bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucose Fluctuations Aggravate Myocardial Fibrosis via the Nuclear Factor-κB-Mediated Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation
Authors: Zhang Zhen-Ye , Dang Shi-Peng , Li Shan-Shan , Liu Ying , Qi Miao-Miao , Wang Ning , Miao Ling-Feng , Wu Ying , Li Xiao-Yan , Wang Chun-Xin , Qian Ling-Ling , Wang Ru-Xing
Published: May 2022

Background

Glucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis.

Methods

Streptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro.

Results

The left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1β, IL-18, transforming growth factor-β1 (TGF-β1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro, the inhibition of NF-κB and inflammasome reversed these effects. In vivo, NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations.

Conclusion

Glucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.
Prognostic Impact of Multiple Lymphocyte-Based Inflammatory Indices in Acute Coronary Syndrome Patients
Authors: Li Qiuxuan , Ma Xiaoteng , Shao Qiaoyu , Yang Zhiqiang , Wang Yufei , Gao Fei , Zhou Yujie , Yang Lixia , Wang Zhijian
Published: May 2022

Background

The aim of this study was to evaluate the prognostic values of five lymphocyte-based inflammatory indices (platelet-lymphocyte ratio [PLR], neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], systemic immune inflammation index [SII], and system inflammation response index [SIRI]) in patients with acute coronary syndrome (ACS).

Methods

A total of 1,701 ACS patients who underwent percutaneous coronary intervention (PCI) were included in this study and followed up for major adverse cardiovascular events (MACE) including all-cause death, non-fatal ischemic stroke, and non-fatal myocardial infarction. The five indices were stratified by the optimal cutoff value for comparison. The association between each of the lymphocyte-based inflammatory indices and MACE was assessed by the Cox proportional hazards regression analysis.

Results

During the median follow-up of 30 months, 107 (6.3%) MACE were identified. The multivariate COX analysis showed that all five indices were independent predictors of MACE, and SIRI seemingly performed best (Hazard ratio [HR]: 3.847; 95% confidence interval [CI]: [2.623–5.641]; p < 0.001; C-statistic: 0.794 [0.731–0.856]). The addition of NLR, MLR, SII, or SIRI to the Global Registry of Acute Coronary Events (GRACE) risk score, especially SIRI (C-statistic: 0.699 [0.646–0.753], p < 0.001; net reclassification improvement [NRI]: 0.311 [0.209–0.407], p < 0.001; integrated discrimination improvement [IDI]: 0.024 [0.010–0.046], p < 0.001), outperformed the GRACE risk score alone in the risk predictive performance.

Conclusion

Lymphocyte-based inflammatory indices were significantly and independently associated with MACE in ACS patients who underwent PCI. SIRI seemed to be better than the other four indices in predicting MACE, and the combination of SIRI with the GRACE risk score could predict MACE more accurately.
Necropsy Validation of a Novel Method for Left Ventricular Mass Quantification in Porcine Transthoracic and Transdiaphragmal Echocardiography
Authors: Kristensen Charlotte Burup , Sattler Stefan Michael , Lubberding Anniek Frederike , Tfelt-Hansen Jacob , Jespersen Thomas , Hassager Christian , Mogelvang Rasmus
Published: May 2022

Introduction

Increased left ventricular mass (LVM) is one of the most powerful predictors of adverse cardiovascular events. Clinical evaluation requires reliable, accurate and reproducible echocardiographic LVM-quantification to manage patients. For this purpose, we have developed a novel two-dimensional (2D) method based on adding the mean wall thickness to the left ventricular volume acquired by the biplane method of disks, which has recently been validated in humans using cardiac magnetic resonance as reference value. We assessed the hypothesis that the novel method has better accuracy than conventional one-dimensional (1D) methods, when compared to necropsy LVM in pigs.

Materials and Methods

Echocardiography was performed during anesthesia in 34 Danish Landrace pigs, weight 47–59 kg. All pigs were euthanized, cardiac necropsy was performed and the left ventricle was trimmed and weighed for necropsy LVM. Trans-thoracic echocardiography was applied for parasternal images. Transdiaphragmal echocardiography was applied for the apical images, which are otherwise difficult to obtain in pigs. We compared the conventional 1D- and 2D-methods and the novel 2D-method to the LVM from cardiac necropsy.

Results

Necropsy LVM was 132 ± 11 g (mean ± SD). The novel method had better accuracy than other methods (mean difference ± 95% limits of agreement; coefficients of variation; standard error of the estimate, Pearson's correlation). Novel (−1 ± 20 g; 8%; 11 g; r = 0.70), Devereux (+26 ± 37 g; 15%; 33 g; r = 0.52), Area-Length (+27 ± 34 g; 13 %; 33 g; r = 0.63), Truncated Ellipsoid (+10 ± 30 g; 12%; 19 g; r = 0.63), biplane endo-/epicardial tracing (−3 ± 2 g; 10%; 14 g; r = 0.57). No proportional bias in linear regression was detected for any method, when compared to necropsy LVM.

Conclusion

We confirm high accuracy of the novel 2D-based method compared to conventional 1D/2D-methods.
12 Plagues of AI in Healthcare: A Practical Guide to Current Issues With Using Machine Learning in a Medical Context
Authors: Doyen Stephane , Dadario Nicholas B.
Published: May 2022

The healthcare field has long been promised a number of exciting and powerful applications of Artificial Intelligence (AI) to improve the quality and delivery of health care services. AI techniques, such as machine learning (ML), have proven the ability to model enormous amounts of complex data and biological phenomena in ways only imaginable with human abilities alone. As such, medical professionals, data scientists, and Big Tech companies alike have all invested substantial time, effort, and funding into these technologies with hopes that AI systems will provide rigorous and systematic interpretations of large amounts of data that can be leveraged to augment clinical judgments in real time. However, despite not being newly introduced, AI-based medical devices have more than often been limited in their true clinical impact that was originally promised or that which is likely capable, such as during the current COVID-19 pandemic. There are several common pitfalls for these technologies that if not prospectively managed or adjusted in real-time, will continue to hinder their performance in high stakes environments outside of the lab in which they were created. To address these concerns, we outline and discuss many of the problems that future developers will likely face that contribute to these failures. Specifically, we examine the field under four lenses: approach, data, method and operation. If we continue to prospectively address and manage these concerns with reliable solutions and appropriate system processes in place, then we as a field may further optimize the clinical applicability and adoption of medical based AI technology moving forward.
Partial Clinical Remission of Type 1 Diabetes: The Need for an Integrated Functional Definition Based on Insulin-Dose Adjusted A1c and Insulin Sensitivity Score
Authors: Nwosu Benjamin Udoka
Published: May 2022

Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.
An Approach for the Dynamic Reliability Assessment of the Digital Power Control System for Nuclear Reactor
Authors: Gui Maolei , Sui Yang , Ding Rui , Xing Shangpeng , Yu Tao , Xu Jintao , Yang Baosong , Meng Fanpeng
Published: May 2022

The digital power control system for nuclear reactor (DPCSNR) for a nuclear power plant has dynamic characteristics including dynamic interaction, time dependence, and causal relationship uncertainty, and it is of great significance to assess its dynamic reliability. This study aimed to propose an approach for the dynamic reliability assessment of the DPCSNR with dynamic characteristics. First, the dynamic fault tree analysis (DFTA) method was used to establish a DFT characterizing the dynamic interaction for the DPCSNR. Then, the dynamic Bayesian network (DBN) method was used to transform the DFT into the initial DBN (IDBN) model characterizing the dynamic interaction and time dependence for the DPCSNR. Furthermore, the fuzzy mathematics (FM) method was used to modify the conditional probability table (CPT) characterizing the causal relationship uncertainty in the IDBN model and to establish the DBN model characterizing the dynamic interaction, time dependence, and causal relationship uncertainty for the DPCSNR. Finally, DBN reasoning was applied to assess the dynamic reliability of the DPCSNR. The results showed that the system reliability under conditions of periodic tests and predictable maintenance was 99.959%, and the computer system was the most critical event of the DPCSNR failure.
Wind Speed Controls Forest Structure in a Subtropical Forest Exposed to Cyclones: A Case Study Using an Individual-Based Model
Authors: Rau E-Ping , Gardiner Barry A. , Fischer Fabian Jörg , Maréchaux Isabelle , Joetzjer Emilie , Sun I-Fang , Chave Jérôme
Published: May 2022

Extreme wind blowdown events can significantly modify the structure and composition of forests, and the predicted shift in tropical cyclone regimes due to climate change could strongly impact forests across the tropics. In this study, we coupled an individual-based and spatially-explicit forest dynamics model (TROLL) with a mechanistic model estimating wind damage as a function of tree size, traits, and allometry (ForestGALES). We assimilated floristic trait data and climate data from a subtropical forest site in Taiwan to explore the effect of wind regimes on forest properties. We found that the average canopy height and biomass stocks decreased as wind disturbance strength increased, but biomass stocks showed a nonlinear response. Above a wind intensity threshold, both canopy height and biomass drastically decreased to near-zero, exhibiting a transition to a non-forest state. Wind intensity strongly regulated wind impact, but varying wind frequency did not cause discernible effects. The implementation of within-stand topographic heterogeneity led to weak effects on within-stand forest structure heterogeneity at the study site. In conclusion, the intensity of wind disturbances can potentially greatly impact forest structure by modifying mortality. Individual-based modeling provides a framework in which to investigate the impact of wind regimes on mortality, other factors influencing wind-induced tree mortality, as well as interaction between wind and other forms of forest disturbance and human land use legacy.
Forest Fire History in Amazonia Inferred From Intensive Soil Charcoal Sampling and Radiocarbon Dating
Authors: Feldpausch Ted R. , Carvalho Lidiany , Macario Kita D. , Ascough Philippa L. , Flores César F. , Coronado Eurídice N. Honorio , Kalamandeen Michelle , Phillips Oliver L. , Staff Richard A.
Published: May 2022

Fire has a historical role in tropical forests related to past climate and ancient land use spanning the Holocene; however, it is unclear from charcoal records how fire varied at different spatiotemporal scales and what sampling strategies are required to determine fire history and their effects. We evaluated fire variation in structurally intact, terra-firme Amazon forests, by intensive soil charcoal sampling from three replicate soil pits in sites in Guyana and northern and southern Peru. We used radiocarbon (14C) measurement to assess (1) locally, how the timing of fires represented in our sample varied across the surface of forest plots and with soil depth, (2) basin-wide, how the age of fires varies across climate and environmental gradients, and (3) how many samples are appropriate when applying the 14C approach to assess the date of last fire. Considering all 14C dates (n = 33), the most recent fires occurred at a similar time at each of the three sites (median ages: 728–851 cal years BP), indicating that in terms of fire disturbance at least, these forests could be considered old-growth. The number of unique fire events ranged from 1 to 4 per pit and from 4 to 6 per site. Based upon our sampling strategy, the N-Peru site—with the highest annual precipitation—had the most fire events. Median fire return intervals varied from 455 to 2,950 cal years BP among sites. Based on available dates, at least three samples (1 from the top of each of 3 pits) are required for the sampling to have a reasonable likelihood of capturing the most recent fire for forests with no history of a recent fire. The maximum fire return interval for two sites was shorter than the time since the last fire, suggesting that over the past ∼800 years these forests have undergone a longer fire-free period than the past 2,000–3,500 years. Our analysis from terra-firme forest soils helps to improve understanding of changes in fire regime, information necessary to evaluate post-fire legacies on modern vegetation and soil and to calibrate models to predict forest response to fire under climate change.
Beech Bark Disease in an Unmanaged Temperate Forest: Patterns, Predictors, and Impacts on Ecosystem Function
Authors: Kish Rosalyn , James Patrick M. A. , Mariani Rachel O. , Schurman Jonathan S. , Thomas Sean C. , Young Emily N. , Martin Adam R.
Published: May 2022

Beech Bark Disease (BBD) is a devastating threat to American beech (Fagus grandifolia), spreading through eastern mixed deciduous forests of North America at unprecedented rates. Understanding how and why some beech trees escape severe BBD effects is important; however, the biotic and abiotic factors that underpin the progression of BBD within unmanaged forests at local scales are not well explored. We surveyed 651 individual beech trees ≥ 10 cm diameter at breast height (DBH) for BBD, in a 13.5-ha unmanaged forest dynamics plot in Ontario, Canada, where >46,000 trees have been identified to species, mapped, and DBH measured at ∼5-year intervals. For each beech tree, BBD severity was ranked on a 5-point severity index, which was then evaluated as a function of tree characteristics including DBH and relative growth rate (RGR). Most beech trees were at either the insect or fungal stage of BBD, with only 22% of beech trees being free of symptoms. Ordinal logistic regression analysis indicated both DBH and RGR were significant predictors of BBD severity. These models, along with both randomization and Moran’s Eigenvector Maps (MEM) analyses, indicated that DBH and RGR and their spatial variation accounted for ∼44.6% of BBD severity in trees. Our MEMs also indicated ∼4.2% of variation in BBD severity was associated with unmeasured spatial variables, which may reflect either the spread of BBD through our study site, or the influence of abiotic variables on BBD severity. At our site, BBD is responsible for at least ∼6.0 Mg C ha–1, or ∼6.5% of the average 92.5 Mg of aboveground biomass C ha–1, transitioning from the live to dead biomass pool. Our study enhances the understanding of the factors predicting the severity of a major forest pathogen in North American temperate forests, assists the integration of BBD severity risk into forest C budget models, and provides insight into how large-scale forest inventories can inform screening for pest or pathogen resistance in trees.
Suberoylanilide Hydroxamic Acid (SAHA) Treatment Reveals Crosstalk Among Proteome, Phosphoproteome, and Acetylome in Nasopharyngeal Carcinoma Cells
Authors: Huang Huichao , Fu Ying , Duan Yankun , Zhang Ye , Lu Miaolong , Chen Zhuchu , Li Maoyu , Chen Yongheng
Published: May 2022

Suberoylanilide hydroxamic acid (SAHA), a famous histone deacetylase (HDAC) inhibitor, has been utilized in clinical treatment for cutaneous T-cell lymphoma. Previously, the mechanisms underlying SAHA anti-tumor activity mainly focused on acetylome. However, the characteristics of SAHA in terms of other protein posttranslational modifications (PTMs) and the crosstalk between various modifications are poorly understood. Our previous work revealed that SAHA had anti-tumor activity in nasopharyngeal carcinoma (NPC) cells as well. Here, we reported the profiles of global proteome, acetylome, and phosphoproteome of 5–8 F cells upon SAHA induction and the crosstalk between these data sets. Overall, we detected and quantified 6,491 proteins, 2,456 phosphorylated proteins, and 228 acetylated proteins in response to SAHA treatment in 5–8 F cells. In addition, we identified 46 proteins exhibiting both acetylation and phosphorylation, such as WSTF and LMNA. With the aid of intensive bioinformatics analyses, multiple cellular processes and signaling pathways involved in tumorigenesis were clustered, including glycolysis, EGFR signaling, and Myc signaling pathways. Taken together, this study highlighted the interconnectivity of acetylation and phosphorylation signaling networks and suggested that SAHA-mediated HDAC inhibition may alter both acetylation and phosphorylation of viral proteins. Subsequently, cellular signaling pathways were reprogrammed and contributed to anti-tumor effects of SAHA in NPC cells.
Impact of IgG Isotype on the Induction of Antibody-Dependent Cellular Phagocytosis of HIV by Human Milk Leukocytes
Authors: Fox Alisa , Liu Xiaomei , Zolla-Pazner Susan , Powell Rebecca L.
Published: May 2022

Approximately 100,000 mother-to-child transmission (MTCT) events of HIV via human milk feeding occur each year. However, only about 15% of infants milk-fed by untreated HIV+ mothers become infected, suggesting a protective effect of the milk itself. Infants ingest 105-108 maternal leukocytes daily via milk, which remain functional beyond ingestion. Such function may be elicited by maternal milk antibody (Ab). Though IgA is dominant in milk, most HIV-specific milk Abs are of the IgG subclass, highlighting the importance of investigating the function of each IgG isotype in the milk context. Though Ab effector function mediated by the constant (Fc) domain via interaction with Fc Receptors (FcRs), such as Ab-dependent cellular phagocytosis (ADCP), are critical in protecting against HIV infection, ADCP is largely unexplored as it relates to mitigation of MTCT. Presently we report the ADCP activity of milk leukocytes against HIV particles and immune complexes (ICs), using 57 unique samples from 34 women, elicited by IgG1/2/3/4 of monoclonal (m)Ab 246-D. Granulocyte ADCP of HIV was most potent compared to other phagocytes when elicited by IgG1/3/4. IgG1/3 activated granulocytes similarly, exhibiting 1.6x-4.4x greater activity compared to IgG2/4, and a preference for virus compared to ICs. Notably, CD16- monocyte ADCP of a given target were unaffected by isotype, and CD16+ monocytes were poorly stimulated by IgG1. IgG2/4 elicited potent IC ADCP, and in terms of total leukocyte IC ADCP, IgG4 and IgG3 exhibited similar function, with IgG4 eliciting 1.6x-2.1x greater activity compared to IgG1/IgG2, and CD16+ monocytes most stimulated by IgG2. These data contribute to a more comprehensive understanding of Fc-mediated functionality of milk leukocytes, which is critical in order to develop therapeutic approaches to eliminating this route of MTCT, including mucosal administration of mAbs and/or a maternal vaccination aimed to elicit a potent milk Ab response.
Sperm Autoantigenic Protein 17 Predicts the Prognosis and the Immunotherapy Response of Cancers: A Pan-Cancer Analysis
Authors: Tu Zewei , Peng Jie , Long Xiaoyan , Li Jingying , Wu Lei , Huang Kai , Zhu Xingen
Published: May 2022

Background

Sperm autoantigen protein 17 (SPA17) is a highly conserved mammalian protein that participates in the acrosome reaction during fertilization and is a recently reported member of the cancer-testicular antigen (CTA) family. It has been reported that the SPA17 expression is limited in adult somatic tissues and re-expressed in tumor tissues. Recently, studies have found that SPA17 regulates the progression of various cancers, but its role in cancer immunotherapy is not clear.

Methods

The pan-cancer and normal tissue transcriptional data were acquired from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. We explored the SPA17 pan-cancer genomic alteration analysis in the cBioPortal webtool. The Human Protein Atlas (HPA) and ComPPI websites were used to mine the SPA17 protein information. We performed a western blotting assay to validate the upregulated SPA17 expression in clinical glioblastoma (GBM) samples. The univariate Cox regression and Kaplan–Meier method were used to assess the prognostic role of SPA17 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was used to search the associated cancer hallmarks with SPA17 expression in each cancer type. TIMER2.0 was the main platform to investigate the immune cell infiltrations related to SPA17 in pan-cancer. The associations between SPA17 and immunotherapy biomarkers were performed by Spearman correlation analysis. The drug sensitivity information from the Connectivity Map (CMap) dataset was downloaded to perform SAP17-specific inhibitor sensitivity analysis.

Findings

SPA17 was aberrantly expressed in most cancer types and exhibited prognosis predictive ability in various cancers. In addition, our results also show that SPA17 was significantly correlated with immune-activated hallmarks (including pathways and biological processes), immune cell infiltrations, and immunoregulator expressions. The most exciting finding was that SPA17 could significantly predict anti-PDL1 and anti-PD1 therapy responses in cancer patients. Finally, specific inhibitors, like irinotecan and puromycin, which correlate with SPA17 expression in different cancer types, were also screened using Connectivity Map (CMap).

Conclusions

Our results reveal that SPA17 was abnormally expressed in cancer tissues, and this expression pattern could be associated with immune cell infiltrations in tumor microenvironments. Clinically, SPA17 not only acted as a potent prognostic factor to predict the clinical outcomes of cancer patients but was also a promising immunotherapy predictive biomarker for cancer patients treated with immune-checkpoint inhibitors (ICIs).
PRI: Re-Analysis of a Public Mass Cytometry Dataset Reveals Patterns of Effective Tumor Treatments
Authors: Hoang Yen , Gryzik Stefanie , Hoppe Ines , Rybak Alexander , Schädlich Martin , Kadner Isabelle , Walther Dirk , Vera Julio , Radbruch Andreas , Groth Detlef , Baumgart Sabine , Baumgrass Ria
Published: May 2022

Recently, mass cytometry has enabled quantification of up to 50 parameters for millions of cells per sample. It remains a challenge to analyze such high-dimensional data to exploit the richness of the inherent information, even though many valuable new analysis tools have already been developed. We propose a novel algorithm “pattern recognition of immune cells (PRI)” to tackle these high-dimensional protein combinations in the data. PRI is a tool for the analysis and visualization of cytometry data based on a three or more-parametric binning approach, feature engineering of bin properties of multivariate cell data, and a pseudo-multiparametric visualization. Using a publicly available mass cytometry dataset, we proved that reproducible feature engineering and intuitive understanding of the generated bin plots are helpful hallmarks for re-analysis with PRI. In the CD4+T cell population analyzed, PRI revealed two bin-plot patterns (CD90/CD44/CD86 and CD90/CD44/CD27) and 20 bin plot features for threshold-independent classification of mice concerning ineffective and effective tumor treatment. In addition, PRI mapped cell subsets regarding co-expression of the proliferation marker Ki67 with two major transcription factors and further delineated a specific Th1 cell subset. All these results demonstrate the added insights that can be obtained using the non-cluster-based tool PRI for re-analyses of high-dimensional cytometric data.
Acutely Inhibiting AQP4 With TGN-020 Improves Functional Outcome by Attenuating Edema and Peri-Infarct Astrogliosis After Cerebral Ischemia
Authors: Sun Chengfeng , Lin Luyi , Yin Lekang , Hao Xiaozhu , Tian Jiaqi , Zhang Xiaoxue , Ren Yan , Li Chanchan , Yang Yanmei
Published: May 2022

Background

Ischemic stroke is one of the leading causes of human death and disability. Brain edema and peri-infarct astrocyte reactivity are crucial pathological changes, both involving aquaporin-4 (AQP4). Studies revealed that acute inhibition of AQP4 after stroke diminishes brain edema, however, its effect on peri-infarct astrocyte reactivity and the subacute outcome is unclear. And if diffusion-weighted imaging (DWI) could reflect the AQP4 expression patterns is uncertain.

Methods

Rats were subjected to middle cerebral artery occlusion (MCAO) and allocated randomly to TGN 020-treated and control groups. One day after stroke, brain swelling and lesion volumes of the rats were checked using T2-weighted imaging (T2-WI). Fourteen days after stroke, the rats successively underwent neurological examination, T2-WI and DWI with standard b-values and ultra-high b-values, apparent diffusion coefficient (ADC) was calculated correspondingly. Finally, the rats’ brains were acquired and used for glial fibrillary acidic protein (GFAP) and AQP4 immunoreactive analysis.

Results

At 1 day after stroke, the TGN-020-treated animals exhibited reduced brain swelling and lesion volumes compared with those in the control group. At 14 days after stroke, the TGN-020-treated animals showed fewer neurological function deficits and smaller lesion volumes. In the peri-infarct region, the control group showed evident astrogliosis and AQP4 depolarization, which were reduced significantly in the TGN-020 group. In addition, the ultra-high b-values of ADC (ADCuh) in the peri-infarct region of the TGN-020 group was higher than that of the control group. Furthermore, correlation analysis revealed that peri-infarct AQP4 polarization correlated negatively with astrogliosis extent, and ADCuh correlated positively with AQP4 polarization.

Conclusion

We found that acutely inhibiting AQP4 using TGN-020 promoted neurological recovery by diminishing brain edema at the early stage and attenuating peri-infarct astrogliosis and AQP4 depolarization at the subacute stage after stroke. Moreover, ADCuh could reflect the AQP4 polarization.
Case Report: Bullous Pemphigoid Associated With Morphea and Lichen Sclerosus: Coincidental Diseases or Pathogenetic Association?
Authors: Maglie Roberto , Baffa Maria Efenesia , Montefusco Francesca , Pipitò Carlo , Senatore Stefano , Capassoni Marco , Maio Vincenza , Cerinic Marco Matucci , Antiga Emiliano , Guiducci Serena
Published: May 2022

Bullous pemphigoid (BP) represents the most common autoimmune bullous disease and is characterized by IgG autoantibodies targeting collagen XVII (BP180). BP has reportedly been occurred in association with other inflammatory skin diseases. Here, we describe the unusual occurrence of BP in a female patient with a concomitant history of generalized morphea (localized scleroderma, LoS) and cutaneous and genital lichen sclerosus (LiS). The occurrence of BP was associated with elevated serum levels of anti-BP180 IgG autoantibodies, which decreased upon clinical remission. Autoimmune bullous diseases and sclerosing dermatitis are immunologically distinct entities, whose association has been rarely described. In this study, we provide a literature review on cases of BP developed in patients with either LoS or LiS. Further, we discussed immunological mechanisms which may have favored the emergence of BP in our patient.
Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma
Authors: Zhang Xuzhao , Wu Zhaoxing , Hao Yuanyuan , Yu Teng , Li Xian , Liang Yun , Li Jinfan , Huang Liansheng , Xu Yang , Li Xiuzhen , Xu Xiaohua , Wang Weiqin , Xu Genbo , Zhang Xiaohong , Lv Qinghua , Fang Yongming , Xu Rongzhen , Qian Wenbin
Published: May 2022

Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.
The Levels of Oxidized Phospholipids in High-Density Lipoprotein During the Course of Sepsis and Their Prognostic Value
Authors: Li Zhaohong , Luo Zengtao , Shi Xiaoqian , Pang Baosen , Ma Yingmin , Jin Jiawei
Published: May 2022

Purpose

To examine the levels of 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero phosphatidylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphatidylcholine (PGPC) (the oxidized phosphatidylcholines) in HDL during the course of sepsis and to evaluate their prognostic value.

Materials and Methods

This prospective cohort pilot study enrolled 25 septic patients and 10 healthy subjects from 2020 to 2021. The HDLs were extracted from patient plasmas at day 1, 3 and 7 after sepsis onset and from healthy plasmas (total 81 plasma samples). These HDLs were then subjected to examining POVPC and PGPC by using an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) system. We further measured the levels of 38 plasma cytokines by Luminex and evaluated the correlation of HDL-POVPC level with these cytokines. Patients were further stratified into survivors and non-survivors to analyze the association of HDL-POVPC level with 28-day mortality.

Results

Septic patients exhibited significant increase of HDL-POVPC at day 1, 3 and 7 after sepsis onset (POVPC-D1, p=0.0004; POVPC-D3, p=0.033; POVPC-D7, p=0.004, versus controls). HDL-PGPC was detected only in some septic patients (10 of 25) but not in healthy controls. Septic patients showed a significant change of the plasma cytokines profile. The correlation assay showed that IL-15 and IL-18 levels were positively correlated with HDL-POVPC level, while the macrophage-derived chemokine (MDC) level was negatively correlated with HDL-POVPC level. Furthermore, HDL-POVPC level in non-survivors was significantly increased versus survivors at day 1 and 3 (POVPC-D1, p=0.002; POVPC-D3, p=0.003). Area under ROC curves of POVPC-D1 and POVPC-D3 in predicting 28-day mortality were 0.828 and 0.851. POVPC-D1and POVPC-D3 were the independent risk factors for the death of septic patients (p=0.046 and 0.035).

Conclusions

HDL-POVPC was persistently increased in the course of sepsis. POVPC-D1 and POVPC-D3 were significantly correlated with 28-mortality and might be valuable to predict poor prognosis.
Long-Term Medical Resource Consumption of Radical Prostatectomy vs. Intensity-Modulated Radiotherapy for Old Patients With Prostate Cancer: A Nationwide Population-Based Cohort Study
Authors: Wu Szu-Yuan , Effendi Fransisca Fortunata , Peng Jhao Yang , Huang Chung-Chien
Published: May 2022

Purpose

Few studies have compared the long-term medical resource consumption between radical prostatectomy (RP) and intensity-modulated radiation therapy (IMRT) among old (≥80 years) patients with localized prostate cancer (LPC), particularly in those at high risk of prostate adenocarcinoma.

Patients and Methods

The propensity score matching was conducted to investigate the medical expenditure of two therapeutic modalities (RP and IMRT) in elderly patients with high-risk LPC (HR-LPC). The generalized linear mixed and logistic regression models were employed to evaluate the number of postdischarge visits and medical reimbursement for urinary diseases or complications and the number of hospitalizations for treatment-related complications over 5 years after treatment, respectively.

Results

Significant differences were observed in the median or mean urology clinic visit numbers across the two therapeutic modalities from the first until fifth year post treatment (p < 0.0001). After adjustment for covariates, the mean difference [95% confidence interval (CI)] of urology clinic visit numbers between RP and IMRT was 13.07 (10.45–15.49, P < 0.0001), 7.47 (8.01–14.92, P < 0.0001), 8.24 (4.59–9.90, P < 0.0001), 6.63 (3.55–11.70, P < 0.0001), and 5.02 (1.12–8.73, P < 0.0001) for the first, second, third, fourth, and fifth years, respectively. In the logistic regression multivariate model with adjustment for covariates [therapy type, age, diagnosis year, income, hospital area, hospital level (academic or nonacademic), clinical and pathological T-stage, grade (Gleason score), pretreatment PSA level (ng/ml), and D'Amico risk classification], the adjusted odds ratio (95% CI) of IMRT was 2.10 (1.37–2.56, P = 0.0013), 1.55 (1.08–2.21, P = 0.0151), 1.35 (1.08–2.21, P = 0.0084), 1.24 (1.07–2.21, P = 0.0071), and 1.09 (1.02–1.81, P = 0.0379) for the first, second, third, fourth, and fifth years, respectively, compared with those of RP. The mean difference (95% CI) of total medical claims amounts of RP and IMRT between the RP and IMRT + ADT groups was 2,69,823 New Taiwan Dollars (NTD) (247,676–291,970, P < 0.0001), 40,803 NTD (17,379–54,228, P < 0.0001), 36,202 NTD (24,375–68,029, P < 0.0001), 26,708 NTD (11,179–54,595, P = 0.0321), and 12,173 NTD (17,140–41,487, P = 0.0187) for the first, second, third, fourth, and fifth years, respectively.

Conclusion

The long-term medical resource consumption was higher in old men with HR-LPC undergoing IMRT than in those undergoing RP.
How Does the Spatial Confinement of FtsZ to a Membrane Surface Affect Its Polymerization Properties and Function?
Authors: Vélez Marisela
Published: May 2022

FtsZ is the cytoskeletal protein that organizes the formation of the septal ring and orchestrates bacterial cell division. Its association to the membrane is essential for its function. In this mini-review I will address the question of how this association can interfere with the structure and dynamic properties of the filaments and argue that its dynamics could also remodel the underlying lipid membrane through its activity. Thus, lipid rearrangement might need to be considered when trying to understand FtsZ’s function. This new element could help understand how FtsZ assembly coordinates positioning and recruitment of the proteins forming the septal ring inside the cell with the activity of the machinery involved in peptidoglycan synthesis located in the periplasmic space.
Altered Metabolism of the Microbiota–Gut–Brain Axis Is Linked With Comorbid Anxiety in Fecal Recipient Mice of Myasthenia Gravis
Authors: Zhang Hanping , Li Yifan , Zheng Peng , Wu Jing , Huang Yu , Tan Xunmin , Hu Xi , Wen Lu , Xie Peijun , Zhou Xingyu , Yu Gang , Zhao Libo , Zhou Chanjuan , Fang Liang , Xie Peng
Published: May 2022

Myasthenia gravis (MG) comorbid anxiety seriously affects the progress of MG. However, the exact relationship remains poorly understood. Recently, our preliminary study has revealed that intestinal microbe disturbance is closely related to MG. Therefore, further exploration of whether the microbiome is involved in MG comorbid anxiety is warranted. In this study, gas chromatography-mass spectrometry metabolomics analysis was used to characterize the metabotype of feces, serum, and three brain regions involved in emotion (i.e., the prefrontal cortex, hippocampus, and striatum), which were obtained from mice that were colonized with fecal microbiota from patients with MG (MMb), healthy individuals (HMb), or co-colonization of both patients and healthy individuals (CMb). Functional enrichment analysis was used to explore the correlation between the “microbiota–gut–brain” (MGB) axis and anxiety-like behavior. The behavioral test showed that female MMb exhibited anxiety-like behavior, which could be reversed by co-colonization. Moreover, metabolic characterization analysis of the MGB axis showed that the metabotype of gut-brain communication was significantly different between MMb and HMb, and 146 differential metabolites were jointly identified. Among these, 44 metabolites in feces; 12 metabolites in serum; 7 metabolites in hippocampus; 2 metabolites in prefrontal cortex; and 6 metabolites in striatum were reversed by co-colonization. Furthermore, the reversed gut microbiota mainly belonged to bacteroides and firmicutes, which were highly correlated with the reversed metabolites within the MGB axis. Among three emotional brain regions, hippocampus was more affected. Therefore, disturbances in gut microbiota may be involved in the progress of anxiety-like behavior in MG due to the MGB axis.
Assembly, Core Microbiota, and Function of the Rhizosphere Soil and Bark Microbiota in Eucommia ulmoides
Authors: Dong Chunbo , Shao Qiuyu , Ren Yulian , Ge Wei , Yao Ting , Hu Haiyan , Huang Jianzhong , Liang Zongqi , Han Yanfeng
Published: May 2022

Medicinal plants are inhabited by diverse microbes in every compartment, and which play an essential role in host growth and development, nutrient absorption, synthesis of secondary metabolites, and resistance to biological and abiotic stress. However, the ecological processes that manage microbiota assembly and the phenotypic and metabolic characteristics of the core microbiota of Eucommia ulmoides remain poorly explored. Here, we systematically evaluated the effects of genotypes, compartment niches, and environmental conditions (climate, soil nutrition, and secondary metabolites) on the assembly of rhizosphere soil and bark associated bacterial communities. In addition, phenotypic and metabolic characteristics of E. ulmoides core microbiota, and their relationship with dominant taxa, rare taxa, and pharmacologically active compounds were deciphered. Results suggested that microbiota assembly along the two compartments were predominantly shaped by the environment (especially pH, relative humidity, and geniposide acid) and not by host genotype or compartment niche. There were 690 shared genera in the rhizosphere soil and bark, and the bark microbiota was mainly derived from rhizosphere soil. Core microbiota of E. ulmoides was a highly interactive “hub” microbes connecting dominant and rare taxa, and its phenotypic characteristics had a selective effect on compartment niches. Metabolic functions of the core microbiota included ammonia oxidation, nitrogen fixation, and polyhydroxybutyrate storage, which are closely related to plant growth or metabolism. Moreover, some core taxa were also significantly correlated with three active compounds. These findings provide an important scientific basis for sustainable agricultural management based on the precise regulation of the rhizosphere soil and bark microbiota of E. ulmoides.
Elevational Gradients Impose Dispersal Limitation on Streptomyces
Authors: Hariharan Janani , Buckley Daniel H.
Published: May 2022

Dispersal governs microbial biogeography, but the rates and mechanisms of dispersal remain poorly characterized for most microbial taxa. Dispersal limitation is driven by limits on dissemination and establishment, respectively. Elevation gradients create striking patterns of biogeography because they produce steep environmental gradients at small spatial scales, and these gradients offer a powerful tool to examine mechanisms of dispersal limitation. We focus on Streptomyces, a bacterial genus common to soil, by using a taxon-specific phylogenetic marker, the RNA polymerase-encoding rpoB gene. By targeting Streptomyces, we assess dispersal limitation at finer phylogenetic resolution than is possible using whole community analyses. We characterized Streptomyces diversity at local spatial scales (100 to 3,000 m) in two temperate forest sites located in the Adirondacks region of New York State: Woods Lake (<100 m elevation change), and Whiteface Mountain (>1,000 m elevation change). Beta diversity varied considerably at both locations, indicative of dispersal limitation acting at local spatial scales, but beta diversity was significantly higher at Whiteface Mountain. Beta diversity varied across elevation at Whiteface Mountain, being lowest at the mountain’s base. We show that Streptomyces taxa exhibit elevational preferences, and these preferences are phylogenetically conserved. These results indicate that habitat preferences influence Streptomyces biogeography and suggest that barriers to establishment structure Streptomyces communities at higher elevations. These data illustrate that Streptomyces biogeography is governed by dispersal limitation resulting from a complex mixture of stochastic and deterministic processes.
Transcriptome Analyses of Chicken Primary Macrophages Infected With Attenuated Salmonella Typhimurium Mutants
Authors: Bhowmik Bijit K. , Kumar Arvind , Gangaiah Dharanesh
Published: May 2022

Salmonella enterica is one of the most common foodborne illnesses in the United States and worldwide, with nearly one-third of the cases attributed to contaminated eggs and poultry products. Vaccination has proven to be an effective strategy to reduce Salmonella load in poultry. The Salmonella Typhimurium Δcrp-cya (MeganVac1) strain is the most commonly used vaccine in the United States; however, the mechanisms of virulence attenuation and host response to this vaccine strain are poorly understood. Here, we profiled the invasion and intracellular survival phenotypes of Δcrp-cya and its derivatives (lacking key genes required for intra-macrophage survival) in HD11 macrophages and the transcriptome response in primary chicken macrophages using RNA-seq. Compared to the parent strain UK1, all the mutant strains were highly defective in metabolizing carbon sources related to the TCA cycle and had greater doubling times in macrophage-simulating conditions. Compared to UK1, the majority of the mutants were attenuated for invasion and intra-macrophage survival. Compared to Δcrp-cya, while derivatives lacking phoPQ, ompR-envZ, feoABC and sifA were highly attenuated for invasion and intracellular survival within macrophages, derivatives lacking ssrAB, SPI13, SPI2, mgtRBC, sitABCD, sopF, sseJ and sspH2 showed increased ability to invade and survive within macrophages. Transcriptome analyses of macrophages infected with UK1, Δcrp-cya and its derivatives lacking phoPQ, sifA and sopF demonstrated that, compared to uninfected macrophages, 138, 148, 153, 155 and 142 genes were differentially expressed in these strains, respectively. Similar changes in gene expression were observed in macrophages infected with these strains; the upregulated genes belonged to innate immune response and host defense and the downregulated genes belonged to various metabolic pathways. Together, these data provide novel insights on the relative phenotypes and early response of macrophages to the vaccine strain and its derivatives. The Δcrp-cya derivatives could facilitate development of next-generation vaccines with improved safety.
Bypassing the Gut–Lung Axis via Microbial Metabolites: Implications for Chronic Respiratory Diseases
Authors: Bulanda Edyta , Wypych Tomasz P.
Published: May 2022

The gut microbiome engages in constant interactions with the immune system, laying down the fundamentals of what we perceive as health or disease. The gut microbiota acts locally in the intestines and distally in other organs, such as the lungs. This influence (termed “the gut–lung axis”) constitutes the basis for harnessing the microbiome to prevent or treat chronic respiratory diseases. Within this context, two approaches gained the most attention: the diet interventions (which shape the microbiome) and the probiotics (which exert beneficial effects directly on the host). Microbial products, which constitute a means of communication along the gut–lung axis, are only now emerging as a new class of potential therapeutics. Here, we provide a comprehensive overview of microbial products active in the airways, describe the immunological mechanisms they trigger, and discuss their clinical advantages and pitfalls.