bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution, 3D Imaging of the Zebrafish Gill-Associated Lymphoid Tissue (GIALT) Reveals a Novel Lymphoid Structure, the Amphibranchial Lymphoid Tissue
Authors: Dalum Alf S. , Kraus Aurora , Khan Shanawaz , Davydova Erna , Rigaudeau Dimitri , Bjørgen Håvard , López-Porras Adrián , Griffiths Gareth , Wiegertjes Geert F. , Koppang Erling O. , Salinas Irene , Boudinot Pierre , Rességuier Julien
Published: November 2021

The zebrafish is extensively used as an animal model for human and fish diseases. However, our understanding of the structural organization of its immune system remains incomplete, especially the mucosa-associated lymphoid tissues (MALTs). Teleost MALTs are commonly perceived as diffuse and scattered populations of immune cells throughout the mucosa. Yet, structured MALTs have been recently discovered in Atlantic salmon (Salmo salar L.), including the interbranchial lymphoid tissue (ILT) in the gills. The existence of the ILT was only recently identified in zebrafish and other fish species, highlighting the need for in-depth characterizations of the gill-associated lymphoid tissue (GIALT) in teleosts. Here, using 3-D high-resolution microscopy, we analyze the GIALT of adult zebrafish with an immuno-histology approach that reveals the organization of lymphoid tissues via the labeling of T/NK cells with an antibody directed to a highly conserved epitope on the kinase ZAP70. We show that the GIALT in zebrafish is distributed over at least five distinct sub-regions, an organization found in all pairs of gill arches. The GIALT is diffuse in the pharyngeal part of the gill arch, the interbranchial septum and the filaments/lamellae, and structured in two sub-regions: the ILT, and a newly discovered lymphoid structure located along each side of the gill arch, which we named the Amphibranchial Lymphoid Tissue (ALT). Based on RAG2 expression, neither the ILT nor the ALT constitute additional thymi. The ALT shares several features with the ILT such as presence of abundant lymphoid cells and myeloid cells embedded in a network of reticulated epithelial cells. Further, the ILT and the ALT are also a site for T/NK cell proliferation. Both ILT and ALT show structural changes after infection with Spring Viraemia of Carp Virus (SVCV). Together, these data suggest that ALT and ILT play an active role in immune responses. Comparative studies show that whereas the ILT seems absent in most neoteleosts (“Percomorphs”), the ALT is widely present in cyprinids, salmonids and neoteleosts, suggesting that it constitutes a conserved tissue involved in the protection of teleosts via the gills.
SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
Authors: Xia Da-Yong , Yuan Jin-Long , Jiang Xiao-Chun , Qi Min , Lai Nian-Sheng , Wu Ling-Yun , Zhang Xiang-Sheng
Published: November 2021

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.
Lactic Acid-Producing Probiotic Saccharomyces cerevisiae Attenuates Ulcerative Colitis via Suppressing Macrophage Pyroptosis and Modulating Gut Microbiota
Authors: Sun Siyuan , Xu Xiuxiu , Liang Ling , Wang Xiaoli , Bai Xue , Zhu Lanping , He Qijin , Liang Huixi , Xin Xin , Wang Li , Lou Chenxi , Cao Xiaocang , Chen Xin , Li Bingzhi , Wang Bangmao , Zhao Jingwen
Published: November 2021

Lactic acid, a metabolic by-product of host and intestinal microbiota, has been recovered as an active signal molecule in the immune system. In this study, a lactic acid biosynthesis pathway that directly produces lactic acid from glucose rather than ethanol with high production was reconstructed in Saccharomyces cerevisiae. The engineered S. cerevisiae showed anti-inflammatory activity in dextran sulfate sodium (DSS)-induced mice with improved histological damage, increased mucosal barrier, and decreased intestinal immune response. Lactic acid regulated the macrophage polarization state and inhibited the expression of pro-inflammatory cytokines in vivo and in vitro. Increasing the macrophage monocarboxylic acid transporter-mediated active lactic acid uptake suppressed the excessive activation of the NLRP3 inflammasome and the downstream caspase-1 pathway in macrophages. Moreover, lactic acid promoted histone H3K9 acetylation and histone H3K18 lactylation. Meanwhile, the engineered S. cerevisiae altered the diversity and composition of the intestinal microbiota and changed the abundance of metabolic products in mice with colitis. In conclusion, this study shows that the application of engineered S. cerevisiae attenuated DSS-induced colitis in mice via suppressing macrophage pyroptosis and modulating the intestinal microbiota, which is an effective and safe treatment strategy for ulcerative colitis.
Inflammation and Platelet Activation After COVID-19 Vaccines - Possible Mechanisms Behind Vaccine-Induced Immune Thrombocytopenia and Thrombosis
Authors: Ostrowski Sisse R. , Søgaard Ole S. , Tolstrup Martin , Stærke Nina B. , Lundgren Jens , Østergaard Lars , Hvas Anne-Mette
Published: November 2021

Introduction of vaccines against COVID-19 has provided the most promising chance to control the world-wide COVID-19 pandemic. However, the adenovirus-vector based Oxford/AstraZeneca [ChAdOx1] (AZ) and Johnson & Johnson [Ad26.CoV2.S] COVID-19 vaccines have been linked with serious thromboembolic events combined with thrombocytopenia, denominated Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). The pathogenesis of COVID-19 VITT remain incompletely understood; especially the initial events that trigger platelet activation, platelet factor (PF)4 release, complex formation and PF4 antibody production are puzzling. This is a prospective study investigating the impact of different COVID-19 vaccines on inflammation (CRP, TNF-α, IL-1β, IL-6, IL-8, IL-10), vascular endothelial activation (syndecan-1, thrombomodulin, E-selectin, ICAM-1, ICAM-3, VCAM-1), platelet activation (P-selectin, TGF-β, sCD40L) and aggregation (Multiplate® impedance aggregometry), whole blood coagulation (ROTEM®), thrombin generation and PF4 antibodies to reveal potential differences between AZ and mRNA vaccines in individuals without VITT. The study included 80 (55 AZ and 55 mRNA) vaccinated individuals and 55 non-vaccinated age- and gender matched healthy controls. The main findings where that both vaccines enhanced inflammation and platelet activation, though AZ vaccination induced a more pronounced increase in several inflammatory and platelet activation markers compared to mRNA vaccination and that post-vaccination thrombin generation was higher following AZ vaccination compared to mRNA vaccination. No difference in neither the PF4 antibody level nor the proportion of individuals with positive PF4 antibodies were observed between the vaccine groups. This is the first study to report enhanced inflammation, platelet activation and thrombin generation following AZ vaccination compared to mRNA vaccination in a head-to-head comparison. We speculate that specific components of the AZ adenovirus vector may serve as initial trigger(s) of (hyper)inflammation, platelet activation and thrombin generation, potentially lowering the threshold for a cascade of events that both trigger complications related to excessive inflammation, platelet and coagulation activation as observed in epidemiological studies and promote development of VITT when combined with high-titer functionally active PF4 antibodies.
Microfluidic Systems to Study Neutrophil Forward and Reverse Migration
Authors: Babatunde Kehinde Adebayo , Ayuso Jose M. , Kerr Sheena C. , Huttenlocher Anna , Beebe David J.
Published: November 2021

During infection, neutrophils are the most abundantly recruited innate immune cells at sites of infection, playing critical roles in the elimination of local infection and healing of the injury. Neutrophils are considered to be short-lived effector cells that undergo cell death at infection sites and in damaged tissues. However, recent in vitro and in vivo evidence suggests that neutrophil behavior is more complex and that they can migrate away from the inflammatory site back into the vasculature following the resolution of inflammation. Microfluidic devices have contributed to an improved understanding of the interaction and behavior of neutrophils ex vivo in 2D and 3D microenvironments. The role of reverse migration and its contribution to the resolution of inflammation remains unclear. In this review, we will provide a summary of the current applications of microfluidic devices to investigate neutrophil behavior and interactions with other immune cells with a focus on forward and reverse migration in neutrophils.
Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
Authors: Kaltenmeier Christof , Yazdani Hamza O. , Morder Kristin , Geller David A. , Simmons Richard L. , Tohme Samer
Published: November 2021

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.
Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation
Authors: Zheng Chaowen , Ricci Jerec , Zhang Qinqin , Alawieh Ali , Yang Xiaofeng , Nadig Satish , He Songqing , Engel Pablo , Jin Junfei , Atkinson Carl , Tomlinson Stephen
Published: November 2021

The complement system has long been recognized as a potential druggable target for a variety of inflammatory conditions. Very few complement inhibitors have been approved for clinical use, but a great number are in clinical development, nearly all of which systemically inhibit complement. There are benefits of targeting complement inhibition to sites of activation/disease in terms of efficacy and safety, and here we describe P-selectin targeted complement inhibitors, with and without a dual function of directly blocking P-selectin-mediated cell-adhesion. The constructs are characterizedin vitroand in murine models of hindlimb ischemia/reperfusion injury and hindlimb transplantation. Both constructs specifically targeted to reperfused hindlimb and provided protection in the hindlimb ischemia/reperfusion injury model. The P-selectin blocking construct was the more efficacious, which correlated with less myeloid cell infiltration, but with similarly reduced levels of complement deposition. The blocking construct also improved tissue perfusion and, unlike the nonblocking construct, inhibited coagulation, raising the possibility of differential application of each construct, such as in thromboticvs. hemorrhagic conditions. Similar outcomes were obtained with the blocking construct following vascularized composite graft transplantation, and treatment also significantly increased graft survival. This is outcome may be particularly pertinent in the context of vascularized composite allograft transplantation, since reduced ischemia reperfusion injury is linked to a less rigorous alloimmune response that may translate to the requirement of a less aggressive immunosuppressive regime for this normally nonlife-threatening procedure. In summary, we describe a new generation of targeted complement inhibitor with multi-functionality that includes targeting to vascular injury, P-selectin blockade, complement inhibition and anti-thrombotic activity. The constructs described also bound to both mouse and human P-selectin which may facilitate potential translation.
Neutrophils Orchestrate the Periodontal Pocket
Authors: Vitkov Ljubomir , Muñoz Luis E. , Schoen Janina , Knopf Jasmin , Schauer Christine , Minnich Bernd , Herrmann Martin , Hannig Matthias
Published: November 2021

The subgingival biofilm attached to tooth surfaces triggers and maintains periodontitis. Previously, late-onset periodontitis has been considered a consequence of dysbiosis and a resultant polymicrobial disruption of host homeostasis. However, a multitude of studies did not show “healthy” oral microbiota pattern, but a high diversity depending on culture, diets, regional differences, age, social state etc. These findings relativise the aetiological role of the dysbiosis in periodontitis. Furthermore, many late-onset periodontitis traits cannot be explained by dysbiosis; e.g. age-relatedness, attenuation by anti-ageing therapy, neutrophil hyper-responsiveness, and microbiota shifting by dysregulated immunity, yet point to the crucial role of dysregulated immunity and neutrophils in particular. Furthermore, patients with neutropenia and neutrophil defects inevitably develop early-onset periodontitis. Intra-gingivally injecting lipopolysaccharide (LPS) alone causes an exaggerated neutrophil response sufficient to precipitate experimental periodontitis. Vice versa to the surplus of LPS, the increased neutrophil responsiveness characteristic for late-onset periodontitis can effectuate gingiva damage likewise. The exaggerated neutrophil extracellular trap (NET) response in late-onset periodontitis is blameable for damage of gingival barrier, its penetration by bacteria and pathogen-associated molecular patterns (PAMPs) as well as stimulation of Th17 cells, resulting in further neutrophil activation. This identifies the dysregulated immunity as the main contributor to periodontal disease.
The Ira Moana Project: A Genetic Observatory for Aotearoa’s Marine Biodiversity
Authors: Liggins Libby , Noble Cory ,   The Ira Moana Network
Published: November 2021

The genetic diversity of populations plays a crucial role in ensuring species and ecosystem resilience to threats such as climate change and habitat degradation. Despite this recognized importance of genetic diversity, and its relevance to the Convention on Biological Diversity and the United Nations Sustainable Development Goals, it remains difficult to observe and synthesize genetic data at a national scale. The “Ira Moana—Genes of the Sea—Project” (https://sites.massey.ac.nz/iramoana/) has worked to improve stewardship of genetic data for Aotearoa New Zealand’s (NZ) marine organisms to facilitate marine genetic biodiversity observation, research, and conservation. The Ira Moana Project has established interoperable data infrastructures and tools that help researchers follow international best-practice (including the FAIR Principles for Data Stewardship and CARE Principles for Indigenous Data Governance) and contribute to a national genetic data resource. Where possible, the Project has employed existing infrastructures (such as the Genomic Observatories Metadatabase, GEOME) to allow interoperability with similar research activities, but has also innovated to accommodate the national interests of NZ. The Ira Moana Project has an inclusive model, and through presentations, workshops, and datathons, it has provided training, education, and opportunities for collaboration among NZ researchers. Here, we outline the motivations for the Ira Moana Project, describe the Project activities and outcomes, and plans for future development. As a timely response to national and international pressures on genetic biodiversity research, it is hoped that the Ira Moana Project will facilitate NZ researchers, communities, and conservation practitioners to navigate this crucial period, and provide tangible solutions nationally and globally.
A History of the Tuna-Dolphin Problem: Successes, Failures, and Lessons Learned
Authors: Ballance Lisa T. , Gerrodette Tim , Lennert-Cody Cleridy E. , Pitman Robert L. , Squires Dale
Published: November 2021

Multispecies aggregations of tuna, dolphins, and seabirds are prevalent and conspicuous in the vast waters of the eastern tropical Pacific and form the basis of a commercial fishery for yellowfin tuna (Thunnus albacares) through setting on schools of dolphins, which is among the largest tuna fisheries in the world. Incidental dolphin mortality associated with the development and early years of the fishery was high; by 1993 it was estimated that eastern spinner dolphins (Stenella longirostris orientalis) had been reduced to 44% and northeastern offshore spotted dolphins (S. attenuata attenuata) to 19% of pre-fishery levels. Efforts to reduce this mortality began at the inception of the fishery and comprised a diverse array of approaches: modifications to fishing methods and fishing gear (backdown, Medina panel, high-intensity floodlights, swimmers to disentangle and release dolphins); U.S. legislation (through the U.S. Marine Mammal Protection Act, MMPA, and subsequent amendments); international agreements (including the International Dolphin Conservation Program that established dolphin mortality limits, and the legally binding multilateral Agreement on the International Dolphin Conservation Program); and economic incentives [notably through establishment of the U.S. dolphin-safe label and positive certification by the Marine Stewardship Council (MSC)]. Together, these bycatch mitigation efforts have been remarkably successful; dolphin mortality due to entanglement as recorded by fisheries observers (hereafter, entanglement mortality) has been reduced by > 99%. Despite this, the degree to which dolphin populations have recovered remains unclear. Multiple lines of evidence indicate that individual dolphins experience multiple sets in their lifetimes and although causality has not been established, research suggests that chase and encirclement might have impacts on dolphins in addition to entanglement mortality. These impacts potentially include increased fetal and/or calf mortality, separation of nursing females and their calves, decreased fecundity, increased predation, disruption of mating and other social systems, and ecological disruption. The strong management emphasis on monitoring entanglement mortality, and the infrastructure necessary to support this monitoring (in particular, 100% observer coverage on large purse-seiners) require funding to the extent that other activities, particularly continued surveys to monitor stock status and clarify the potential influence of other effects of the fishery on dolphin populations, are currently inadequately funded.
Hybrid Effect of PVA Fibre and Carbon Nanotube on the Mechanical Properties and Microstructure of Geopolymers
Authors: Meng Tao , Yang Xiufen , Yu Yue , Yu Hongming , Huang Miaozhou
Published: November 2021

The concept of geopolymers has been widely studied since it was proposed. However, the wide range of applications of geopolymers is affected by brittleness and poor crack resistance. In this study, the mechanical properties of geopolymers with single-doped PVA fibres, single-doped carbon nanotubes, and mixed PVA fibers and carbon nanotubes were studied respectively first. It was found that PVA fibres and carbon nanotubes had a positive effect on improving the mechanical properties of geopolymers, especially bending strength and flexural strength. Moreover, the incorporation of PVA fibre could improve the damage morphology of geopolymers. Additionally, the phase analysis, structural group analysis, and strengthening mechanism were studied via scanning electron microscopy, mercury intrusion porosimetry analysis, X-ray diffraction pattern characterisation, Fourier transform infrared spectroscopy analysis, and magic angle spinning nuclear magnetic resonance analysis. It was found that the strengthening effect of PVA fiber to the geopolymer was primarily a physical strengthening effect, whereas the strengthening effect of carbon nanotubes to the geopolymers was both chemical and physical. Finally, based on the previous study, a multi-scale dual-fibre strengthening mechanism was proposed. Micro-nano fibre composites were used to improve microstructure via physical and chemical effects. This is helpful to improve the performance and application of geopolymers. Furthermore, it lays a preliminary theoretical foundation for engineering applications and technical improvement of geopolymers in the future.
Changes of Brain Functional Connectivity in End-Stage Renal Disease Patients Receiving Peritoneal Dialysis Without Cognitive Decline
Authors: Chang Ting-Yu , Wu Hsin-Hsu , Li Yi-Jung , Liu Ho-Ling , Yeh Chih-Hua , Jian Hui-Shan , Huang Kuo-Lun , Lee Tsong-Hai , Tian Ya-Chung , Wu Changwei W.
Published: November 2021

Background: Functional connectivity detected by resting-state functional MRI (R-fMRI) helps to discover the subtle changes in brain activities. Patients with end-stage renal disease (ESRD) on hemodialysis (HD) have impaired brain networks. However, the functional changes of brain networks in patients with ESRD undergoing peritoneal dialysis (PD) have not been fully delineated, especially among those with preserved cognitive function. Therefore, it is worth knowing about the brain functional connectivity in patients with PD by using R-fMRI.

Methods: This case-control study prospectively enrolled 19 patients with ESRD receiving PD and 24 age- and sex- matched controls. All participants without a history of cognitive decline received mini-mental status examination (MMSE) and brain 3-T R-fMRI. Comprehensive R-fMRI analyses included graph analysis for connectivity and seed-based correlation networks. Independent t-tests were used for comparing the graph parameters and connectivity networks between patients with PD and controls.

Results: All subjects were cognitively intact (MMSE > 24). Whole-brain connectivity by graph analysis revealed significant differences between the two groups with decreased global efficiency (Eglob, p < 0.05), increased betweenness centrality (BC) (p < 0.01), and increased characteristic path length (L, p < 0.01) in patients with PD. The functional connections of the default-mode network (DMN), sensorimotor network (SMN), salience network (SN), and hippocampal network (HN) were impaired in patients with PD. Meanwhile, in DMN and SN, elevated connectivity was observed in certain brain regions of patients with PD.

Conclusion: Patients with ESRD receiving PD had specific disruptions in functional connectivity. In graph analysis, Eglob, BC, and L showed significant connectivity changes compared to the controls. DMN and SN had the most prominent alterations among the observed networks, with both decreased and increased connectivity regions. Our study confirmed that significant changes in cerebral connections existed in cognitively intact patients with PD.
Donor Death Category Is an Effect Modifier Between Cold Ischemia Time and Post-transplant Graft Function in Deceased-Donor Kidney Transplant Recipients
Authors: Luo You , Dong Zhanwen , Hu Xiao , Tang Zuofu , Zhang Jinhua , Deng Weiming , Wei Xiangling , Miao Bin , Qin Feng , Na Ning
Published: November 2021

Objectives: We aimed to analyze the effect of cold ischemia time (CIT) on post-transplant graft function through mixed-effect model analysis to reduce the bias caused by paired mate kidneys.

Methods: We reviewed all kidney transplantation records from 2015 to 2019 at our center. After applying the exclusion criteria, 561 cases were included for analysis. All donor characteristics, preservation and matching information, and recipient characteristics were collected. Transplant outcomes included delayed graft function (DGF) and estimated glomerular filtration rate (eGFR). Generalized linear mixed models were applied for analysis. We also explored potential effect modifiers, namely, donor death category, expanded criteria donors, and donor death causes.

Results: Among the 561 cases, 79 DGF recipients developed DGF, and 15 recipients who died after surgery were excluded from the eGFR estimation. The median stable eGFR of the 546 recipients was 60.39 (47.63, 76.97) ml/min/1.73 m2. After adjusting for confounding covariates, CIT had a negative impact on DGF incidence [odds ratio = 1.149 (1.006, 1.313), P = 0.041]. In the evaluation of the impact on eGFR, the regression showed that CIT had no significant correlation with eGFR [β = −0.287 (−0.625, 0.051), P = 0.096]. When exploring potential effect modifiers, only the death category showed a significant interaction with CIT in the effect on eGFR (Pinteraction = 0.027). In the donation after brain death (DBD) group, CIT had no significant effect on eGFR [β = 0.135 (−0.433, 0.702), P = 0.642]. In the donation after circulatory death/donation after brain death followed by circulatory death (DCD/DBCD) group, CIT had a significantly negative effect on eGFR [β= −0.700 (−1.196, −0.204), P = 0.006]. Compared to a CIT of 0–6 h, a CIT of 6–8 or 8–12 h did not decrease the post-transplant eGFR. CIT over 12 h (12–16 h or over 16 h) significantly decreased eGFR. With the increase in CIT, the regenerated eGFR worsened (Ptrend = 0.011).

Conclusion: Considering the effect of paired mate kidneys, the risk of DGF increased with prolonged CIT. The donor death category was an effect modifier between CIT and eGFR. Prolonged CIT did not reduce the eGFR level in recipients from DBDs but significantly decreased the eGFR in recipients from DCDs/DBCDs. This result indicates the potential biological interaction between CIT and donor death category.
Comparative Efficacy and Safety of Anterograde vs. Retrograde Iodine Staining During Esophageal Chromoendoscopy: A Single-Center, Prospective, Parallel-Group, Randomized, Controlled, Single-Blind Trial
Authors: Tian Xu , Yang Wei , Chen Wei-Qing
Published: November 2021

Background and Aim: Chromoendoscopy with iodine staining is an important diagnostic method for esophageal carcinomas or precancerous lesions. Unfortunately, iodine staining can be associated with numerous adverse events (AEs). We found that the starting position of spraying iodine solution is likely the main reason of causing AEs. We conducted this work to determine whether clinical outcomes from anterograde iodine staining were superior to those achieved after retrograde iodine staining.

Methods: A total of 134 subjects with a health risk appraisal flushing (HRA-F) score of >6 for esophageal cancer were randomly assigned to receive anterograde or retrograde iodine staining in the esophagus. The primary endpoints were the pain and the amount of iodine solution consumption. The secondary endpoints were iodine-staining effect, detection yield, and response to starch indicator.

Results: Nine patients suffered from pain and six patients revealed positive response to starch indicator in retrograde iodine-staining group; however, no patient reported pain (0/67) and all patients revealed a negative response to starch indicator in anterograde iodine-staining group. The amount of iodine solution consumption in anterograde iodine-staining group (4.97 mL) was significantly lower than that (6.23 mL) in retrograde iodine-staining group; however, the iodine-staining effect and detection yield were comparable between the two groups.

Conclusions: Anterograde iodine staining during Lugol chromoendoscopy appears to be as effective, but significantly safer than retrograde iodine staining.
Androgen Receptor Pathway Activity Assay for Sepsis Diagnosis and Prediction of Favorable Prognosis
Authors: Bouwman Wilbert , Verhaegh Wim , Stolpe Anja van de
Published: November 2021

Introduction: Sepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis as well as assessment of prognosis is difficult. Aside from antibiotics-based treatment of the causative infection and supportive measures, treatment options have remained limited. Better understanding of the immuno-pathophysiology of sepsis is expected to lead to improved diagnostic and therapeutic solutions.

Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways, that are active in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities have been analyzed in whole blood samples from patients with sepsis.

Methods: A validated and previously published set of signal transduction pathway (STP) assays, enabling determination of immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathways.

Results: Activity of AR and TGFβ pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold for abnormal STP activity, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a positive prediction value (PPV) of 99% and negative prediction value (NPV) of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).

Conclusion: The AR and TGFβ pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.
Clinical Significance of Diffusely Increased Uptake of 68Ga-FAPI in Thyroid Gland
Authors: Liu Huipan , Yang Xiao , Liu Lin , Lei Lei , Wang Li , Chen Yue
Published: November 2021

Purpose: To determine the clinical significance of diffuse uptake of 68Ga-FAPI in the thyroid.

Methods: From January 2020 to September 2021, all subjects with diffuse thyroid uptake in 68Ga-FAPI PET/CT were investigated in our hospital, and compared with the age and sex matched control group. The 68Ga-FAPI uptake in the thyroid gland was analyzed semi-quantitatively using the maximum standardized uptake value (SUVmax), and regression analysis was used to analyze the correlation between available serum thyroid stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb).

Results: Among 815 subjects, 39 subjects were found diffuse FAPI uptake in thyroid gland; 11 subjects refused further examination; a total of 28 subjects were included in the analysis, and 27 subjects were diagnosed with chronic thyroiditis (including 20 subjects with Hashimoto's thyroiditis), 3 subjects with Grave's disease, 3 subjects with only serum TSH elevated, and 1 subject with malignant of thyroid and thyroiditis. The SUVmax of 27 subjects with thyroiditis was 5.75 ± 5.45. No significant correlation was found between the SUVmax and the level of serum TSH (P = 0.389) or TPOAb (P = 0.426).

Conclusion: The incidentally discovered diffusely increased 68Ga-FAPI uptake in the thyroid gland is mostly related to chronic lymphocytic (Hashimoto's) thyroiditis. 68Ga-FAPI uptake level correlated neither with the degree of hypothyroidism nor with the titer of TPOAb. In addition, immune-related thyroiditis with immune checkpoint inhibitors may be accidentally found on 68Ga-FAPI, which may be helpful in facilitate timely intervention.
Mapping Knowledge Structure and Themes Trends of Osteoporosis in Rheumatoid Arthritis: A Bibliometric Analysis
Authors: Wu Haiyang , Cheng Kunming , Guo Qiang , Yang Weiguang , Tong Linjian , Wang Yulin , Sun Zhiming
Published: November 2021

Background: Rheumatoid arthritis is a chronic disabling disease characterized by chronic inflammation, articular cartilage destruction, and reduced bone mass. Multiple studies have revealed that the development of osteoporosis in rheumatoid arthritis (RA; ORA) patients could be led to a reduced quality of life and increased healthcare costs. Nevertheless, no attempt has been made to analyze the field of ORA research with the bibliometric method. This study aimed to provide a comprehensive overview of the knowledge structure and theme trends in the field of ORA research from a bibliometric perspective.

Methods: Articles and reviews regarding ORA from 1998 to 2021 were identified from the Web of Science database. An online bibliometric platform, CiteSpace, and VOSviewer software were used to generate visualization knowledge maps including co-authorship, co-citation, and co-occurrence analysis. SPSS, R, and Microsoft Excel software were used to conduct curve fitting and correlation analysis, and to analyze quantitative indicators, such as publication and citation counts, h-index, and journal citation reports.

Results: A total of 1,081 papers with 28,473 citations were identified. Publications were mainly concentrated in North America, Western Europe, and Eastern Asia. Economic strength is an important factor affecting scientific output. The United States contributed the most publications (213) with the highest h-index value (46) as of September 14, 2021. Diakonhjemmet Hospital and professor Haugeberg G were the most prolific institution and influential authors, respectively. Journal of Rheumatology was the most productive journal concerning ORA research. According to the burst references, “anti-citrullinated protein antibodies” and “preventing joint destruction” have been recognized as the hot research issues in the domain. The keywords co-occurrence analysis identified “teriparatide,” “interleukin-6,” “Wnt,” and “vertebral fractures” as the important future research directions.

Conclusion: This was the first bibliometric study comprehensively summarizing the trends and development of ORA research. Our findings could offer practical sources for scholars to understand the key information in this field, and identify the potential research frontiers and hot directions in the near future.
Pleural Effusion Caused by Mycolicibacterium mageritense in an Immunocompetent Host: A Case Report
Authors: Niitsu Takayuki , Kuge Tomoki , Fukushima Kiyoharu , Matsumoto Yuki , Abe Yuko , Okamoto Masashi , Haduki Kako , Saito Haruko , Nitta Tadayoshi , Kawano Akira , Matsuki Takanori , Motooka Daisuke , Tsujino Kazuyuki , Miki Keisuke , Nakamura Shota , Kida Hiroshi , Kumanogoh Atsushi
Published: November 2021

Mycolicibacterium mageritense (M. mageritense) is a rare species among rapidly growing mycobacteria, and M. mageritense pleurisy is very rare. Here, we report for the first time, an immunocompetent patient with pleurisy caused by M. mageritense. The patient had no history of immunodeficiency and no recurrence of lung cancer after surgery. However, 8 months after surgery, he developed a new lung shadow and pleurisy. Although whole-genome analysis of the colony cultured from the patient's pleural fluid revealed M. mageritense, we could not identify it in time, resulting in a poor outcome. M. mageritense pleurisy in this case might have occurred via a bulla rupture of the lung lesion because computed tomography of the patient's chest showed pneumothorax and a lung lesion in contact with thoracic cavity. This case emphasized that nontuberculous mycobacterial pleurisy should be considered in the differential diagnoses of pleural effusion even in immunocompetent patients. Advancement of comprehensive and rapid analyses of genomic data from clinical specimens will lead to better treatment strategies.
Discovery and Community Dynamics of Novel ssRNA Mycoviruses in the Conifer Pathogen Heterobasidion parviporum
Authors: Sutela Suvi , Piri Tuula , Vainio Eeva J.
Published: November 2021

Heterobasidion species are highly destructive basidiomycetous conifer pathogens of the Boreal forest region. Earlier studies have revealed dsRNA virus infections of families Curvulaviridae and Partitiviridae in Heterobasidion strains, and small RNA deep sequencing has also identified infections of Mitoviridae members in these fungi. In this study, the virome of Heterobasidion parviporum was examined for the first time by RNA-Seq using total RNA depleted of rRNA. This method successfully revealed new viruses representing two established (+)ssRNA virus families not found earlier in Heterobasidion: Narnaviridae and Botourmiaviridae. In addition, we identified the presence of a recently described virus group tentatively named “ambiviruses” in H. parviporum. The H. parviporum isolates included in the study originated from experimental forest sites located within 0.7 km range from each other, and a population analysis including 43 isolates was conducted at one of the experimental plots to establish the prevalence of the newly identified viruses in clonally spreading H. parviporum individuals. Our results indicate that viral infections are considerably more diverse and common among Heterobasidion isolates than known earlier and include ssRNA viruses with high prevalence and interspecies variation.
Development of a Molecular Serotyping Scheme for Morganella morganii
Authors: Liu Bin , Guo Xi , Wang Jing , Wu Pan , Li Shujie , Feng Lu , Liu Bin , Wang Lei
Published: November 2021

Morganella morganii, which is often regarded as a human commensal organism, can be an opportunistic pathogen, causing a variety of clinical infections with serious morbidity and mortality. An efficient and convenient method for subtyping and identifying M. morganii strains in epidemiological surveillance and control is urgently needed. Serotyping based on bacterial surface polysaccharide antigens (O-antigen or K-antigens) is a standard subtyping method for many gram-negative bacteria. Here, through whole genome sequencing and comparative genomics analysis of 27 strains, we developed a molecular serotyping scheme based on the genetic variation of O-antigen gene clusters (O-AGC) in M. morganii, and 11 distinct O-AGC types were identified. A conventional serotyping scheme was also developed by the production of antisera and agglutination experiments, which was shown to be perfectly consistent with the molecular serotyping scheme, confirming that the variation in M. morganii O-AGC correlated with phenotypic O-antigen diversification. Furthermore, a microsphere-based suspension array (MSA) with high specificity was developed based on the specific genes within each O-AGC type. The sensitivity of MSA was determined to be 0.1 ng of genomic DNA and 103 CFU of pure culture. We further analyzed 104 M. morganii genomes available in GenBank, and an additional six novel O-AGC types were identified, indicating that the extension of this molecular serotyping scheme is convenient. Our work provides an important tool for the detection and epidemiological surveillance of M. morganii, and this method has the potential to be widely utilized, especially for bacterial genera/species without an efficient typing approach.
WebMaBoSS: A Web Interface for Simulating Boolean Models Stochastically
Authors: Noël Vincent , Ruscone Marco , Stoll Gautier , Viara Eric , Zinovyev Andrei , Barillot Emmanuel , Calzone Laurence
Published: November 2021

WebMaBoSS is an easy-to-use web interface for conversion, storage, simulation and analysis of Boolean models that allows to get insight from these models without any specific knowledge of modeling or coding. It relies on an existing software, MaBoSS, which simulates Boolean models using a stochastic approach: it applies continuous time Markov processes over the Boolean network. It was initially built to fill the gap between Boolean and continuous formalisms, i.e., providing semi-quantitative results using a simple representation with a minimum number of parameters to fit. The goal of WebMaBoSS is to simplify the use and the analysis of Boolean models coping with two main issues: 1) the simulation of Boolean models of intracellular processes with MaBoSS, or any modeling tool, may appear as non-intuitive for non-experts; 2) the simulation of already-published models available in current model databases (e.g., Cell Collective, BioModels) may require some extra steps to ensure compatibility with modeling tools such as MaBoSS. With WebMaBoSS, new models can be created or imported directly from existing databases. They can then be simulated, modified and stored in personal folders. Model simulations are performed easily, results visualized interactively, and figures can be exported in a preferred format. Extensive model analyses such as mutant screening or parameter sensitivity can also be performed. For all these tasks, results are stored and can be subsequently filtered to look for specific outputs. This web interface can be accessed at the address: https://maboss.curie.fr/webmaboss/ and deployed locally using docker. This application is open-source under LGPL license, and available at https://github.com/sysbio-curie/WebMaBoSS.
The Role of Notch Signaling Pathway in Non-Alcoholic Fatty Liver Disease
Authors: Xu Hao , Wang Lin
Published: November 2021

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH), liver cirrhosis, or hepatocellular carcinoma (HCC). NAFLD is a kind of metabolic disordered disease, which is commonly associated with lipid metabolism, insulin resistance, oxidative stress, inflammation, and fibrogenesis, as well as autophagy. Growing studies have shown Notch signaling pathway plays a pivotal role in the regulation of NAFLD progression. Here, we review the profile of the Notch signaling pathway, new evidence of Notch signaling involvement in NAFLD, and describe the potential of Notch as a biomarker and therapeutic target for NAFLD treatment.
Spinal Cord Parenchyma Vascular Redistribution Underlies Hemodynamic and Neurophysiological Changes at Dynamic Neck Positions in Cervical Spondylotic Myelopathy
Authors: Yu Zhengran , Cheng Xing , Chen Jiacheng , Huang Zhong , He Shaofu , Hu Hao , Lin Sixiong , Zou Zhiyuan , Huang Fangli , Chen Bolin , Wan Yong , Peng Xinsheng , Zou Xuenong
Published: November 2021

Cervical spondylotic myelopathy (CSM) is a degenerative condition of the spine that caused by static and dynamic compression of the spinal cord. However, the mechanisms of motor and somatosensory conduction, as well as pathophysiological changes at dynamic neck positions remain unclear. This study aims to investigate the interplay between neurophysiological and hemodynamic responses at dynamic neck positions in the CSM condition, and the pathological basis behind. We first demonstrated that CSM patients had more severe dynamic motor evoked potentials (DMEPs) deteriorations upon neck flexion than upon extension, while their dynamic somatosensory evoked potentials (DSSEPs) deteriorated to a similar degree upon extension and flexion. We therefore generated a CSM rat model which developed similar neurophysiological characteristics within a 4-week compression period. At 4 weeks-post-injury, these rats presented decreased spinal cord blood flow (SCBF) and oxygen saturation (SO2) at the compression site, especially upon cervical flexion. The dynamic change of DMEPs was significantly correlated with the change in SCBF from neutral to flexion, suggesting they were more sensitive to ischemia compared to DSSEPs. We further demonstrated significant vascular redistribution in the spinal cord parenchyma, caused by angiogenesis mainly concentrated in the anterior part of the compressed site. In addition, the comparative ratio of vascular densities at the anterior and posterior parts of the cord was significantly correlated with the perfusion decrease at neck flexion. This exploratory study revealed that the motor and somatosensory conductive functions of the cervical cord changed differently at dynamic neck positions in CSM conditions. Compared with somatosensory conduction, the motor conductive function of the cervical cord suffered more severe deteriorations upon cervical flexion, which could partly be attributed to its higher susceptibility to spinal cord ischemia. The uneven angiogenesis and vascular distribution in the spinal cord parenchyma might underlie the transient ischemia of the cord at flexion.