bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
Authors: Yang Xiaoli , Ali Shafaqat , Zhao Manman , Richter Lisa , Schäfer Vanessa , Schliehe-Diecks Julian , Frank Marian , Qi Jing , Larsen Pia-Katharina , Skerra Jennifer , Islam Heba , Wachtmeister Thorsten , Alter Christina , Huang Anfei , Bhatia Sanil , Köhrer Karl , Kirschning Carsten , Weighardt Heike , Kalinke Ulrich , Kalscheuer Rainer , Uhrberg Markus , Scheu Stefanie
Published: April 2022

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte–macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNβ production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.
Epigenetic Regulation in Kidney Transplantation
Authors: Xiang Xiaohong , Zhu Jiefu , Dong Guie , Dong Zheng
Published: April 2022

Kidney transplantation is a standard care for end stage renal disease, but it is also associated with a complex pathogenesis including ischemia-reperfusion injury, inflammation, and development of fibrosis. Over the past decade, accumulating evidence has suggested a role of epigenetic regulation in kidney transplantation, involving DNA methylation, histone modification, and various kinds of non-coding RNAs. Here, we analyze these recent studies supporting the role of epigenetic regulation in different pathological processes of kidney transplantation, i.e., ischemia-reperfusion injury, acute rejection, and chronic graft pathologies including renal interstitial fibrosis. Further investigation of epigenetic alterations, their pathological roles and underlying mechanisms in kidney transplantation may lead to new strategies for the discovery of novel diagnostic biomarkers and therapeutic interventions.
Characterization of Erythroferrone in a Teleost Fish (Dicentrarchus labrax) With Two Functional Hepcidin Types: More Than an Erythroid Regulator
Authors: Neves João V. , Barroso Carolina , Carvalho Pedro , Nunes Magda , Gonçalves José F. M. , Rodrigues Pedro N. S.
Published: April 2022

Erythroferrone is a recently identified erythroid regulator produced by erythroblasts in the mammalian bone marrow and extramedullary sites, known to be induced in conditions of anemia or blood loss. Iron metabolism is affected by erythroferrone through its capacity to inhibit hepcidin production, leading to the increase of iron availability required for erythropoiesis. However, little is known about erythroferrone function in other vertebrates, in particular teleost fish, that unlike mammals, present two different functional types of hepcidin, one type mostly involved in iron metabolism and the other in antimicrobial response. The study of erythroferrone evolution and its biological role in teleost fish can give us valuably new insights into its function. To address these questions, we characterized erythroferrone in the European sea bass (Dicentrarchus labrax), a species presenting two hepcidin types, and evaluated variations in its expression levels in response to different experimental conditions. During experimental anemia, erythroferrone responds by increasing its expression and suppressing hepcidin production, following the pattern observed in mammals, but it is not influenced by iron overload. However, during bacterial infection, erythroferrone is downregulated and hepcidin levels increase. Furthermore, administration of Hamp1 but not of Hamp2 peptides suppresses erythroferrone expression. In conclusion, in dual hepcidin teleost fish erythroferrone seems to only interact with type 1 hepcidin, known to be involved in iron homeostasis, but not with type 2, which has an almost exclusive antimicrobial role.
Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency
Authors: Labrador-Horrillo Moisés , Franco-Jarava Clara , Garcia-Prat Marina , Parra-Martínez Alba , Antolín María , Salgado-Perandrés Sandra , Aguiló-Cucurull Aina , Martinez-Gallo Mónica , Colobran Roger
Published: April 2022

SASH3 is a lymphoid-specific adaptor protein. In a recent study, SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans. The small number of patients reported to date showed recurrent sinopulmonary, cutaneous and mucosal infections, and autoimmune cytopenia. Here we describe an adult patient previously diagnosed with common variable immunodeficiency (CVID) due to low IgG and IgM levels and recurrent upper tract infections. Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38. Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*). The patient’s immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation. The patient showed a suboptimal response to Streptococcus pneumoniae (polysaccharide) vaccine, and a normal response to Haemophilus influenzae type B (conjugate) vaccine and SARS-CoV-2 (RNA) vaccine. In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID. Two severe episodes of viral infection alerted us to a possible T-cell defect, and genetic testing led to SASH3 deficiency. Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity.
Thymic Microenvironment: Interactions Between Innate Immune Cells and Developing Thymocytes
Authors: Wang Helen , Zúñiga-Pflücker Juan Carlos
Published: April 2022

The thymus is a crucial organ for the development of T cells. T cell progenitors first migrate from the bone marrow into the thymus. During the journey to become a mature T cell, progenitors require interactions with many different cell types within the thymic microenvironment, such as stromal cells, which include epithelial, mesenchymal and other non-T-lineage immune cells. There are two crucial decision steps that are required for generating mature T cells: positive and negative selection. Each of these two processes needs to be performed efficiently to produce functional MHC-restricted T cells, while simultaneously restricting the production of auto-reactive T cells. In each step, there are various cell types that are required for the process to be carried out suitably, such as scavengers to clean up apoptotic thymocytes that fail positive or negative selection, and antigen presenting cells to display self-antigens during positive and negative selection. In this review, we will focus on thymic non-T-lineage immune cells, particularly dendritic cells and macrophages, and the role they play in positive and negative selection. We will also examine recent advances in the understanding of their participation in thymus homeostasis and T cell development. This review will provide a perspective on how the thymic microenvironment contributes to thymocyte differentiation and T cell maturation.
Wave Impact Analysis on a Beach-Dune System to Support Coastal Management and Nourishment Works: The Showcase of Mira, Portugal
Authors: Fontán-Bouzas Ángela , Andriolo Umberto , Silva Paulo A. , Baptista Paulo
Published: April 2022

At coasts, sandy beach-dune systems act as natural barriers to environmental forcing, preventing coastal flooding and protecting coastal communities. In the context of coastal studies, it is fundamental to identify beach-dune sectors exposed to wave impact to support coastal management and suggest soft engineering interventions. This work examines the morphodynamics of the Mira beach-dune system on the northern-central littoral of Portugal over the winter 2016-2017. Coupling topographic data with the estimation of wave runup and total water level (TWL) timeseries, we proposed an operational framework to spot the beach-dune system sectors most vulnerable to dune collision and overwash. The highest topographic variations occurred in the northern sector of the study area, where overwash events occurred due to low dune crest (DC) elevation. The dune toe (DT) was frequently collided by waves in the central sector, where the upper beach profile was the most variable during winter. Overall, wave collision and overwash events were registered not only during storms, but also during spring tides and mild wave conditions. Results highlight the importance of uploading the intertidal beach slope when computing the total water levels on wave-dominated mesotidal sandy beaches, and therefore, the need for a consistent monitoring program of the coastal zones. Findings of this work also supported the coastal management of beach-dune systems, where regional authorities need to restore dune ridges to prevent further overwash events and erosion. The presented framework can be applied to build a beach-dune system vulnerability map in response to wave forecast and predicted sea-level rise.
Effect of Multi-Source Ultrasonic on the Microstructure and Mechanical Properties of a Large Scale 2219 Al Alloy Ingot During Casting
Authors: Li Anqing , Jiang Ripeng , Liu Zhilin , Li Ruiqing , Zhang Yun
Published: April 2022

Usage of high-energy ultrasonic vibration is an effective approach that can dramatically improve the performance of large-scale ingots. In this work, it was applied to manufacture large 2219 aluminum alloy ingots (630 mm in diameter and 4,500 mm in length). The degassing efficiency, the average size of α-Al grains, the morphology of the Al2Cu phase under double-source ultrasound (DSU), and three-source ultrasound (TSU) were compared. Meanwhile, the influence of the ultrasonic field on the macroscopic segregation of the Cu content and mechanical properties was scientifically investigated. It was found that the degassing efficiency of TSU was significantly higher than that of DSU. The results also indicated that α-Al grains were effectively refined under the TSU technology from the center to the edge of the ingot. Additionally, the distribution of the macroscopic Cu content was more uniform, and the area fraction of the Al2Cu phase was evidently decreased. The mechanical properties of the ingot were superior to samples with DSU technology. Furthermore, it was demonstrated that the stress concentration of the coarse Al2Cu phase at the center of the DSU process led to the deterioration of the mechanical properties.
Recurrent Pneumonia With Tuberculosis and Candida Co-infection Diagnosed by Metagenomic Next-Generation Sequencing: A Case Report and Literature Review
Authors: Ma Ning , Chen Mei , Ding Jingyi , Wang Fang , Jin Jingbo , Fan Sitong , Chen Jiajia
Published: April 2022

An 82-year-old male patient was hospitalized in the Respiratory Department for “repeated cough and shortness of breath for 10 years, recurrence worsened for 1 month.” Later, he was transferred for further diagnosis and treatment, to the Infectious Disease Department for further hospitalization. Previously, the patient had repeatedly undergone tuberculosis-related examinations including bronchoscopy examinations. However, no evidence of Mycobacterium tuberculosis (MTB) infection was found. Early anti-infection treatments failed. Due to repeated symptoms, we performed bronchoscopy again and sent alveolar lavage fluid for the metagenomic next-generation sequencing (mNGS) test. Subsequently, MTB and Candida albicans were detected by mNGS. After antituberculosis and antifungal treatments, the symptoms were significantly relieved, and the chest CT showed resolution of the lung lesions. Therefore, we successfully diagnosed and treated a case of recurrent pneumonia with tuberculosis and Candida co-infection diagnosed by mNGS.
Long-Term Observation of Higher-Order Aberrations and Microdistortions in Bowman’s Layer After Small Incision Lenticule Extraction for the Correcting Myopia With Spherical Equivalent Higher Than −9.0 Diopters
Authors: Zhou Xueyi , Qin Bing , Han Tian , Shang Jianmin , Chen Zhuoyi , Zhao Jing , Yao Peijun , Zhou Xingtao
Published: April 2022

Purpose

To evaluate the outcomes in corneal higher-order aberrations (HOAs) and microdistortions in the Bowman’s layer after femtosecond laser small incision lenticule extraction (SMILE) for correcting extremely high myopia.

Methods

This prospective study included patients with myopia with spherical equivalent ≥ -9.0 Diopters (D). SMILE was performed in forty eyes of 40 patients. Pentacam was used to evaluate HOAs before and at 1 day, 3 months, 6 months, and 2 years after surgery. Fourier-domain optical coherence tomography was used to evaluate microdistortions at 2 years postoperatively. Thirty-two eyes of 32 patients receiving femtosecond laser-assisted in situ keratomileusis (FS-LASIK) were enrolled as the control group. HOAs were measured before, at 1 day and at least 1 year postoperatively.

Results

After SMILE, the long-term safety and effectiveness index was 1.25 and 0.85, respectively. Microdistortions were observed in 73.5% of the eyes at 2 years, with an average number of 1.20 ± 1.22 microdistortions and an average width of 287.37 ± 259.00 μm. We detected more microdistortions in the horizontal meridian than in the vertical meridian (p = 0.035). The average number and width of microdistortions were both higher in the central region (≤4 mm) than in the peripheral region (4–8 mm) (both p < 0.001). With the exception of horizontal trefoil in the SMILE group and vertical trefoil in the FS-LASIK group, significant changes over time were observed in all other HOAs (all p < 0.05). Meanwhile, we detected significant increases in the total corneal HOA, spherical aberration (SA), and coma at all time-points after both surgeries (all p < 0.01). Compared with FS-LASIK, SMILE induced less SA (p < 0.001) and more horizontal coma (p = 0.036). In the SMILE group, the HOA, SA, and trefoil were more in the small optical zone (≤6.0 mm) than in the large optical zone (>6.0 mm) (all p < 0.05). The increase in SA and most trefoil correlated with the mean number of central microdistortions number (all p < 0.05).

Conclusion

For myopia over −9.0D, the microdistortions in the Bowman’s layer were still detectable in most eyes long-term after SMILE. Both SMILE and FS-LASIK induced more HOAs, mainly HOA, SA, and coma. The small optical zone and microdistortions may affect postoperative aberrations.
Simulation-Based Medical Education and Training Enhance Anesthesia Residents' Proficiency in Erector Spinae Plane Block
Authors: Torrano Vito , Zadek Francesco , Bugada Dario , Cappelleri Gianluca , Russo Gianluca , Tinti Giulia , Giorgi Antonio , Langer Thomas , Fumagalli Roberto
Published: April 2022

Background

Advances in regional anesthesia and pain management led to the advent of ultrasound-guided fascial plane blocks, which represent a new and promising route for the administration of local anesthetics. Both practical and theoretical knowledge of locoregional anesthesia are therefore becoming fundamental, requiring specific training programs for residents. Simulation-based medical education and training (SBET) has been recently applied to ultrasound-guided regional anesthesia (UGRA) with remarkable results. With this in mind, the anesthesia and intensive care residency program of the University of Milano-Bicocca organized a 4-h regional anesthesia training workshop with the BlockSim® (Accurate Srl, Cesena) simulator. Our study aimed to measure the residents' improvement in terms of reduction in time required to achieve an erector spinae plane (ESP) block.

Methods

Fifty-two first-year anesthesia residents were exposed to a 4-h training workshop focused on peripheral blocks. The course included an introductory theoretical session held by a locoregional anesthetist expert, a practical training on human models and mannequins using Onvision® (B. Braun, Milano) technologies, and two test performances on the BlockSim simulator. Residents were asked to perform two ESP blocks on the BlockSim: the first without previous practice on the simulator, the second at the end of the course. Trainees were also also asked to complete a self-assessment questionnaire.

Results

The time needed to achieve the block during the second attempt was significantly shorter (131 [83, 198] vs. 68 [27, 91] s, p < 0.001). We also observed a reduction in the number of needle insertions from 3 [2, 7] to 2 [1, 4] (p = 0.002), and an improvement aiming correctly at the ESP from 30 (58%) to 46 (88%) (p < 0.001). Forty-nine (94%) of the residents reported to have improved their regional anesthesia knowledge, 38 (73%) perceived an improvement in their technical skills and 46 (88%) of the trainees declared to be “satisfied/very satisfied” with the course.

Conclusions

A 4-h hands-on course based on SBET may enhance first-year residents' UGRA ability, decrease the number of punctures and time needed to perform the ESP block, and improve the correct aim of the fascia.
Bacteria, Protists, and Fungi May Hold Clues of Seamount Impact on Diversity and Connectivity of Deep-Sea Pelagic Communities
Authors: Zhao Rongjie , Zhao Feng , Zheng Shan , Li Xuegang , Wang Jianing , Xu Kuidong
Published: April 2022

The topography and hydrography around seamounts have a strong influence on plankton biogeography. The intrinsic properties of various biological taxa inherently also shape their distribution. Therefore, it is hypothesized that different pelagic groups respond differently to effects of seamounts regarding their distribution and connectivity patterns. Herein, bacterial, protist, and fungal diversity was investigated across the water column around the Kocebu Guyot in the western Pacific Ocean. A higher connectivity was detected for bacteria than for protists and an extremely low connectivity for fungi, which might be attributed to parasitic and commensal interactions of many fungal taxa. The seamount enhanced the vertical connectivity of bacterial and protist communities, but significantly reduced protist connectivity along horizontal dimension. Such effects provide ecological opportunities for eukaryotic adaption and diversification. All the bacterial, protist, and fungal communities were more strongly affected by deterministic than stochastic processes. Drift appeared to have a more significant role in influencing the fungal community than other groups. Our study indicates the impact of seamounts on the pelagic community distribution and connectivity and highlights the mechanism of horizontally restricted dispersal combined with vertical mixing, which promotes the diversification of eukaryotic life.
Changes in the Gut Metabolic Profile of Gestational Diabetes Mellitus Rats Following Probiotic Supplementation
Authors: Zheng Qing-Xiang , Wang Hai-Wei , Jiang Xiu-Min , Ge Li , Lai Yu-Ting , Jiang Xin-Yong , Huang Ping-Ping , Chen Fan , Chen Xiao-Qian
Published: April 2022

The roles of gut microbiota and metabolomics in women with gestational diabetes mellitus (GDM) are not well understood. This study investigated the gut metabolomic profiling of GDM rats and GDM rats treated with probiotic supplements. Associations between gut metabolites and microbiota were also studied in GDM rats. Liquid chromatography–mass spectrometry was used to detect gut metabolites in GDM rats and GDM rats treated with probiotic supplements of 0.5 g (low-dose group) or 1 g (high-dose group) for 15 days. Each gram of probiotic supplement contained 5 × 107 colony-forming units (CFU) of Lactobacillus rhamnosus LGG and 1 × 108 CFU of Bifidobacterium animalis subspecies lactis Bb12. The association between gut metabolites and microbiota in GDM rats was investigated using Spearman’s correlation. Finally, 10 rats in the normal pregnant group, eight rats in the GDM model group, eight GDM rats in the low-dose probiotics group, and nine GDM rats in the high-dose probiotics group were further studied. Serum parameters and pancreatic and colon histology were significantly changed in GDM rats, and these were restored using probiotic supplements. In total, 999 gut metabolites were detected in the feces, and GDM rats were distinguished from normal rats. The levels of 44 metabolites were increased in GDM rats, and they were alleviated using probiotic supplements. Changes in metabolites in GDM rats were associated with amino acids and bile acids metabolism signaling pathways. Furthermore, changes in metabolites after probiotic supplementation were associated with porphyrin and chlorophyll metabolism pathways. We found that the Allobaculum genus displayed strong positive correlations, whereas the Bryobacter and Gemmatimonas genera displayed strong negative correlations with metabolisms of amino acids and bile acids in GDM rats. The Lactobacillus and Bifidobacterium genera were positively correlated with gut metabolites. Overall, our results showed that metabolism signaling pathways of amino acids and bile acids are associated with the development of GDM. Probiotic supplements alleviate the pathology of GDM through the metabolism pathways of amino acids, bile acids, porphyrin, and chlorophyll.
Analysis of Interaction Network Between Host Protein and M Protein of Swine Acute Diarrhea Syndrome Coronavirus
Authors: Xu Jingya , Cao Ze , Ji Chihai , Zhou Ling , Yan Xiaoling , Sun Yuan , Ma Jingyun
Published: April 2022

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an enterovirus that can cause acute diarrhea and death in piglets and cause serious economic losses to the pig industry. SADS-CoV membrane (M) protein mainly plays a key role in biological processes, such as virus assembly, budding, and host innate immune regulation. Understanding the interaction between M protein and host proteins is very important to define the molecular mechanism of cells at the protein level and to understand specific cellular physiological pathways. In this study, 289 host proteins interacting with M protein were identified by glutathione-S-transferase (GST) pull-down combined with liquid chromatography-mass spectrometry (LC-MS/MS), and the protein-protein interaction (PPI) network was established by Gene Ontology (GO) terms and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathways analysis. Results showed that SADS-CoV M protein was mainly associated with the host metabolism, signal transduction, and innate immunity. The Co-Immunoprecipitation (CO-IP) validation results of six randomly selected proteins, namely, Rab11b, voltage-dependent anion-selective channel 1 (VDAC1), Ribosomal Protein L18 (RPL18), RALY, Ras Homolog Family Member A (RHOA), and Annexin A2 (ANXA2), were consistent with LC-MS results. In addition, overexpression of RPL18 and PHOA significantly promoted SADS-CoV replication, while overexpression of RALY antagonized viral replication. This work will help to clarify the function of SADS-CoV M protein in the life cycle of SADS-CoV.
Study on the Biochemical Characterization and Selectivity of Three β-Glucosidases From Bifidobacterium adolescentis ATCC15703
Authors: Hu Yanbo , Zhai Liyuan , Hong Huili , Shi Zenghui , Zhao Jun , Liu Duo
Published: April 2022

Three β-glucosidases from Bifidobacterium adolescentis ATCC15703, namely, BaBgl1A, BaBgl3A, and BaBgl3B, were overexpressed in Escherichia coli. The recombinant β-glucosidases were sufficiently purified using Ni2+ affinity chromatography, and BaBgl1A exhibited the best purification efficiency with a purification factor of 2.3-fold and specific activity of 71.2 U/mg. Three recombinant β-glucosidases acted on p-nitrophenyl-β-glucopyranoside (pNPβGlc) at around pH 7.0 and 30–50°C. The results of the substrate specificity assay suggested that BaBgl1A acted exclusively as β-1,2-glucosidase, while BaBgl3A and BaBgl3B acted mostly as β-1,3-glucosidase and β-1,4-glucosidase, respectively. The substrate specificity of the three recombinant enzymes was further studied using the ginsenosides Rb1 and Rd as substrates. The results of thin-layer chromatography and high-performance liquid chromatography analyses showed that BaBgl1A exhibited the highest bioconversion ability on Rb1 and Rd, where it hydrolyzed the outer C-3 glucose moieties of Rb1 and Rd into the rare ginsenosides Gypenoside XVII and F2; BaBgl3A exhibited medium bioconversion ability on Rb1, where it hydrolyzed both the outer C-3 and C-20 glucose moieties of Rb1 into Gyp XVII and Rd; and BaBgl3B was not active on Rb1 and Rd. These β-glucosidases will act as new biocatalytic tools for transforming ginsenosides and preparing active glycosides and aglycone.
The Emerging Role of Hedgehog Signaling in Viral Infections
Authors: Zhou Yulin , Huang Jinhua , Jin Boxin , He Su , Dang Yongfang , Zhao Tiejun , Jin Zhigang
Published: April 2022

The hedgehog (HH) signaling pathway is one of the key pathways that is indispensable for many developmental processes and postnatal tissue homeostasis. Dysregulated HH signaling could lead to developmental disorders and tumorigenesis in a variety of tissues via inherited or sporadic mutation, gene overexpression, and crosstalk with other signaling pathways. Recently, accumulating evidence has shown that HH signaling is targeted by viruses to facilitate viral transcription, immune evasion, and uncontrolled growth, leading to effective viral replication and pathogenesis. In this study, we will summarize recent advances in functional interaction between HH signaling and different types of viruses, particularly focusing on the pathological role of HH signaling in viral infections and related diseases.
Multiplatform Metabolomics Studies of Human Cancers With NMR and Mass Spectrometry Imaging
Authors: Zhong Anya B. , Muti Isabella H. , Eyles Stephen J. , Vachet Richard W. , Sikora Kristen N. , Bobst Cedric E. , Calligaris David , Stopka Sylwia A. , Agar Jeffery N. , Wu Chin-Lee , Mino-Kenudson Mari A. , Agar Nathalie Y. R. , Christiani David C. , Kaltashov Igor A. , Cheng Leo L.
Published: April 2022

The status of metabolomics as a scientific branch has evolved from proof-of-concept to applications in science, particularly in medical research. To comprehensively evaluate disease metabolomics, multiplatform approaches of NMR combining with mass spectrometry (MS) have been investigated and reported. This mixed-methods approach allows for the exploitation of each individual technique’s unique advantages to maximize results. In this article, we present our findings from combined NMR and MS imaging (MSI) analysis of human lung and prostate cancers. We further provide critical discussions of the current status of NMR and MS combined human prostate and lung cancer metabolomics studies to emphasize the enhanced metabolomics ability of the multiplatform approach.
Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration
Authors: Vilchez Mercedes Samuel A. , Bocci Federico , Ahmed Mona , Eder Ian , Zhu Ninghao , Levine Herbert , Onuchic José N. , Jolly Mohit Kumar , Wong Pak Kin
Published: April 2022

Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of immunocytochemistry, single cell biosensors, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration.
Serum Metabolomic Patterns in Patients With Aldosterone-Producing Adenoma
Authors: Chen Yule , Wang Hanjiang , Wang Ke , Zhu Guodong , Yang Zhishang , Wang Min , Song Wenbin
Published: April 2022

Aldosterone-producing adenoma (APA), the main cause of endocrine hypertension, has recently been reported to be associated with other diseases, such as metabolic syndrome, but the detailed mechanism underlying this association remains unclear. Here, we used untargeted metabolomics and compared the abundance of serum metabolites between essential hypertension (EHT) and APA patients, as well as the serum metabolites of APA patients before and after adrenalectomy. Our results revealed 44 differential metabolites between APA and EHT patients and 39 differential metabolites between pre- and postoperative APA patients. Several metabolites involved in cardiovascular disease, obesity, and diabetes were dysregulated in APA patients compared to EHT patients, including arachidonic acid metabolites [e.g., 5(S)-HpETE and 12-HETE], amino acids (e.g., L-carnitine, taurine, and L-arginine), nucleotide metabolites (e.g., hypoxanthine) and cholesterol 3-sulfate. Importantly, the levels of hypoxanthine and cholesterol 3-sulfate, two metabolites that promote the development of atherosclerotic lesions and obesity, were originally increased in APA patients, but those elevated levels were reversed by adrenalectomy. Conversely, levels of L-carnitine and (3-carboxypropyl) trimethylammonium cation, two metabolites participating in lipid metabolism, were decreased in APA patients but increased postoperatively. We conclude that APA might participate in cardiovascular and metabolic diseases by regulating serum metabolites.
Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells
Authors: Brylski Oliver , Shrestha Puja , House Philip J. , Gnutt Patricia , Mueller Jonathan Wolf , Ebbinghaus Simon
Published: April 2022

Cellular sulfation pathways rely on the activated sulfate 3′-phosphoadenosine-5′-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome. The APS kinase domain of PAPSS2 catalyzes the rate-limiting step in PAPS biosynthesis. In this study, we show that clinically described disease mutations located in the naturally fragile APS kinase domain are associated either with its destabilization and aggregation or its deactivation. Our findings provide novel insights into possible molecular mechanisms that could give rise to disease phenotypes associated with sulfation pathway genes.
Association of Endogenous Erythropoietin Levels and Iron Status With Cognitive Functioning in the General Population
Authors: Ayerdem Gizem , Bosma Matthijs J. , Vinke Joanna Sophia J. , Ziengs Aaltje L. , Potgieser Adriaan R. E. , Gansevoort Ron T. , Bakker Stephan J. L. , De Borst Martin H. , Eisenga Michele F.
Published: April 2022

Background

Emerging data suggest that erythropoietin (EPO) promotes neural plasticity and that iron homeostasis is needed to maintain normal physiological brain function. Cognitive functioning could therefore be influenced by endogenous EPO levels and disturbances in iron status.

Objective

To determine whether endogenous EPO levels and disturbances in iron status are associated with alterations in cognitive functioning in the general population.

Materials and Methods

Community-dwelling individuals from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a general population-based cohort in Groningen, Netherlands, were surveyed between 2003 and 2006. Additionally, endogenous EPO levels and iron status, consisting of serum iron, transferrin, ferritin, and transferrin saturation were analyzed. Cognitive function was assessed by scores on the Ruff Figural Fluency Test (RFFT), as a reflection of executive function, and the Visual Association Test (VAT), as a reflection of associative memory.

Results

Among 851 participants (57% males; mean age 60 ± 13 years), higher endogenous EPO levels were independently associated with an improved cognitive function, reflected by RFFT scores (ß = 0.09, P = 0.008). In multivariable backward linear regression analysis, EPO levels were among the most important modifiable determinants of RFFT scores (ß = 0.09, P = 0.002), but not of VAT scores. Of the iron status parameters, only serum ferritin levels were inversely associated with cognitive function, reflected by VAT scores, in multivariable logistic regression analysis (odds ratio, 0.77; 95% confidence interval 0.63–0.95; P = 0.02 for high performance on VAT, i.e., ≥11 points). No association between iron status parameters and RFFT scores was identified.

Conclusion

The findings suggest that endogenous EPO levels and serum ferritin levels are associated with specific cognitive functioning tests in the general population. Higher EPO levels are associated with better RFFT scores, implying better executive function. Serum ferritin levels, but not other iron status parameters, were inversely associated with high performance on the VAT score, implying a reduced ability to create new memories and recall recent past. Further research is warranted to unravel underlying mechanisms and possible benefits of therapeutic interventions.
Robot Assisted Treatment of Hand Functional Rehabilitation Based on Visual Motor Imagination
Authors: Li Long , Zhang Yanlong , Huang Liang , Zhao Jie , Wang Jue , Liu Tian
Published: April 2022

This pilot study implements a hybrid brain computer interface paradigm based on motor imagery (MI) and steady-state visual evoked potential (SSVEP), in order to explore the neural mechanism and clinical effect of MI-SSVEP intervention paradigm on upper limb functional rehabilitation. In this study, EEG data of 12 healthy participants were collected, and the activation regions of MI-SSVEP paradigm were identified by power spectral density (PSD). By analyzing the inter trial phase consistency (ITPC) of characteristic regions and the causal relationship of brain network, the motor cognitive process including high-level somatosensory joint cortex in the intervention process of MI-SSVEP was studied. Subsequently, this study verified the clinical effect of MI-SSVEP intervention paradigm for 61 stroke patients. The results show that the robot assisted therapy using MI-SSVEP intervention paradigm can more effectively improve the rehabilitation effect of patients.
The T-Type Calcium Channel Cav3.2 in Somatostatin Interneurons in Spinal Dorsal Horn Participates in Mechanosensation and Mechanical Allodynia in Mice
Authors: Zhi Yu-Ru , Cao Feng , Su Xiao-Jing , Gao Shu-Wen , Zheng Hao-Nan , Jiang Jin-Yan , Su Li , Liu Jiao , Wang Yun , Zhang Yan , Zhang Ying
Published: April 2022

Somatostatin-positive (SOM+) neurons have been proposed as one of the key populations of excitatory interneurons in the spinal dorsal horn involved in mechanical pain. However, the molecular mechanism for their role in pain modulation remains unknown. Here, we showed that the T-type calcium channel Cav3.2 was highly expressed in spinal SOM+ interneurons. Colocalization of Cacna1h (which codes for Cav3.2) and SOMtdTomato was observed in the in situ hybridization studies. Fluorescence-activated cell sorting of SOMtdTomato cells in spinal dorsal horn also proved a high expression of Cacna1h in SOM+ neurons. Behaviorally, virus-mediated knockdown of Cacna1h in spinal SOM+ neurons reduced the sensitivity to light touch and responsiveness to noxious mechanical stimuli in naïve mice. Furthermore, knockdown of Cacna1h in spinal SOM+ neurons attenuated thermal hyperalgesia and dynamic allodynia in the complete Freund’s adjuvant-induced inflammatory pain model, and reduced both dynamic and static allodynia in a neuropathic pain model of spared nerve injury. Mechanistically, a decrease in the percentage of neurons with Aβ-eEPSCs and Aβ-eAPs in superficial dorsal horn was observed after Cacna1h knockdown in spinal SOM+ neurons. Altogether, our results proved a crucial role of Cav3.2 in spinal SOM+ neurons in mechanosensation under basal conditions and in mechanical allodynia under pathological pain conditions. This work reveals a molecular basis for SOM+ neurons in transmitting mechanical pain and shows a functional role of Cav3.2 in tactile and pain processing at the level of spinal cord in addition to its well-established peripheral role.
Physics Clues on the Mind Substrate and Attributes
Authors: Torres Joaquin J. , Marro Joaquín
Published: April 2022

The last decade has witnessed a remarkable progress in our understanding of the brain. This has mainly been based on the scrutiny and modeling of the transmission of activity among neurons across lively synapses. A main conclusion, thus far, is that essential features of the mind rely on collective phenomena that emerge from a willful interaction of many neurons that, mediating other cells, form a complex network whose details keep constantly adapting to their activity and surroundings. In parallel, theoretical and computational studies developed to understand many natural and artificial complex systems, which have truthfully explained their amazing emergent features and precise the role of the interaction dynamics and other conditions behind the different collective phenomena they happen to display. Focusing on promising ideas that arise when comparing these neurobiology and physics studies, the present perspective article shortly reviews such fascinating scenarios looking for clues about how high-level cognitive processes such as consciousness, intelligence, and identity can emerge. We, thus, show that basic concepts of physics, such asdynamical phasesandnon-equilibrium phase transitions, become quite relevant to the brain activity while determined by factors at the subcellular, cellular, and network levels. We also show how these transitions depend on details of the processing mechanism of stimuli in a noisy background and, most important, that one may detect them in familiar electroencephalogram (EEG) recordings. Thus, we associate the existence of such phases, which reveal a brain operating at (non-equilibrium) criticality, with the emergence of most interesting phenomena during memory tasks.
Safety and Efficacy of Early Rehabilitation After Stroke Using Mechanical Thrombectomy: A Pilot Randomized Controlled Trial
Authors: Wang Wei , Wei Ming , Cheng Yuanyuan , Zhao Hua , Du Hutao , Hou Weijia , Yu Yang , Zhu Zhizhong , Qiu Lina , Zhang Tao , Wu Jialing
Published: April 2022

Background

Early rehabilitation (ER) has been reported to be both safe and feasible for patients' post-stroke. To date, however, ER-related outcomes concerning patients who have undergone mechanical thrombectomy (MT) have not been investigated. This study aimed to determine the feasibility of ER and whether it improves prognosis in such patients.

Methods

In this single-center, double-blinded, randomized controlled study involving 103 patients who met the study criteria (i.e., has undergone MT), we randomly divided patients (1:1) into ER and conventional rehabilitation groups. The primary outcome was mortality, while secondary outcomes included favorable outcomes (modified Rankin scale of 0–2), the incidence of non-fatal complications, and Barthel Index (BI) scores. We assessed outcomes at 3 months and 1-year post-stroke.

Results

No significant between-group differences were found in terms of mortality and favorable outcomes at 3 months and 1-year post-stroke. At 3 months, 15 (28.8%) patients in the ER group and 29 (56.9%) in the conventional rehabilitation group (p = 0.002) had non-fatal complications. The BI in the ER and conventional rehabilitation groups was 100 (85–100) and 87.5 (60–100), respectively, (p = 0.007). At 1 year, the incidence of non-fatal complications was similar between both groups [BI in the ER group, 100 (90–100), p = 0.235; BI in the conventional rehabilitation group, 90 (63.8–100); p = 0.003].

Conclusion

Early rehabilitation (ER) reduces the incidence of early immobility-related complications and effectively improves patients' activities of daily living on a short- and long-term basis. Our results indicate that MT contributes to ER in patients with stroke.

Clinical Trial Registration

www.chictr.org.cn, identifier: ChiCTR1900022665.
Temporal Changes in Serum S100B Levels From Prehospital to Early In-Hospital Sampling in Patients Suffering Traumatic Brain Injury
Authors: Seidenfaden Sophie-Charlott , Kjerulff Julie Linding , Juul Niels , Kirkegaard Hans , Fogh Møller Mette , Bloch Münster Anna-Marie , Thingemann Bøtker Morten
Published: April 2022

Background

The biomarker S100B is used for the rule-out of intracranial lesions in patients with mild traumatic brain injury (TBI) and is suggested for prehospital use in Europe. Early kinetics of S100B are not exhaustively investigated in human TBI. This post hoc descriptive study of the data from the PreTBI studies aimed to characterize the early temporal changes of S100B using two-sample timepoints.

Materials and Methods

Two consecutive blood samples were taken prehospital and in-hospital after injury and assayed for S100B. The endpoint adjudication of the outcome intracranial lesion was done by the evaluation of electronic medical patient journals. The data were analyzed using descriptive statistics, scatterplots, and temporal changes estimated by the locally weighted scatterplot smoothing (LOWESS) regression line.

Results

A total of 592 adult patients with TBI were included; 566 with Glasgow Coma Scale (GCS) 14-15, 20 with GCS 9-13, and 6 with GCS 3-8. Intracranial lesions were diagnosed in 44/566 (7.4%) of patients. In 90% of patients, S100B concentrations decreased from prehospital to in-hospital sampling. The mean decrease was−0.34 μg/L. S100B concentrations seem to decline already within 60 min. Patients sampled very close to trauma and patients suffering intracranial lesions may express a slight incline before this decline. Temporal changes of S100B did not differ in patients >65 years of age, in antiplatelet/-coagulant treatment, alcohol intoxicated, or suffering extra-cranial injuries.

Conclusion

S100B concentrations may peak earlier than expected from previous studies of temporal changes in human TBI. Patterns of S100B stand robust to parameters stated as limiting factors to the use for early rule-out of intracranial lesions in the current guidelines. Further studies are needed to investigate the ultra-early temporal profiles of other novel TBI biomarkers to assess prehospital applicability and optimal diagnostic performance in TBI.
Aberrant Inter-hemispheric Connectivity in Patients With Recurrent Major Depressive Disorder: A Multimodal MRI Study
Authors: Zheng Guo , Yingli Zhang , Shengli Chen , Zhifeng Zhou , Bo Peng , Gangqiang Hou , Yingwei Qiu
Published: April 2022

Objective

Inter-hemispheric network dysconnectivity has been well-documented in patients with recurrent major depressive disorder (MDD). However, it has remained unclear how structural networks between bilateral hemispheres relate to inter-hemispheric functional dysconnectivity and depression severity in MDD. Our study attempted to investigate the alterations in corpus callosum macrostructural and microstructural as well as inter-hemispheric homotopic functional connectivity (FC) in patients with recurrent MDD and to determine how these alterations are related with depressive severity.

Materials and Methods

Resting-state functional MRI (fMRI), T1WI anatomical images and diffusion tensor MRI of the whole brain were performed in 140 MDD patients and 44 normal controls matched for age, sex, years of education. We analyzed the macrostructural and microstructural integrity as well as voxel-mirrored homotopic functional connectivity (VMHC) of corpus callosum (CC) and its five subregion. Two-sample t-test was used to investigate the differences between the two groups. Significant subregional metrics were correlated with depression severity by spearman's correlation analysis, respectively.

Results

Compared with control subjects, MDD patients had significantly attenuated inter-hemispheric homotopic FC in the bilateral medial prefrontal cortex, and impaired anterior CC microstructural integrity (each comparison had a corrected P < 0.05), whereas CC macrostructural measurements remained stable. In addition, disruption of anterior CC microstructural integrity correlated with a reduction in FC in the bilateral medial prefrontal cortex, which correlated with depression severity in MDD patients. Furthermore, disruption of anterior CC integrity exerted an indirect influence on depression severity in MDD patients through an impairment of inter-hemispheric homotopic FC.

Conclusion

These findings may help to advance our understanding of the neurobiological basis of depression by identifying region-specific interhemispheric dysconnectivity.