analysis. A total of 437 (76 known and 361 novel miRNAs) were identified, among which 178 miRNAs were classified into 91 miRNA families. Transcripts per million analysis revealed 12 differentially expressed miRNAs between the Cry1S1000 and G88 strains. Specifically, nine miRNAs were down-regulated and three up-regulated in the Cry1S1000 strain compared to the G88 strain. Next, we predicted the potential target genes of these differentially expressed miRNAs and carried out GO and KEGG pathway analyses. We found that the cellular process, metabolism process, membrane and the catalytic activity were the most enriched GO terms and the Hippo, MAPK signaling pathway might be involved in Bt resistance of DBM. In addition, the expression patterns of these miRNAs and their target genes were determined by RT-qPCR, showing that partial miRNAs negatively while others positively correlate with their corresponding target genes. Subsequently, novel-miR-240, one of the differentially expressed miRNAs with inverse correlation with its target genes, was confirmed to interact with Px017590 and Px007885 using dual luciferase reporter assays. Our study highlights the characteristics of differentially expressed miRNAs in midguts of the Cry1S1000 and G88 strains, paving the way for further investigation of miRNA roles in mediating Bt resistance.
Antagonism of Protease Activated Receptor-2 by GB88 Reduces Inflammation Triggered by Protease Allergen Tyr-p3
Authors: Wang Yun-Ju , Yu Sheng-Jie , Tsai Jaw-Ji , Yu Ching-Hsiang , Liao En-Chih
Published: September 2021

The occurrence of allergic diseases induced by aeroallergens has increased in the past decades. Among inhalant allergens, mites remain the important causal agent of allergic diseases. Storage mites- Tyrophagus putrescentiae are found in stored products or domestic environments. Major allergen Tyr-p3 plays a significant role in triggering IgE-mediated hypersensitivity. However, its effects on pulmonary inflammation, internalization, and activation in human epithelium remain elusive. Protease-activated receptors (PARs) are activated upon cleavage by proteases. A549 cells were used as an epithelial model to examine the PAR activation by Tyr-p3 and therapeutic potential of PAR-2 antagonist (GB88) in allergic responses. Enzymatic properties and allergen localization of Tyr-p3 were performed. The release of inflammatory mediators, phosphorylation of mitogen-activated protein kinase (MAPK), and cell junction disruptions were evaluated after Tyr-p3 challenge. Enzymatic properties determined by substrate digestion and protease inhibitors indicated that Tyr-p3 processes a trypsin-like serine protease activity. The PAR-2 mRNA levels were significantly increased by nTyr-p3 but inhibited by protease inhibitors or GB88. Protease allergen of nTyr-p3 significantly increased the levels of pro-inflammatory cytokines (IL-6 and TNF-α), chemokine (IL-8), and IL-1β in epithelial cells. nTyr-p3 markedly increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and MAP kinase. When cells were pretreated with GB88 then added nTyr-p3, the phosphorylated ERK1/2 did not inhibit by GB88. GB88 increased ERK1/2 phosphorylation in human epithelium cells. GB88 is able to block PAR-2-mediated calcium signaling which inhibits the nTyr-p3-induced Ca2+ release. Among the pharmacologic inhibitors, the most effective inhibitor of the nTyr-p3 in the induction of IL-8 or IL-1β levels was GB88 followed by SBTI, MAPK/ERK, ERK, and p38 inhibitors. Levels of inflammatory mediators, including GM-CSF, VEGF, COX-2, TSLP, and IL-33 were reduced by treatment of GB88 or SBTI. Further, GB88 treatment down-regulated the nTyr-p3-induced PAR-2 expression in allergic patients with asthma or rhinitis. Tight junction and adherens junction were disrupted in epithelial cells by nTyr-p3 exposure; however, this effect was avoided by GB88. Immunostaining with frozen sections of the mite body showed the presence of Tyr-p3 throughout the intestinal digestive system, especially in the hindgut around the excretion site. In conclusion, our findings suggest that Tyr-p3 from domestic mites leads to disruption of the airway epithelial barrier after inhalation. Proteolytic activity of Tyr-p3 causes the PAR-2 mRNA expression, thus leading to the release of numerous inflammatory mediators. Antagonism of PAR2 activity suggests GB88 as the therapeutic potential for anti-inflammation medicine, especially in allergy development triggered by protease allergens.
The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis
Authors: Li Huan , Tang Dongling , Chen Juanjuan , Hu Yuanhui , Cai Xin , Zhang Pingan
Published: September 2021

Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro, we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.
Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells
Authors: Keane Jeremy T. , Afrasiabi Ali , Schibeci Stephen D. , Fewings Nicole , Parnell Grant P. , Swaminathan Sanjay , Booth David R.
Published: September 2021

Multiple Sclerosis (MS) is a complex immune-mediated disease of the central nervous system. Treatment is based on immunomodulation, including specifically targeting B cells. B cells are the main host for the Epstein-Barr Virus (EBV), which has been described as necessary for MS development. Over 200 genetic loci have been identified as increasing susceptibility to MS. Many MS risk genes have altered expression in EBV infected B cells, dependent on the risk genotype, and are themselves regulated by the EBV transcription factor EBNA2. Females are 2-3 times more likely to develop MS than males. We investigated if MS risk loci might mediate the gender imbalance in MS. From a large public dataset, we identified gender-specific associations with EBV traits, and MS risk SNP/gene pairs with gender differences in their associations with gene expression. Some of these genes also showed gender differences in correlation of gene expression level with Estrogen Receptor 2. To test if estrogens may drive these gender specific differences, we cultured EBV infected B cells (lymphoblastoid cell lines, LCLs), in medium depleted of serum to remove the effects of sex hormones as well as the estrogenic effect of phenol red, and then supplemented with estrogen (100 nM estradiol). Estradiol treatment altered MS risk gene expression, LCL proliferation rate, EBV DNA copy number and EBNA2 expression in a sex-dependent manner. Together, these data indicate that there are estrogen-mediated gender-specific differences in MS risk gene expression and EBV functions. This may in turn contribute to gender differences in host response to EBV and to MS susceptibility.
Circulating Metabolomic Signature in Generalized Pustular Psoriasis Blunts Monocyte Hyperinflammation by Triggering Amino Acid Response
Authors: Yu Ning , Peng Chen , Chen Wenjuan , Sun Ziwen , Zheng Jianfeng , Zhang Shujie , Ding Yangfeng , Shi Yuling
Published: September 2021

Generalized pustular psoriasis (GPP), the most grievous variant of psoriasis, is featured by dysregulated systemic inflammatory response. The cellular and molecular basis of GPP is poorly understood. Blood monocytes are key players of host defense and producers of inflammatory cytokines including IL-1β. How the immune response of monocytes is affected by metabolic internal environment in GPP remains unclear. Here, we performed a metabolomic and functional investigation of GPP serum and monocytes. We demonstrated a significant increase in IL-1β production from GPP monocytes. In GPP circulation, serum amyloid A (SAA), an acute-phase reactant, was dramatically increased, which induced the release of IL-1β from monocytes in a NLRP3-dependent manner. Using metabolomic analysis, we showed that GPP serum exhibited an amino acid starvation signature, with glycine, histidine, asparagine, methionine, threonine, lysine, valine, isoleucine, tryptophan, tyrosine, alanine, proline, taurine and cystathionine being markedly downregulated. In functional assay, under amino acid starvation condition, SAA-stimulated mature IL-1β secretion was suppressed. Mechanistically, at post-transcriptional level, amino acid starvation inhibited the SAA-mediated reactive oxygen species (ROS) formation and NLRP3 inflammasome activation. Moreover, the immune-modulatory effect of amino acid starvation was blocked by silencing general control nonderepressible 2 kinase (GCN2), suggesting the involvement of amino acid response (AAR) pathway. Collectively, our results suggested that decreased serum amino acids in GPP blunted the innate immune response in blood monocytes through AAR pathway, serving as a feedback mechanism preventing excessive inflammation in GPP.
A Novel ELISA Assay for the Detection of Anti-Prothrombin Antibodies in Antiphospholipid Syndrome Patients at High Risk of Thrombosis
Authors: Chinnaraj Mathivanan , Pengo Vittorio , Pozzi Nicola
Published: September 2021

Autoantibodies targeting prothrombin (aPT) can be found in antiphospholipid syndrome (APS) patients. However, their detection has proven difficult to standardize. Here, we developed a new ELISA assay to improve the identification of aPT and compared its performance with currently available anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and autoantibodies targeting prothrombin bound to the plastic plate (aPT-A) assays using a cohort of 27 APS patients at high risk of thrombosis. We generated a novel prothrombin variant, ProTS525A-Biot, carrying an artificial tag at the C-terminus suitable for site-specific biotinylation and added the mutation S525A to improve stability. ProTS525A-Biot was immobilized to neutravidin-coated plates at the desired density and with a defined orientation, i.e., pointing the N-terminal fragment-1 toward the solvent. Antibodies against ProTS525A-Biot (aPT-Bio) were found in 24 out of 27 triple-positive APS patients (88%). When compared to aPS/PT and aPT-A, aPT-Bio showed an excellent linear correlation with aPS/PT (R2 = 0.85) but not with aPT-A (R2 = 0.40). Since aPS/PT but not aPT-A are an emerging biomarker of thrombosis in APS, this method may find utility for detecting pathogenic aPT in APS but also other prothrombotic conditions such as COVID-19.
Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19
Authors: Morrison Alexandra L. , Sharpe Sally , White Andrew D. , Bodman-Smith Mark
Published: September 2021

Antigen-specific vaccines developed for the COVID-19 pandemic demonstrate a remarkable achievement and are currently being used in high income countries with much success. However, new SARS-CoV-2 variants are threatening this successviamutations that lessen the efficacy of antigen-specific antibodies. One simple approach to assisting with this issue is focusing on strategies that build on the non-specific protection afforded by the innate immune response. The BCG vaccine has been shown to provide broad protection beyond tuberculosis disease, including against respiratory viruses, and ongoing studies are investigating its efficacy as a tool against SARS-CoV-2. Gamma delta (γδ) T cells, particularly the Vδ2 subtype, undergo rapid expansion after BCG vaccination due to MHC-independent mechanisms. Consequently, γδ T cells can produce diverse defenses against virally infected cells, including direct cytotoxicity, death receptor ligands, and pro-inflammatory cytokines. They can also assist in stimulating the adaptive immune system. BCG is affordable, commonplace and non-specific, and therefore could be a useful tool to initiate innate protection against new SARS-CoV-2 variants. However, considerations must also be made to BCG vaccine supply and the prioritization of countries where it is most needed to combat tuberculosis first and foremost.
Measuring Stony Coral Tissue Loss Disease Induction and Lesion Progression Within Two Intermediately Susceptible Species, Montastraea cavernosa and Orbicella faveolata
Authors: Eaton Katherine R. , Landsberg Jan H. , Kiryu Yasunari , Peters Esther C. , Muller Erinn M.
Published: September 2021

During the last several decades, Florida’s Coral Reef (FCR) has been impacted by both global and local stressors that have devastated much of its living coral cover. Additionally, since 2014 FCR has experienced a lethal disease outbreak termed stony coral tissue loss disease (SCTLD). Here, we examined SCTLD spreading dynamics within and among fragmented coral colonies and quantified lesion progression rate of two intermediately susceptible species—Montastraea cavernosaandOrbicella faveolata—through induction experiments conducted in laboratory aquaria.M. cavernosacolonies showing subacute tissue loss were sequentially fragmented parallel to the lesion edge to determine whether isolated tissue that showed no tissue-loss signs, referred to as isolated apparently healthy (AH) donor fragments, would subsequently exhibit tissue loss. Additionally, AHM. cavernosaandO. faveolatafragments, referred to as recipient fragments, were placed in direct contact with theM. cavernosadonor fragments to assess incidence of new tissue-loss lesions. Finally, AHM. cavernosadonor fragments were placed in direct contact with recipientM. cavernosaandO. faveolatafragments to account for aggression from direct contact. Samples were collected for histopathology of the corals through time. Many isolated AH donor fragments developed tissue-loss lesions during the 60-day study, suggesting SCTLD may be systemic within small-sized colonies. Our results confirmed that physical contact between recipient fragments and subacute SCTLD-lesioned tissue often led to tissue loss in recipient fragments. None of the control recipient or donor fragments experienced tissue loss. Grossly, multifocal lesions started on or adjacent to the septal and costal basal body walls with tissue loss progressing across the polyp septa and coenenchyme, respectively, in both species. Histologically, initial tissue-loss lesions in both species exhibited characteristic lytic necrosis (LN) at the basal body wall of the gastrodermis.O. faveolataexhibited higher rates of lesion appearance and subsequent mortality compared toM. cavernosa, but once a lesion appeared,M. cavernosalost tissue faster thanO. faveolata.This work contributes to the growing knowledge of SCTLD dynamics and highlights the differences in lesion progression within susceptible species.
The Differences and Changes of Semi-Quantitative and Quantitative CT Features of Coronavirus Disease 2019 Pneumonia in Patients With or Without Smoking History
Authors: Xie Xingzhi , Zhong Zheng , Zhao Wei , Wu Shangjie , Liu Jun
Published: September 2021

Objective: To assess CT features of COVID-19 patients with different smoking status using quantitative and semi-quantitative technologies and to investigate changes of CT features in different disease states between the two groups.

Methods: 30 COVID-19 patients with current smoking status (29 men, 1 woman) admitted in our database were enrolled as smoking group and 56 COVID-19 patients without smoking history (24 men, 32 women) admitted during the same period were enrolled as a control group. Twenty-seven smoking cases and 55 control cases reached recovery standard and were discharged. Initial and follow-up CT during hospitalization and follow-up CT after discharge were acquired. Thirty quantitative features, including the ratio of infection volume and visual-assessed interstitial changes score including total score, score of ground glass opacity, consolidation, septal thickening, reticulation and honeycombing sign, were analyzed.

Results: Initial CT images of the smoking group showed higher scores of septal thickening [4.5 (0–5) vs. 0 (0–4), p = 0.001] and reticulation [0 (0–5.25) vs 0 (0–0), p = 0.001] as well as higher total score [7 (5–12.25) vs. 6 (5–7), p = 0.008] with statistical significance than in the control group. The score of reticulation was higher in the smoking group than in the control group when discharged [0.89 (0–0) vs. 0.09 (0–0), p = 0.02]. The score of septal thickening tended to be higher in the smoking group than the control group [4 (0–4) vs. 0 (0–4), p = 0.007] after being discharged. Quantitative CT features including infection ratio of whole lung and left lung as well as infection ratio within HU (−750, −300) and within HU (−300, 49) were higher in the control group of initial CT with statistical differences. The infection ratio of whole lung and left lung, infection ratio within HU (−750), and within HU (−750, −300) were higher in the control group with statistical differences when discharged. This trend turned adverse after discharge and the values of quantitative features were generally higher in the smoking group than in the control group without statistical differences.

Conclusions: Patients with a history of smoking presented more severe interstitial manifestations and more residual lesion after being discharged. More support should be given for COVID-19 patients with a smoking history during hospitalization and after discharge.
Stability of Intraocular Lens With Different Haptic Design: A Swept-Source Optical Coherence Tomography Study
Authors: Xiao Zixuan , Wang Geng , Zhen Miaoru , Zhao Zifeng
Published: September 2021

Purpose: To investigate the stability of intraocular lens (IOLs) with different haptics by swept-source anterior-segment optical coherence tomography (AS-OCT).

Methods: Sixty-eight eyes from 55 patients received the implantation of Rayner 920H (Closed C-loop Group), Zeiss 509M (Plate Group) or Lenstec SOFTEC HD (C-loop Group) IOLs. The tilt and decentration of IOLs were evaluated using AS-OCT at least 1 month postoperatively.

Results: Mean decentration and tilt of IOLs were 0.18 ± 0.12 mm (range 0.02 to 0.59 mm) and 5.63 ± 1.65° (range 2.2 to 9.6°) respectively. Decentration was significantly smaller in the plate haptic group (0.12 ± 0.06 mm) as compared to the C-loop group (0.22 ± 0.13 mm, P = 0.02). The tilt of IOL was also significantly smaller in the plate haptic group (4.96 ± 0.89°) as compared to the C-loop group (6.28 ± 1.83°, P = 0.01). There was marginal difference between the Closed C-loop group (5.52 ± 1.74°) and C-loop group (6.28 ± 1.83°, P = 0.07).

Conclusions: The Plate-haptic IOLs should have better stability for the decentration and tilt than the C-loop design IOLs.
miR-6869-5p Transported by Plasma Extracellular Vesicles Mediates Renal Tubule Injury and Renin-Angiotensin System Activation in Obesity
Authors: Liu Huan-Huan , Li Xia-Qing , Liu Jin-Feng , Cui Shuang , Liu Han , Hu Bo , Huang Si-Bo , Wang Li , Yang Wah , Wang Cun-Chuan , Meng Yu
Published: September 2021

Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs)in vitro. Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injuryin vivo. The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.
The Association Between Risk Perception and COVID-19 Vaccine Hesitancy for Children Among Reproductive Women in China: An Online Survey
Authors: Du Min , Tao Liyuan , Liu Jue
Published: September 2021

Background: This study aimed to explore the association between risk perception and coronavirus disease 2019 (COVID-19) vaccine hesitancy among reproductive women in China to supplement limited studies in this area.

Methods: From December 14, 2020, to January 31, 2021, an anonymous cross-sectional online survey was conducted on COVID-19 vaccine hesitancy for children among reproductive women in China. We assessed risk perception, including perceived susceptibility, severity, barriers, and benefits using the health belief model, and then classified each variable into three groups (low, moderate, and high) based on tertiles. Information on sociodemographic characteristics, health status, and knowledge of COVID-19 was also collected. The Pearson χ2-test was used to compare vaccine hesitancy among the above mentioned factors. Logistic regression models were used to calculate the adjusted odds ratio (aOR) of risk perception related to vaccine hesitancy after controlling for the above covariates.

Results: Among 3,011 reproductive women, 8.44% (95%CI: 7.44. 9.43) had COVID-19 vaccine hesitancy. Vaccine hesitancy was observed more in women who lived in eastern China (11.63%), aged >45 years (12.00%), had a lower than high school education level (12.77%), and a low score on knowledge of COVID-19 (12.22%). Vaccine hesitancy was associated with lower perceived susceptibility (moderate: aOR = 1.72, 95%CI: 1.17–2.54, P = 0.0061; low: aOR = 2.44, 95%CI: 1.60–3.70, P < 0.0001), high perceived barriers (aOR = 2.86, 95%CI: 1.57–5.22, P < 0.0001), and lower perceived benefit (moderate: aOR = 3.29, 95%CI: 2.30–4.70, P < 0.0001; low: aOR = 4.59, 95%CI: 2.98–7.07, P < 0.0001), but not with perceived severity.

Conclusions: Although the proportion of COVID-19 vaccine hesitancy for children among Chinese reproductive women was <1 out of 10, to improve COVID-19 vaccine hesitancy, our findings suggest that tailored public health measures are needed to increase perceived susceptibility and benefit, and decrease perceived barriers among reproductive women.