bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypertension in Acromegaly in Relationship to Biochemical Control and Mortality: Global ACROSTUDY Outcomes
Authors: Vila Greisa , Luger Anton , van der Lely Aart Jan , Neggers Sebastian J. C. M. M. , Webb Susan M. , Biller Beverly M. K. , Valluri Srinivas , Hey-Hadavi Judith
Published: November 2020

Context

Hypertension is a major cardiovascular risk factor related to increased mortality in acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment in patients with hypertension. This analysis evaluates outcomes in patients with hypertension and acromegaly included in ACROSTUDY.

Methods

ACROSTUDY is a global non-interventional surveillance study of long-term treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively divided in two subgroups: patients with and without hypertension. Stepwise logistic regression and Kaplan-Meyer analyses were performed for testing predictors of mortality.

Results

The total cohort included 2,090 patients with acromegaly treated with PEGV who were followed for a median of 6.8 years (range up to 12.1 years). In ACROSTUDY there were 1,344 patients with hypertension (52.3% males). This subgroup was older, had a higher BMI, and higher prevalence of diabetes, hyperlipidemia, and cardiovascular disease (CVD) when compared to patients without hypertension. During ACROSTUDY, 68 deaths were reported in the hypertension cohort, vs 10 in the cohort without hypertension. Both CVD (p<0.0001) and anterior pituitary deficiencies (p=0.0105) at study entry independently predicted mortality in patients with acromegaly and hypertension; Kaplan-Meier analysis confirmed that CVD significantly impairs survival.

Conclusions

Hypertension is common in patients with acromegaly and significantly increases mortality, especially when there is concomitant CVD. These data suggest that treatment goals should extend beyond IGF-I normalization, and include optimisation of substitution of pituitary deficiencies and scrutinous screening and treatment of CVD.
Prognostic Impact of Hyponatremia and Hypernatremia in COVID-19 Pneumonia. A HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19) Registry Analysis
Authors: Ruiz-Sánchez Jorge Gabriel , Núñez-Gil Ivan J. , Cuesta Martin , Rubio Miguel A. , Maroun-Eid Charbel , Arroyo-Espliguero Ramón , Romero Rodolfo , Becerra-Muñoz Victor Manuel , Uribarri Aitor , Feltes Gisela , Trabattoni Daniela , Molina María , García Aguado Marcos , Pepe Martino , Cerrato Enrico , Alfonso Emilio , Castro Mejía Alex Fernando , Roubin Sergio Raposeiras , Buzón Luis , Bondia Elvira , Marin Francisco , López Pais Javier , Abumayyaleh Mohammad , D’Ascenzo Fabrizio , Rondano Elisa , Huang Jia , Fernandez-Perez Cristina , Macaya Carlos , de Miguel Novoa Paz , Calle-Pascual Alfonso L. , Estrada Perez Vicente , Runkle Isabelle ,   HOPE COVID-19 investigators
Published: November 2020

Dysnatremia is associated with increased mortality in patients with community-acquired pneumonia. SARS-COV2 (Severe-acute-respiratory syndrome caused by Coronavirus-type 2) pneumonia can be fatal. The aim of this study was to ascertain whether admittance dysnatremia is associated with mortality, sepsis, or intensive therapy (IT) in patients hospitalized with SARS-COV2 pneumonia. This is a retrospective study of the HOPE-COVID-19 registry, with data collected from January 1th through April 31th, 2020. We selected all hospitalized adult patients with RT-PCR-confirmed SARS-COV2 pneumonia and a registered admission serum sodium level (SNa). Patients were classified as hyponatremic (SNa <135 mmol/L), eunatremic (SNa 135–145 mmol/L), or hypernatremic (SNa >145 mmol/L). Multivariable analyses were performed to elucidate independent relationships of admission hyponatremia and hypernatremia, with mortality, sepsis, or IT during hospitalization. Four thousand six hundred sixty-four patients were analyzed, median age 66 (52–77), 58% males. Death occurred in 988 (21.2%) patients, sepsis was diagnosed in 551 (12%) and IT in 838 (18.4%). Hyponatremia was present in 957/4,664 (20.5%) patients, and hypernatremia in 174/4,664 (3.7%). Both hyponatremia and hypernatremia were associated with mortality and sepsis. Only hyponatremia was associated with IT. In conclusion, hyponatremia and hypernatremia at admission are factors independently associated with mortality and sepsis in patients hospitalized with SARS-COV2 pneumonia.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT04334291, NCT04334291.
A Potential Role for Endogenous Glucagon in Preventing Post-Bariatric Hypoglycemia
Authors: Lobato Carolina B. , Pereira Sofia S. , Guimarães Marta , Hartmann Bolette , Wewer Albrechtsen Nicolai J. , Hilsted Linda , Holst Jens J. , Nora Mário , Monteiro Mariana P.
Published: November 2020

Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective long-term treatment to achieve weight loss and obesity comorbidity remission. Post-bariatric hypoglycemia (PBH) is a late complication of bariatric surgery most commonly reported after Roux-en-Y gastric bypass (RYGB). PBH is the end result of postprandial hyperinsulinemia but additional endocrine mechanisms involved are still under debate. Our aim was to characterize entero-pancreatic hormone dynamics associated with postprandial hypoglycemia after RYGB. Individuals previously submitted to RYGB (N=23) in a single tertiary hospital presenting PBH symptoms (Sym, n=14) and asymptomatic weight-matched controls (Asy, n=9) were enrolled. Participants underwent a mixed-meal tolerance test (MMTT) to assess glucose, total amino acids (total AA), insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and neurotensin (NT). We found that hypoglycemia during the MMTT was equally frequent in Sym and Asy groups (p=1.000). Re-grouped according to glucose nadir during the MMTT (Hypo n=11 vs NoHypo n=12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: p=0.527) or metabolic features (HbA1c: p=0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar (p>0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: p<0.01), with overall greater glycemic variability in Hypo group (minimum-to-maximum glucose ratio: p<0.001). Hypo group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: p<0.01) and higher insulin (t=30 min: p<0.05, t=45 min: p<0.001), C-peptide (t=30 min: p<0.01, t=45 min: p<0.001, t=60 min: p<0.05), and GLP-1 (t=45 min: p<0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia (p<0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir (p<0.01), and prevented postprandial hypoglycemia (p<0.05). A higher insulin to glucagon balance in Hypo was observed (p<0.05). No differences were observed in total AA, GIP or NT excursions (p>0.05). In sum, after RYGB, postprandial hyperinsulinemia is key in triggering PBH, but a parallel and earlier rise in endogenous glucagon might sustain the inter-individual variability in glycemic outcome beyond the effect of hyperinsulinism, advocating a potential pivotal role for glucagon in preventing hyperinsulinemic hypoglycemia.
A Matter of Life and Death: Alternative Stable States in Trees, From Xylem to Ecosystems
Authors: Hammond William M.
Published: November 2020

Global forests are experiencing widespread climate-induced mortality. Predicting this phenomenon has proven difficult, despite recent advances in understanding physiological mechanisms of mortality in individual trees along with environmental drivers of mortality at broad scales. With heat and drought as primary climatic drivers, and convergence on hydraulic failure as a primary physiological mechanism, new models are needed to improve our predictions of Earth’s forests under future climate conditions. While much of ecology focuses on equilibrium states, transitions from one stable state to another are often described with alternative stable state theory (ASST), where systems can settle to more than one stable condition. Recent studies have identified threshold responses of hydraulic failure during tree mortality, indicating that alternative stable states may be present. Here, I demonstrate that the xylem of trees has characteristics indicative of alternative stable states. Through empirical evidence, I identify a catastrophic shift during hydraulic failure which prevents trees from returning to pre-droughted physiological states after environmental stressors (e.g., drought, heat) are relieved. Thus, the legacy of climate-induced hydraulic failure likely contributes to reduced resilience of forests under future climate. I discuss the implications and future directions for including ASST in models of tree mortality.
Integrative Analysis Extracts a Core ceRNA Network of the Fetal Hippocampus With Down Syndrome
Authors: Wang Shengran , Tang Xia , Qin Litao , Shi Weili , Bian Shasha , Wang Zhaokun , Wang Qingqing , Wang Xin , Gu Jianqin , Hao Bingtao , Ding Keyue , Liao Shixiu
Published: November 2020

Accumulating evidence suggests that circular RNAs (circRNAs)—miRNA–mRNA ceRNA regulatory network—may play an important role in neurological disorders, such as Alzheimer’s disease (AD). Interestingly, neuropathological changes that closely resemble AD have been found in nearly all Down syndrome (DS) cases > 35 years. However, few studies have reported circRNA transcriptional profiling in DS cases, which is caused by a chromosomal aberration of trisomy 21. Here, we characterized the expression profiles of circRNAs in the fetal hippocampus of DS patients (n = 8) and controls (n = 6) by using microarray. MiRNA, mRNA expression profiling of DS from our previous study and scRNA-seq data describing normal fetal hippocampus development (GEO) were also integrated into the analysis. The similarity between circRNAs/genes with traits/cell-types was calculated by weighted correlation network analysis (WGCNA). miRanda and miRWalk2 were used to predict ceRNA network interactions. We identified a total of 7,078 significantly differentially expressed (DE) circRNAs, including 2,637 upregulated and 4,441 downregulated genes, respectively. WGCNA obtained 15 hub circRNAs and 6 modules with cell type–specific expression patterns among scRNA-seq data. Finally, a core ceRNA network was constructed by 14 hub circRNAs, 17 DE miRNA targets and 245 DE mRNA targets with a cell type–specific expression pattern annotation. Known functional molecules in DS or neurodegeneration (e.g., miR-138, OLIG1, and TPM2) were also included in this network. Our findings are the first to delineate the landscape of circRNAs in DS and the first to effectively integrate ceRNA regulation with scRNA-seq data. These data may provide a valuable resource for further research on the molecular mechanisms or therapeutic targets underlying DS neuropathy.
Generation of Multi-Transgenic Pigs Using PiggyBac Transposons Co-expressing Pectinase, Xylanase, Cellulase, β-1.3-1.4-Glucanase and Phytase
Authors: Wang Haoqiang , Li Guoling , Zhong Cuili , Mo Jianxin , Sun Yue , Shi Junsong , Zhou Rong , Li Zicong , Wu Zhenfang , Liu Dewu , Zhang Xianwei
Published: November 2020

The current challenges facing the pork industry are to maximize feed efficiency and minimize fecal emissions. Unlike ruminants, pigs lack several digestive enzymes such as pectinase, xylanase, cellulase, β-1.3-1.4-glucanase, and phytase which are essential to hydrolyze the cell walls of grains to release endocellular nutrients into their digestive tracts. Herein, we synthesized multiple cellulase and pectinase genes derived from lower organisms and then codon-optimized these genes to be expressed in pigs. These genes were then cloned into our previously optimized XynB (xylanase)- EsAPPA (phytase) bicistronic construct. We then successfully generated transgenic pigs that expressed the four enzymes [Pg7fn (pectinase), XynB (xylanase), EsAPPA (phytase), and TeEGI (cellulase and β-glucanase)] using somatic cell cloning. The expression of these genes was parotid gland specific. Enzymatic assays using the saliva of these founders demonstrated high levels of phytase (2.0∼3.4 U/mL) and xylanase (0.25∼0.42 U/mL) activities, but low levels of pectinase (0.06∼0.08 U/mL) activity. These multi-transgenic pigs are expected to contribute to enhance feed utilization and reduce environmental impact.
Detection of Pathogenic Microbe Composition Using Next-Generation Sequencing Data
Authors: Zhao Haiyong , Wang Shuang , Yuan Xiguo
Published: November 2020

Next-generation sequencing (NGS) technologies have provided great opportunities to analyze pathogenic microbes with high-resolution data. The main goal is to accurately detect microbial composition and abundances in a sample. However, high similarity among sequences from different species and the existence of sequencing errors pose various challenges. Numerous methods have been developed for quantifying microbial composition and abundance, but they are not versatile enough for the analysis of samples with mixtures of noise. In this paper, we propose a new computational method, PGMicroD, for the detection of pathogenic microbial composition in a sample using NGS data. The method first filters the potentially mistakenly mapped reads and extracts multiple species-related features from the sequencing reads of 16S rRNA. Then it trains an Support Vector Machine classifier to predict the microbial composition. Finally, it groups all multiple-mapped sequencing reads into the references of the predicted species to estimate the abundance for each kind of species. The performance of PGMicroD is evaluated based on both simulation and real sequencing data and is compared with several existing methods. The results demonstrate that our proposed method achieves superior performance. The software package of PGMicroD is available athttps://github.com/BDanalysis/PGMicroD.
IGLR-2, a Leucine-Rich Repeat Domain Containing Protein, Is Required for the Host Defense in Caenorhabditis elegans
Authors: Kuo Cheng-Ju , Hsu Ya-Chu , Wang Sin-Tian , Liou Bang-Yu , Lim Serene Boon-Yuean , Chen Yi-Wei , Chen Chang-Shi
Published: November 2020

EnterohemorrhagicEscherichia coli(EHEC), a human pathogen, also infectsCaenorhabditis elegans. We demonstrated previously thatC. elegansactivates the p38 MAPK innate immune pathway to defend against EHEC infection. However, whether aC. eleganspattern recognition receptor (PRR) exists to regulate the immune pathway remains unknown. PRRs identified in other metazoans contain several conserved domains, including the leucine-rich repeat (LRR). By screening a focused RNAi library, we identified the IGLR-2, a transmembrane protein containing the LRR domain, as a potential immune regulator inC. elegans. Our data showed thatiglr-2regulates the host susceptibility to EHEC infection. Moreover,iglr-2is required for pathogen avoidance to EHEC. Theiglr-2overexpressed strain, which was more resistant to EHEC originally, showed hypersusceptibility to EHEC upon knockdown of the p38 MAPK pathway. Together, our data suggested thatiglr-2plays an important role inC. elegansto defend EHEC by regulating pathogen-avoidance behavior and the p38 MAPK pathway.
Identification of Mutated Peptides in Bladder Cancer From Exomic Sequencing Data Reveals Negative Correlation Between Mutation-Specific Immunoreactivity and Inflammation
Authors: Wang Chen , Ding Yu , Liu Yuanyong , Zhang Qingchen , Xu Shiqiang , Xia Liliang , Duan Huangqi , Wang Shujun , Ji Ping , Huang Weiren , Zhao Guoping , Cao Zhiwei , Shen Haibo , Wang Ying
Published: November 2020

Introduction and Objective

Neoantigen-based immunotherapy is one of the breakthroughs in cancer immunotherapy. Benefit from the Cancer Genome Atlas database, we intended to identify mutant peptides with neoantigen property in bladder cancer (BC). Correlations between the immunoreactivity of candidate neoantigens and clinical manifestations were further analyzed.

Methods

HLA-A*02:01 restricted mutant (MT) and wildtype (WT) peptides were predicted by using whole exome sequencing data of 412 BC patients in the TCGA database. Binding affinity to HLA-A2 molecules was determined by using T2 cell-based binding assay. The immunoreactivity to WT and MT peptides in HLA-A2+ BC patients was determined by using an ELISPOT assay upon in vitro stimulation with MT and WT peptides individually. Clinical relevance to peptide-specific immunoreactivity was analyzed by Pearson correlation analysis. The disease free survival (DFS) curves were plotted using the Kaplan–Meier method in BC patients with or without mutations and compared using the log-rank test online.

Results

Fifty-seven HLA-A*02:01 restricted WT and MT peptides were selected based on predicted high affinity and expression frequency, among which 12 MT peptides from 12 individual genes exhibited strong affinity to HLA-A2 molecules when compared to WT counterparts. MT peptides induced more peptide-specific IFNγ spot forming units (SFUs) than WT counterparts in HLA-A2+ BC patients upon in vitro stimulation. They were negatively correlated to the counts of peripheral leukocytes and platelets. Patients with higher C-reactive protein level exhibited lower immunoreactivity to MT peptides. Combination of MT peptides from 6 genes, including CDKN1AG61V, RHOBP75L, DDB1S25L, AHNAKD4855Y, ANP32AS56L and MKI67H84L covered 47.5% of the patients under investigation. Patients harboring combinational mutations in these genes were associated with a longer DFS according to the cBioportal online analysis.

Conclusion

Twelve HLA-A*02:01 restricted MT peptides have been identified exhibiting higher binding affinity to HLA-A2 molecules and stronger immunoreactivity than WT counterparts in BC patients. Combination of MT peptides from six genes might be potential as neoantigen candidates in cancer immunotherapy against BC in the future. Inflammatory modulation is inclined to be a strategy to enhance the efficacy of neoantigen-based immunotherapy.
Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys
Authors: Collignon Catherine , Bol Vanesa , Chalon Aurélie , Surendran Naveen , Morel Sandra , van den Berg Robert A. , Capone Stefania , Bechtold Viviane , Temmerman Stéphane T.
Published: November 2020

Replication-deficient chimpanzee adenovirus (ChAd) vectors represent an attractive vaccine platform and are thus employed as vaccine candidates against several infectious diseases. Since inducing effective immunity depends on the interplay between innate and adaptive immunity, a deeper understanding of innate immune responses elicited by intramuscularly injected ChAd vectors in tissues can advance the platform’s development. Using different candidate vaccines based on the Group C ChAd type 155 (ChAd155) vector, we characterized early immune responses in injected muscles and draining lymph nodes (dLNs) from mice, and complemented these analyses by evaluating cytokine responses and gene expression patterns in peripheral blood from ChAd155-injected macaques. In mice, vector DNA levels gradually decreased post-immunization, but local transgene mRNA expression exhibited two transient peaks [at 6 h and Day (D)5], which were most obvious in dLNs. This dynamic pattern was mirrored by the innate responses in tissues, which developed as early as 1–3 h (cytokines/chemokines) or D1 (immune cells) post-vaccination. They were characterized by a CCL2- and CXCL9/10-dominated chemokine profile, peaking at 6 h (with CXCL10/CCL2 signals also detectable in serum) and D7, and clear immune-cell infiltration peaks at D1/D2 and D6/D7. Experiments with a green fluorescent protein-expressing ChAd155 vector revealed infiltrating hematopoietic cell subsets at the injection site. Cell infiltrates comprised mostly monocytes in muscles, and NK cells, T cells, dendritic cells, monocytes, and B cells in dLNs. Similar bimodal dynamics were observed in whole-blood gene signatures in macaques: most of the 17 enriched immune/innate signaling pathways were significantly upregulated at D1 and D7 and downregulated at D3, and clustering analysis revealed stronger similarities between D1 and D7 signatures versus the D3 signature. Serum cytokine responses (CXCL10, IL1Ra, and low-level IFN-α) in macaques were predominantly observed at D1. Altogether, the early immune responses exhibited bimodal kinetics with transient peaks at D1/D2 and D6/D7, mostly with an IFN-associated signature, and these features were remarkably consistent across most analyzed parameters in murine tissues and macaque blood. These compelling observations reveal a novel aspect of the dynamics of innate immunity induced by ChAd155-vectored vaccines, and contribute to ongoing research to better understand how adenovectors can promote vaccine-induced immunity.
PD-L1-Mediated Immunosuppression in Glioblastoma Is Associated With the Infiltration and M2-Polarization of Tumor-Associated Macrophages
Authors: Zhu Zhiyuan , Zhang Hongbo , Chen Baodong , Liu Xing , Zhang Shizhong , Zong Zhitao , Gao Mengqi
Published: November 2020

There has been no significant improvements for immune checkpoint inhibitors since its first use. Tumour-associated macrophages (TAMs) are critical mediators in the PD-1/PD-L1 axis, contributing to the immunosuppressive tumour microenvironment. This study aims to investigate the potential role of PD-L1 in regulating TAMs in glioblastoma. Gene expression data and clinical information of glioma patients were collected from TCGA (n = 614) and CGGA (n = 325) databases. Differentially expressed genes between PD-L1high and PD-L1low groups were identified and subjected to bioinformatical analysis. We found that PD-L1 was frequently expressed in gliomas with a grade-dependent pattern. Higher PD-L1 expression predicted shorter overall survival. Moreover, PD-L1 was positively correlated with immunosuppressive cells (macrophage, neutrophil and immature DC) and negatively correlated with cytocidal immune cells (CD8+ T cell and Th1). Importantly, PD-L1 high expression was significantly correlated with M2-polarization of macrophages (M2-TAMs). We conclude that PD-L1 is an unfavourable prognostic marker for patients with glioblastoma; PD-L1-mediated immunosuppression may attribute to the infiltration and M2-polarization of TAMs.
Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity
Authors: Zahid Ayesha , Ismail Hazrat , Li Bofeng , Jin Tengchuan
Published: November 2020

DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.
The Intestinal Microbiota and Colorectal Cancer
Authors: Cheng Yiwen , Ling Zongxin , Li Lanjuan
Published: November 2020

The intestinal microbiota, composed of a large population of microorganisms, is often considered a “forgotten organ” in human health and diseases. Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). The roles for intestinal microorganisms that initiated and facilitated the CRC process are becoming increasingly clear. Hypothesis models have been proposed to illustrate the complex relationship between the intestinal microbiota and CRC. Recent studies have identified Streptococcus bovis, enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius as CRC candidate pathogens. In this review, we summarized the mechanisms involved in microbiota-related colorectal carcinogenesis, including inflammation, pathogenic bacteria, and their virulence factors, genotoxins, oxidative stress, bacterial metabolites, and biofilm. We also described the clinical values of intestinal microbiota and novel strategies for preventing and treating CRC.
Numerical Development of Heat Transfer Coefficient Correlation for Spray Cooling in Continuous Casting
Authors: Ma Haibo , Silaen Armin , Zhou Chenn
Published: November 2020

The desire to remain competitive and continuously produce high quality and high strength steel at the maximum production rate in continuous casting requires dynamic control over the spray cooling rate. Efficient and uniform heat removal without cracking or deforming the slab during spray cooling is critical. The challenge is to obtain accurate Heat Transfer Coefficient (HTC) on the slab surface as boundary condition for solidification calculations. Experiment based HTC correlations are limited to handful operating conditions and they might fail when changes occur. The current study presents a numerical model for spray cooling featuring the simulation of atomization and droplet impingement heat transfer in continuous casting. With the aid of high-performance computer, parametric studies were performed and the results were converted into mathematically simple HTC correlations as a function of essential operating parameters. Finally, a Graphic User Interface (GUI) was developed to facilitate future applications of the correlations. The HTC prediction is stored in the versatile comma-separated values (csv) format and it can be directly applied to solidification calculations. The proposed numerical methodology should benefit the steel industry by expediting the development process of HTC correlations and can further improve the accuracy of the existing casting control systems.
Thirty-Day Mortality and Morbidity in COVID-19 Positive vs. COVID-19 Negative Individuals and vs. Individuals Tested for Influenza A/B: A Population-Based Study
Authors: Nersesjan Vardan , Amiri Moshgan , Christensen Hanne K. , Benros Michael E. , Kondziella Daniel
Published: November 2020

Background: As of October 2020, COVID-19 has caused 1,000,000 deaths worldwide. However, large-scale studies of COVID-19 mortality and new-onset comorbidity compared to individuals tested negative for COVID-19 and individuals tested for influenza A/B are lacking. We investigated COVID-19 30-day mortality and new-onset comorbidity compared to individuals with negative COVID-19 test results and individuals tested for influenza A/B.

Methods and findings: This population-based cohort study utilized electronic health records covering roughly half (n = 2,647,229) of Denmark's population, with nationwide linkage of microbiology test results and death records. All individuals ≥18 years tested for COVID-19 and individuals tested for influenza A/B were followed from 11/2017 to 06/2020. Main outcome was 30-day mortality after a test for either COVID-19 or influenza. Secondary outcomes were major comorbidity diagnoses 30-days after the test for either COVID-19 or influenza A/B. In total, 224,639 individuals were tested for COVID-19. To enhance comparability, we stratified the population for in- and outpatient status at the time of testing. Among inpatients positive for COVID-19, 356 of 1,657 (21%) died within 30 days, which was a 3.0 to 3.1-fold increased 30-day mortality rate, when compared to influenza and COVID-19-negative inpatients (all p < 0.001). For outpatients, 128 of 6,263 (2%) COVID-19-positive patients died within 30 days, which was a 5.5 to 6.9-fold increased mortality rate compared to individuals tested negative for COVID-19 or individuals tested positive or negative for influenza, respectively (all p < 0.001). Compared to hospitalized patients with influenza A/B, new-onset ischemic stroke, diabetes and nephropathy occurred more frequently in inpatients with COVID-19 (all p < 0.05).

Conclusions: In this population-based study comparing COVID-19 positive with COVID-19 negative individuals and individuals tested for influenza, COVID-19 was associated with increased rates of major systemic and vascular comorbidity and substantially higher mortality. Results should be interpreted with caution because of differences in test strategies for COVID-19 and influenza, use of aggregated data, the limited 30-day follow-up and the possibility for changing mortality rates as the pandemic unfolds. However, the true COVID-19 mortality may even be higher than the stated 3.0 to 5.5-fold increase, owing to more extensive testing for COVID-19.
Relationship Between T-Cell Exosomes and Cellular Subsets in SLE According to Type I IFN-Signaling
Authors: López Patricia , Rodríguez-Carrio Javier , Caminal-Montero Luis , Suárez Ana
Published: November 2020

Objective: To quantify the levels of circulating exosomes derived from T-cells and monocytes and their possible associations with leukocyte subpopulations and cytokine milieu in Systemic Lupus Erythematosus (SLE).

Methods: Total circulating exosomes (CD9+-Ex) and those derived from T-cells (CD3+-Ex) and monocytes (CD14+-Ex) were quantified by flow cytometry in 82 SLE patients and 32 controls. Leukocyte subsets and serum cytokines were analyzed by flow cytometry or by immunoassays. IFN-score was evaluated by real time RT-PCR in whole blood samples from a subgroup of 73 patients and 24 controls.

Results: Activation markers (IFNR1 and BLyS) on monocytes, neutrophils and B-cells correlated inversely with circulating exosomes (CD9+-Ex, CD3+-Ex, and CD14+-Ex) in controls but directly with CD3+-Ex in patients (all p < 0.05). Although CD9+-Ex were increased in SLE, no differences were found in CD3+-Ex, supporting that exosome content accounts for this opposite role. Interestingly, CD4+CD28null cells correlated with CD3+-Ex in patients and controls, and displayed similar associations with leukocyte subsets in both groups. Additionally, CD3+-Ex correlated in patients with the expression of CD25 in CD4+CD28null cells. Furthermore, the activated status of this senescent subset was related to IFNα serum levels in controls and to IFN-score in SLE patients. Finally, patients presenting high IFN-score, in addition to elevated CD25+CD28null cells associated with the activation of myeloid cells, displayed higher levels of inflammatory cytokines and chemokines.

Conclusion: Our results support a relationship between T-cell exosomes and cellular subsets in SLE according to type I IFN-signaling, which could amplify chronic immune activation and excessive cytokine/chemokine response.
Plant Growth Promoting Rhizobacteria Alleviate Aluminum Toxicity and Ginger Bacterial Wilt in Acidic Continuous Cropping Soil
Authors: Zhang Shuting , Jiang Qipeng , Liu Xiaojiao , Liu Liehua , Ding Wei
Published: November 2020

Long-term monoculture cropping is usually accompanied by soil acidification and microbial community shifts. Soil aluminum ions are dissolved under acidic condition (pH < 5.0), and the resulting aluminum bioavailability can cause toxic effects in plants. In this study, we investigated the bacterial community compositions and aluminum toxicity in fields monocultured with ginger for 35 years, 15 years, and 1 year. Within these fields are ginger plants without and with ginger bacterial wilt disease. The results confirmed that the degree of aluminum toxicity in the diseased soil was more severe than that in the healthy soil. Continuous cropping can significantly increase the bacterial diversity and change the bacterial community composition of ginger rhizosphere soil. The relative abundance of plant growth-promoting rhizobacteria (PGPRs) was increased in the soils used for the continuous cropping of ginger. Additionally, aluminum toxicity had a significant positive correlation withBacillus, Pseudomonas, Arthrobacter, andSerratiain healthy soils. Based on these results, aluminum stress may stimulate the increase of PGPRs (Bacillus, Pseudomonas, Arthrobacter, andSerratia), thereby alleviating ginger aluminum toxicity and bacterial wilt in extremely acidic soil (pH < 4.5).
The Rho-Dependent Transcription Termination Is Involved in Broad-Spectrum Antibiotic Susceptibility in Escherichia coli
Authors: Hafeezunnisa Md. , Sen Ranjan
Published: November 2020

One of the major ways of acquiring multidrug resistance in bacteria is via drug influx and efflux pathways. Here, we show thatE. coliwith compromised Rho-dependent transcription termination function has enhanced broad-spectrum antibiotic susceptibility, which arises from the inefficient TolC-efflux process and increased permeability of the membrane. The Rho mutants have altered morphology, distinct cell surface, and increased levels of lipopolysaccharide in their outer membrane, which might have rendered the TolC efflux pumps inefficient. These alterations are due to the upregulations of poly-N-acetyl-glucosamine and lipopolysaccharide synthesis operons because of inefficient Rho functions. The Rho mutants are capable of growing on various dipeptides and carbohydrate sources, unlike their WT counterpart. Dipeptides uptake arises from the upregulations of the di-peptide permease operon in these mutants. The metabolomics of the Rho mutants revealed the presence of a high level of novel metabolites. Accumulation of these metabolites in these Rho mutants might titrate out the TolC-efflux pumps, which could further reduce their efficiency. We conclude that the transcription termination factor, Rho, regulates the broad-spectrum antibiotic susceptibility ofE. colithrough multipartite pathways in a TolC-dependent manner. The involvement of Rho-dependent termination in multiple pathways and its association with antibiotic susceptibility should make Rho-inhibitors useful in the anti-bacterial treatment regimen.
Peripheral Inflammation and Cognitive Performance in Middle-Aged Adults With and Without Type 2 Diabetes: Results From the ENBIND Study
Authors: Dyer Adam H. , McKenna Louise , Batten Isabella , Jones Karen , Widdowson Matthew , Dunne Jean , Conlon Niall , Reilly Richard , Woods Conor P. , O’Neill Desmond , Gibney James , Bourke Nollaig M. , Kennelly Sean P.
Published: November 2020

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with a greater risk of dementia in later life. Peripheral inflammation and its impact on cognition is proposed as one of the pathological mechanisms mediating this link. However, studies have primarily focused on older individuals with established cognitive impairment and a long duration of T2DM. Importantly, knowledge of which individuals with midlife T2DM who are at greatest risk of later cognitive decline is lacking. We examined the cross-sectional relationship between serum levels of 8 pro-inflammatory markers (IL-1β, IL-6, TNF-α, IL-8, MCP-1, CXCL10, IL-12p70, CRP) and performance on a detailed neuropsychological assessment battery in middle-aged adults with uncomplicated T2DM (N = 89; 52 ± 8.1 years, 47% female) and matched healthy controls (N = 50; 52 ± 8.3 years, 59% female). Linear regression was used to analyze associations between serum markers and cognitive performance in the overall cohort, followed by a T2DM∗protein concentration interaction analysis to identify any T2DM-specific effects. We observed a significant T2DM-specific association between serum TNF-α levels and scores on the Paired Associates Learning (PAL) task (β: −3.16, SE: 1.32, p = 0.01, Std. Beta: −0.94), a task with significant working memory demands previously implicated in T2DM-related cognitive dysfunction. However, this did not persist on controlling for multiple testing. We provide exploratory evidence for a significant T2DM-specific relationship between serum TNF-α and memory performance. These findings require further replication and longitudinal analysis with the aim of selecting-out individuals with midlife T2DM at risk of future cognitive decline for potential preventative interventions.
Deep Learning-Based Method to Differentiate Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis
Authors: Kim Hyunjin , Lee Youngin , Kim Yong-Hwan , Lim Young-Min , Lee Ji Sung , Woo Jincheol , Jang Su-Kyeong , Oh Yeo Jin , Kim Hye Weon , Lee Eun-Jae , Kang Dong-Wha , Kim Kwang-Kuk
Published: November 2020

Background: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS) is crucial in the field of diagnostics because, despite their similarities, the treatments for these two diseases are substantially different, and disease-modifying treatments for MS can worsen NMOSD. As brain magnetic resonance imaging (MRI) is an important tool to distinguish the two diseases, extensive research has been conducted to identify the defining characteristics of MRI images corresponding to these two diseases. However, the application of such research in clinical practice is still limited. In this study, we investigate the applicability of a deep learning-based algorithm for differentiating NMOSD from MS.

Methods: In this study, we included 338 participants (213 patients with MS, 125 patients with NMOSD) who visited the Asan medical center between February 2009 and February 2020. A 3D convolutional neural network, which is a deep learning-based algorithm, was trained using fluid-attenuated inversion recovery images and clinical information of the participants. The performance of the final model in differentiating NMOSD from MS was evaluated and compared with that of two neurologists.

Results: The deep learning-based model exhibited an area under the receiver operating characteristic curve of 0.82 (95% CI, 0.75–0.89). It differentiated NMOSD from MS with an accuracy of 71.1% (sensitivity = 87.8%, specificity = 61.6%), which is comparable to that exhibited by the neurologists. The intra-rater reliability of the two neurologists was moderate (κ = 0.47, 0.50), which was in contrast with the consistent classification of the deep learning-based model.

Conclusion: The proposed model was verified to be capable of differentiating NMOSD from MS with accuracy comparable to that of neurologists, exhibiting the advantage of consistent classification. As a result, it can aid differential diagnosis between two important central nervous system inflammatory diseases in clinical practice.
Impact of COVID-19 on Stroke Admissions and the Medical Care System in the Tokyo Metropolitan Area
Authors: Ota Takahiro , Shiokawa Yoshiaki , Hirano Teruyuki
Published: November 2020

Aims: This study aimed to assess the number of patients with acute stroke seeking medical emergency care since the declaration of the state of emergency in the COVID-19 pandemic in the Tokyo metropolitan area of Japan.

Methods: In this combined retrospective and prospective multicenter survey, data on the numbers of hospital admissions due to acute ischemic stroke, of large vessel occlusion (LVO) cases, and of reperfusion therapies performed from February to July 2020, restrictions of the medical care system, and comprehensive stroke center (CSC) scale scores were collected in 19 stroke centers in Tokyo.

Results: In the survey period, 3,456 patients were admitted with acute stroke. There was a decrease in the number of admissions (−22%), LVO (−22%), thrombolysis (−6%), and thrombectomy (−23%) during the state of emergency, but the ratio of thrombectomy to LVO cases was not different. The acceptance of acute stroke cases by emergency transport and emergent operations in the central eastern area of Tokyo, was also significantly decreased to <50% and remains <60%. According to CSC scores, each hospital restricted their infrastructure or educational activities according to their medical resources. There was only one stroke case with COVID-19 (thrombectomy case) in all 3,456 patients in this study.

Conclusion: The COVID-19 pandemic had a major impact on stroke care in Tokyo, including stroke admissions and medical care systems, resulting in a significant reduction in thrombolysis and thrombectomy. The extent of the drop may be the result of the number of COVID-19 patients.
Increased Left Putamen Volume Correlates With Pain in Ankylosing Spondylitis Patients
Authors: Hua Kelei , Wang Peijun , Lan Zhihong , Li Meng , Zhao Wenkai , Wang Tianyue , Li Shumei , Ma Xiaofen , Li Chao , Fu Shishun , Yin Yi , Liu Ping , Fang Jin , Li Tianwang , Jiang Guihua
Published: November 2020

Ankylosing spondylitis (AS) mainly affects the axial skeleton and is an important factor leading to chronic lower back pain in young individuals. However, few studies have explored alterations of brain gray matter volume in AS patients. The purpose of the present study was to describe brain gray matter abnormalities associated with AS pain. A total of 61 AS patients and 52 healthy controls (HCs) were included in this study. Using voxel-based morphometrics, we detected abnormal gray matter volume in AS patients. Based on the voxel-wise analysis, the gray matter volume in the left putamen of the AS group was increased significantly compared with that of the HC group. In addition, we found that the gray matter volume of the left putamen was positively correlated with the duration of AS and total back pain scores, whereas it was not significantly correlated with Bath Ankylosing Spondylitis Disease Activity Index scores, C-reactive protein, or erythrocyte sedimentation rate in AS patients. Taken together, our findings improve our understanding of the neural substrates of pain in AS and provide evidence of AS-related neurological impairment. Hence, further investigation of the pathophysiology of the left putamen in AS is warranted.
Superiority of Epstein-Barr Virus DNA in the Plasma Over Whole Blood for Prognostication of Extranodal NK/T Cell Lymphoma
Authors: Ha Joo Young , Cho Hyungwoo , Sung Heungsup , Jung Ah Ra , Lee Yoon Sei , Lee Sang-Wook , Ryu Jin-Sook , Chae Eun Jin , Kim Kyung Won , Huh Jooryung , Park Chan-Sik , Kim Dong-Joon , Kim Seon-Ok , Yoon Dok Hyun
Published: November 2020

Background

Extranodal natural killer T cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma with invariable infection of lymphoma cells with Epstein-Barr virus (EBV), and the presence of EBV-DNA in the blood is a well-known prognosticator. However, there is no consensus on which blood compartment is more optimal for predicting survival outcomes.

Methods

We analyzed 60 patients who were newly diagnosed with ENKTL from a prospectively collected database. EBV-DNA was measured in the whole-blood (WB) and plasma at the time of diagnosis and after treatment completion.

Results

EBV-DNA was detected in pre-treatment WB and plasma in 37 (61.7%) and 23 (38.3%) patients, respectively. The presence of pre-treatment plasma EBV-DNA was significantly associated with advanced stage while presence of WB EBV-DNA did not. Positivity of pre-treatment plasma-EBV, but not WB EBV-DNA, was independently associated with poor PFS (HR, 4.22;95% CI, 1.79–9.97; P=0.001) and OS (HR, 8.38; 95% CI, 3.03–23.19; P<0.001) in the multivariate analysis. After treatment completion, positivity of plasma-EBV was independently associated with poor PFS (HR, 9.41; 95% CI, 2.27–39.02; P=0.002) and OS (HR, 32.38; 95% CI, 3.25–322.56; P=0.003), whereas no significant association was observed between WB-EBV status and survival outcomes.

Conclusions

Our results suggest that EBV-DNA in the plasma has better prognostic values than WB in patients with ENKTL.
Riproximin Exhibits Diversity in Sugar Binding, and Modulates some Metastasis-Related Proteins with Lectin like Properties in Pancreatic Ductal Adenocarcinoma
Authors: Sagini Micah N. , Klika Karel D. , Orry Andrew , Zepp Michael , Mutiso Joshua , Berger Martin R.
Published: November 2020

Riproximin (Rpx) is a type II ribosome-inactivating protein with specific anti-proliferative activity. It was purified from Ximenia americana by affinity chromatography using a resin coupled with lactosyl residues. The same technique facilitated isolation of proteins with lectin-like properties from human Suit2-007 and rat ASML pancreatic cancer cells, which were termed lactosyl-sepharose binding proteins (LSBPs). The role of these proteins in cancer progression was investigated at mRNA level using chip array data of Suit2-007 and ASML cells re-isolated from nude rats. These data compared significant mRNA expression changes when relating primary (pancreas) and metastatic (liver) sites following orthotopic and intraportal implantation of Pancreatic Ductal Adenocarcinoma (PDAC) cells, respectively. The affinity of Rpx to 13 simple sugar structures was modeled by docking experiments, the ranking of which was principally confirmed by NMR-spectroscopy. In addition, Rpx and LSBPs were evaluated for anti-proliferative activity and their cellular uptake was assessed by fluorescence microscopy. From 13 monosaccharides evaluated, open-chain rhamnose, β-d-galactose, and α-l-galactopyranose showed the highest affinities for site 1 of Rpx’s B-chain. NMR evaluation yielded a similar ranking, as galactose was among the best binders. Both, Rpx and LSBPs reduced cell proliferation in vitro, but their anti-proliferative effects were decreased by 15–20% in the presence of galactose. The program “Ingenuity Pathway Analysis” identified 2,415 genes showing significantly modulated mRNA expression following exposure of Suit2-007 cells to Rpx in vitro. These genes were then matched to those 1,639 genes, which were significantly modulated in the rat model when comparing primary and metastatic growth of Suit2-007 cells. In this overlap analysis, LSBP genes were considered separately. The potential suitability of Rpx for treating metastatic Suit2-007 PDAC cells was reflected by those genes, which were modulated by Rpx in a way opposite to that observed in cancer progression. Remarkably, these were 14% of all genes modulated during cancer progression, but 71% of the respective LSBP gene subgroup. Based on these findings, we predict that Rpx has the potential to treat PDAC metastasis by modulating genes involved in metastatic progression, especially by targeting LSBPs.