bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibody-Mediated LILRB2-Receptor Antagonism Induces Human Myeloid-Derived Suppressor Cells to Kill Mycobacterium tuberculosis
Authors: Singh Vipul K. , Khan Arshad , Xu Yitian , Mai Sunny , Zhang Licheng , Mishra Abhishek , Restrepo Blanca I. , Pan Ping-Ying , Chen Shu-Hsia , Jagannath Chinnaswamy
Published: June 2022

Tuberculosis is a leading cause of death in mankind due to infectious agents, and Mycobacterium tuberculosis (Mtb) infects and survives in macrophages (MФs). Although MФs are a major niche, myeloid-derived suppressor cells (MDSCs) are an alternative site for pathogen persistence. Both MФs and MDSCs express varying levels of leukocyte immunoglobulin-like receptor B (LILRB), which regulate the myeloid cell suppressive function. Herein, we demonstrate that antagonism of LILRB2 by a monoclonal antibody (mab) induced a switch of human MDSCs towards an M1-macrophage phenotype, increasing the killing of intracellular Mtb. Mab-mediated antagonism of LILRB2 alone and its combination with a pharmacological blockade of SHP1/2 phosphatase increased proinflammatory cytokine responses and phosphorylation of ERK1/2, p38 MAPK, and NF-kB in Mtb-infected MDSCs. LILRB2 antagonism also upregulated anti-mycobacterial iNOS gene expression and an increase in both nitric oxide and reactive oxygen species synthesis. Because genes associated with the anti-mycobacterial function of M1-MФs were enhanced in MDSCs following mab treatment, we propose that LILRB2 antagonism reprograms MDSCs from an immunosuppressive state towards a pro-inflammatory phenotype that kills Mtb. LILRB2 is therefore a novel therapeutic target for eradicating Mtb in MDSCs.
Aberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review
Authors: Thawley Alexandra Jade , Veneziani Luciana Peixoto , Rabelo-da-Ponte Francisco Diego , Riederer Ingo , Mendes-da-Cruz Daniella Areas , Bambini-Junior Victorio
Published: June 2022

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterised by stereotyped behaviours, specific interests, and impaired communication skills. Elevated levels of pro-inflammatory cytokines, such as interleukin-17A (IL-17A or IL-17), have been implicated as part of immune alterations that may contribute to this outcome. In this context, rodent models have helped elucidate the role of T-cell activation and IL-17 secretion in the pathogenesis of ASD. Regarding the preclinical findings, the data available is contradictory in offspring but not in the pregnant dams, pointing to IL-17 as one of the main drivers of altered behaviour in some models ASD, whilst there are no alterations described in IL-17 levels in others. To address this gap in the literature, a systematic review of altered IL-17 levels in rodent models of ASD was conducted. In total, 28 studies that explored IL-17 levels were included and observed that this cytokine was generally increased among the different models of ASD. The data compiled in this review can help the choice of animal models to study the role of cytokines in the development of ASD, seeking a parallel with immune alterations observed in individuals with this condition.

Systematic Review Registration

PROSPERO, identifier CRD42022306558.
Myeloid-Derived Suppressor Cells: The Expanding World of Helminth Modulation of the Immune System
Authors: Stevenson Mary M. , Valanparambil Rajesh M. , Tam Mifong
Published: June 2022

Infection with helminths or parasitic worms are highly prevalent worldwide especially in developing regions. Helminths cause chronic infections that are associated with suppression of immune responses to unrelated pathogens, vaccines, and by-stander antigens responsible for dysregulated immune responses as occurs in diseases such as allergies. Helminths use multiple mechanisms to modulate the immune system to evade the highly polarized type 2 immune response required to expel adult worms and for immunity to reinfection. Anthelmintic drugs are efficient in reducing adult worm burdens in helminth-infected individuals, but resistance to these drugs is rapidly increasing and vaccines against these pathogens are not available. Emerging evidence indicate that helminths induce myeloid-derived suppressor cells (MDSC), originally described in tumor-bearing mice and cancer patients. MDSC are a heterogenous population of immature cells that consist of two distinct sub-populations, polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC based on morphology and phenotype. MDSC suppress the function of T cells and other innate and adaptive immune cells including NK cells and B cells. During cancer or infection with bacteria or viruses, there is marked expansion of MDSC. Furthermore, the frequencies of MDSC correlate inversely with the prognosis and survival of tumor-bearing hosts as well as bacterial and viral burdens, persistence, and outcome in infected hosts. Currently, there is a paucity of data on MDSC and helminth infections. Here, we provide a survey of the evidence accumulated so far that overall support a role for MDSC in modulating immune responses during helminth infections. We review data from studies in various helminths, including those that infect humans. Finally, we summarize the progress to date in understanding the role of MDSC in helminth infections and briefly discuss potential host-directed strategies to target MDSC-mediated suppression of immune responses to helminths in favor of development of immunity to eliminate adult worms and possibly induce protection against reinfection.
Effect of the Combination of Everolimus and Mesenchymal Stromal Cells on Regulatory T Cells Levels and in a Liver Transplant Rejection Model in Rats
Authors: Vandermeulen Morgan , Erpicum Pauline , Bletard Noella , Poma Laurence , Jouret François , Detry Olivier
Published: June 2022

Introduction

Mesenchymal stromal cells (MSCs) have particular properties that are of interest in organ transplantation, including the expansion of regulatory T cells (Tregs), a key factor in transplant tolerance induction. However, the most effective immunosuppressive drug to associate with MSCs has yet to be defined. Additionally, the impact of the association of everolimus with MSCs on Treg expansion, and on the induction of liver graft tolerance, has never been studied. The aim of this study was to evaluate the effects of MSCs in combination, or not, with everolimus on Treg expansion and in a model of rejection after liver transplantation (LT) in the rat.

Methods

Firstly, 24 Lewis rats were assigned to 4 groups (n=6 in each group) receiving intravenous MSCs or saline injection at day (D)9 with/without subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was performed at D0, D14 and D28. In a second set of experiment, 30 Lewis rats were randomized in 3 groups 48hours after LT with a Dark Agouti rat liver: everolimus (subcutaneous for 14 days), MSCs (intravenous injection at post-operative day 2 and 9), or both everolimus and MSCs. Rejection of the liver graft was assessed by liver tests, histology and survival.

Results

Individually, MSC infusion and everolimus promoted Treg expansion in rats, and everolimus had no negative impact on Treg expansion in combination with MSCs. However, in the LT model, injections of MSCs two and nine days following LT were not effective at preventing acute rejection, and the combination of MSCs with everolimus failed to show any synergistic effect when compared to everolimus alone.

Conclusion

Everolimus may be used in association with MSCs. However, in our model of LT in the rat, post-transplant MSC injections did not prevent acute rejection, and the association of MSCs with everolimus did not show any synergistic effect.
Case Report: Dual Inhibition of HDAC and BTK for Diffuse Large B-Cell Lymphoma After Failure to CD19-Targeted CAR-T Therapy
Authors: Zhu Weiguo , Tao Shi , Miao Wenchun , Liu Hui , Yuan Xianggui
Published: June 2022

Background

Failure to CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), is an emerging clinical problem. There is no consensus on the treatment for these patients and treatment remains empirical.

Case Report

We reported a case of an elderly R/R DLBCL patient who had TP53 mutation and relapsed 12 months after initial response to CAR T-cell therapy. The patient did not respond to salvage chemotherapy with the GDP regimen and could not tolerate any aggressive chemotherapy. Thereafter, the patient was given chidamide and zanubrutinib. After two months of treatment, the patient achieved sustained complete remission. At the last follow-up, the patient remains in radiographic CR 22 months after CAR-T infusion and 10 months after the initiation of the combination treatment.

Conclusion

We report the first successful case of dual inhibition of HDAC and BTK for the treatment of R/R DLBCL after failure to CAR-T cell therapy, which opens a new therapeutic possibility for the future.
The Role of NLRP3 Inflammasome Activation Pathway of Hepatic Macrophages in Liver Ischemia–Reperfusion Injury
Authors: Wu Tong , Zhang Cheng , Shao Tianfeng , Chen Jianzhong , Chen Diyu
Published: June 2022

Ischemia-reperfusion injury (IRI) is considered an inherent component involved in liver transplantation, which induce early organ dysfunction and failure. And the accumulating evidences indicate that the activation of host innate immune system, especially hepatic macrophages, play a pivotal role in the progression of LIRI. Inflammasomes is a kind of intracellular multimolecular complexes that actively participate in the innate immune responses and proinflammatory signaling pathways. Among them, NLRP3 inflammasome is the best characterized and correspond to regulate caspase-1 activation and the secretion of proinflammatory cytokines in response to various pathogen-derived as well as danger-associated signals. Additionally, NLRP3 is highly expressed in hepatic macrophages, and the assembly of NLRP3 inflammasome could lead to LIRI, which makes it a promising therapeutic target. However, detailed mechanisms about NLRP3 inflammasome involving in the hepatic macrophages-related LIRI is rarely summarized. Here, we review the potential role of the NLRP3 inflammasome pathway of hepatic macrophages in LIRI, with highlights on currently available therapeutic options.
Intestinal Uptake and Tolerance to Food Antigens
Authors: Xiong Yuhong , Xu Guifeng , Chen Mingwu , Ma Hongdi
Published: June 2022

Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms responsible for the occurrence and development of food allergy have not yet been fully elucidated, effective individualized treatment options are lacking. In this review, we summarize the pathways through which food antigens enter the intestine and review the proposed mechanisms describing how the intestine acquires and tolerates food antigens. When oral tolerance is not established, food allergy occurs. In addition, we also discuss the contribution of commensal bacteria of the gut in shaping tolerance to food antigens in the intestinal tract. Finally, we propose that elucidating the mechanisms of intestinal uptake and tolerance of food antigens will provide additional clues for potential treatment options for food allergy.
Comprehensive Analysis and Reinforcement Learning of Hypoxic Genes Based on Four Machine Learning Algorithms for Estimating the Immune Landscape, Clinical Outcomes, and Therapeutic Implications in Patients With Lung Adenocarcinoma
Authors: Sun Zhaoyang , Zeng Yu , Yuan Ting , Chen Xiaoying , Wang Hua , Ma Xiaowei
Published: June 2022

Background

Patients with lung adenocarcinoma (LUAD) exhibit significant heterogeneity in therapeutic responses and overall survival (OS). In recent years, accumulating research has uncovered the critical roles of hypoxia in a variety of solid tumors, but its role in LUAD is not currently fully elucidated. This study aims to discover novel insights into the mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers by exploring the potential association between hypoxia and LUAD.

Methods

Four machine learning approaches were implemented to screen out potential hypoxia-related genes for the prognosis of LUAD based on gene expression profile of LUAD samples obtained from The Cancer Genome Atlas (TCGA), then validated by six cohorts of validation datasets. The risk score derived from the hypoxia-related genes was proven to be an independent factor by using the univariate and multivariate Cox regression analyses and Kaplan–Meier survival analyses. Hypoxia-related mechanisms based on tumor mutational burden (TMB), the immune activity, and therapeutic value were also performed to adequately dig deeper into the clinical value of hypoxia-related genes. Finally, the expression level of hypoxia genes was validated at protein level and clinical samples from LUAD patients at transcript levels.

Results

All patients in TCGA and GEO-LUAD group were distinctly stratified into low- and high-risk groups based on the risk score. Survival analyses demonstrated that our risk score could serve as a powerful and independent risk factor for OS, and the nomogram also exhibited high accuracy. LUAD patients in high-risk group presented worse OS, lower TMB, and lower immune activity. We found that the model is highly sensitive to immune features. Moreover, we revealed that the hypoxia-related genes had potential therapeutic value for LUAD patients based on the drug sensitivity and chemotherapeutic response prediction. The protein and gene expression levels of 10 selected hypoxia gene also showed significant difference between LUAD tumors tissues and normal tissues. The validation experiment showed that the gene transcript levels of most of their genes were consistent with the levels of their translated proteins.

Conclusions

Our study might contribute to the optimization of risk stratification for survival and personalized management of LUAD patients by using the hypoxia genes, which will provide a valuable resource that will guide both mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers.
Heparanase Is a Putative Mediator of Endothelial Glycocalyx Damage in COVID-19 – A Proof-of-Concept Study
Authors: Drost Carolin Christina , Rovas Alexandros , Osiaevi Irina , Rauen Matthias , van der Vlag Johan , Buijsers Baranca , Salmenov Rustem , Lukasz Alexander , Pavenstädt Hermann , Linke Wolfgang A. , Kümpers Philipp
Published: June 2022

Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.
Causal Association Between Inflammatory Bowel Disease and Psoriasis: A Two-Sample Bidirectional Mendelian Randomization Study
Authors: Li Yajia , Guo Jia , Cao Ziqin , Wu Jianhuang
Published: June 2022

Background

Previous observational studies have found an association between inflammatory bowel disease (IBD) and psoriasis. Using the mendelian randomization (MR) approach, we aim to determine whether there was a causal association between IBD and psoriasis.

Methods

We performed a two-sample MR with the genetic instruments identified for IBD and its main subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), from a genome-wide association study (GWAS) involving 25,042 cases with an IBD diagnosis and 34,915 controls. Summarized data for psoriasis were obtained from different GWAS studies which included 4510 cases and 212,242 controls without psoriasis. Causal estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs).

Results

The overall outcome of MR analysis was to demonstrate that genetic predisposition to IBD was associated with an increased risk of psoriasis (OR: 1.1271; 95% CI: 1.0708 to 1.1864). Psoriatic arthritis (PsA) had a significant association with total IBD (OR: 1.1202; 95% CI: 1.0491 to 1.1961). Casual relationship was also identified for CD-psoriasis (OR: 1.1552; 95% CI: 1.0955 to 1.2182) and CD-PsA (OR: 1.1407; 95% CI: 1.0535 to 1.2350). The bidirectional analysis did not demonstrate that a genetic predisposition to psoriasis was associated with total IBD, although psoriasis showed association with CD (OR: 1.2224; 95% CI: 1.1710 to 1.2760) but not with UC. A genetic predisposition to PsA had a borderline association with IBD (OR: 1.0716; 95% CI: 1.0292 to 1.1157) and a suggestive association with CD (OR: 1.0667; 95% CI: 1.0194 to 1.1162).

Conclusion

There appears to be a causal relationship between IBD and psoriasis, especially for PsA, but for psoriasis and IBD, only total psoriasis and PsA were associated with CD. Understanding that specific types of psoriasis and IBD constitute mutual risk factors facilitates the clinical management of two diseases.
How RA Associated HLA-DR Molecules Contribute to the Development of Antibodies to Citrullinated Proteins: The Hapten Carrier Model
Authors: Roudier Jean , Balandraud Nathalie , Auger Isabelle
Published: June 2022

The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid motif: the shared epitope (SE). RA is preceded by the emergence of disease specific anti citrullinated protein antibodies (ACPA). SE positive HLA-DRB1 alleles are associated with ACPA and ACPA positive RA, not with ACPA negative RA, suggesting that ACPA contribute to the pathogenesis of RA. Understanding how HLA-DRB1 genotypes influence ACPA could lead to a curative or preventive treatment of RA. The “Shared epitope binds citrullinated peptides “ hypothesis suggests that RA associated HLA-DR alleles present citrullinated peptides to T cells that help ACPA producing B cells. The “Hapten carrier model” suggests that PAD4 is the target of the T cells which help ACPA specific B cells through a hapten carrier mechanism in which PAD4 is the carrier and citrullinated peptides are the haptens. Direct binding assay of citrullinated peptides to purified HLA-DR molecules does not support the “shared epitope binds citrullinated peptides” hypothesis. The Odds Ratios to develop ACPA positive RA associated with each of 12 common HLA-DRB1 genotypes match the probability that the two HLA-DR molecules they encode can bind at least one peptide from PAD4, not from citrullinated fibrinogen. Thus, PAD4 tolerization might stop the carrier effect and switch off production of ACPA.
suPAR to Risk-Stratify Patients With Malaria
Authors: Stefanova Veselina , Crowley Valerie M. , Weckman Andrea M. , Kain Kevin C.
Published: June 2022

Severe malaria (SM) is a leading cause of global morbidity and mortality, particularly in children in sub-Saharan Africa. However, existing malaria diagnostic tests do not reliably identify children at risk of severe and fatal outcomes. Dysregulated host immune and endothelial activation contributes to the pathogenesis of SM. Current research suggests that measuring markers of these pathways at presentation may have clinical utility as prognostic indicators of disease progression and risk of death. In this review, we focus on the available evidence implicating soluble urokinase-type plasminogen activator receptor (suPAR) as a novel and early predictor of severe and fatal malaria and discuss its potential utility for malaria triage and management.
Toxicity and Bioaccumulation of Copper in Phaeodactylum tricornutum Under Different Macronutrient Conditions
Authors: Zhou Beibei , Zou Yue , Ma Jie , Li Yanping , Pan Ke
Published: June 2022

In this study, we investigated cell physiological and biochemical responses to copper (Cu) accumulation in the marine diatom Phaeodactylum tricornutum under different nitrogen (N) and phosphorus (P) conditions. Cells with sufficient N and P (+N+P) showed the highest total Cu concentrations and displayed a higher metal-tolerance ability. In the +N+P treatments, 36.5% of dissolved Cu was adsorbed on the frustules (cell walls), 54.9% was occluded in organelles, and 8.6% was in the soluble fraction. In comparison, cells with N and/or P shortages (+N−P, −N+P, and −N−P) adsorbed 10.8–13.1% of the total Cu onto their cell walls, 74.5–80% was occluded in organelles, and 9.2–12.4% was in the soluble fraction. The Cu2+ influx on the +N+P cell wall was faster due to sufficient metal ligands on the cell walls and up-regulated metal-related transporters. A significant increase in protein content occurred under N and/or P shortages, which was accompanied by the inhibition of the antioxidative enzymatic system and cell membrane damage. Our findings indicate that N and P play an important role in both Cu adsorption (cell surface) and uptake (intracellular), and they provide multifaceted evidence of the Cu acquisition mechanism in P. tricornutum under different macronutrient conditions.
Biotic Response to Rapid Environmental Changes During the Permian–Triassic Mass Extinction
Authors: Li Guoshan , Wang Yongbiao , Li Sheng , Wang Tan , Liao Wei , Deng Baozhu , Lai Zhongping
Published: June 2022

The divergent patterns of Permian–Triassic mass extinction (PTME) have been extensively documented in varying water depth settings. We here investigated fossil assemblages and sedimentary microfacies on high-resolution samples from two adjacent sections of the South China Block: Chongyang from shallow-water platform and Chibi from deeper-water slop. At Chongyang, abundant benthos (over 80%), including rugose corals, fusulinids, calcareous algae, and large foraminifers, disappeared precipitously at the topmost of Changxing Formation grainstone, which suggested complete damage of the benthic ecosystem, confirming a sudden single-pulse extinction pattern. The end-Permian regression, marked by a karst surface, provided a plausible explanation for this extinction pattern. Whereas for the fauna in Chibi, the benthos was relatively abundant (20%–55%) with more trace fossils and lacking calcareous algae. Benthic abundance in Chibi reduced by two steps at the two claystone beds (Beds 10 and 18): bioclastic content dropped from an average of 50% in Beds 1–9 to 10% in Beds 11–17 and then to less than 5% in Beds 19–23, suggesting a two-pulse extinction. At the first pulse, large foraminifers were prominent victims in both shallow- and deeper-water settings. A plausible survival strategy for small-sized foraminifers was to migrate to deeper water to avoid extreme heat in shallow water. The early Triassic transgression prompted some small foraminifers to migrate back to original platforms and flourish briefly as disaster forms. At the Early Triassic mudstone with bottom-water settings in Chibi, the appearance of abundant small pyrite framboids (diameters of 4.74–5.96 μm), an indicator of intensified oxygen deficiency, was simultaneous with the two-step reduction of benthic diversity and abundance. Thus, anoxic conditions might be the main cause of the PTME at deeper-water settings. Our study is an example of the wider debate about biotic response to rapid environmental change for both the Permian–Triassic transition and modern days.
Polymyxin B/Tigecycline Combination vs. Polymyxin B or Tigecycline Alone for the Treatment of Hospital-Acquired Pneumonia Caused by Carbapenem-Resistant Enterobacteriaceae or Carbapenem-Resistant Acinetobacter baumannii
Authors: Chang Kang , Wang Haibo , Zhao Jianping , Yang Xianghong , Wu Bo , Sun Wenkui , Huang Man , Cheng Zhenshun , Chen Hong , Song Yuanlin , Chen Ping , Chen Xiangqi , Gan Xin , Ma Wanli , Xing Lihua , Wang Yimin , Gu Xiaoying , Zou Xiaohui , Cao Bin
Published: June 2022

Introduction

It is not clear whether polymyxin B/tigecycline (PMB/TGC) combination is better than PMB or TGC alone in the treatment of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant organisms (CROs).

Methods

We conducted a multicenter, retrospective cohort study in patients with HAP caused by CROs. The primary outcome was 28-day mortality, and the secondary outcomes included clinical success and the incidence of acute kidney injury (AKI). Multivariate Cox regression analysis was performed to examine the relationship between antimicrobial treatments and 28-day mortality by adjusting other potential confounding factors.

Results

A total of 364 eligible patients were included in the final analysis, i.e., 99 in the PMB group, 173 in the TGC group, and 92 in the PMB/TGC combination group. The 28-day mortality rate was 28.3% (28/99) in the PMB group, 39.3% (68/173) in the TGC group, and 48.9% (45/92) in the PMB/TGC combination group (p= 0.014). The multivariate Cox regression model showed that there was a statistically significant lower risk of 28-day mortality among participants in the PMB group when compared with the PMB/TGC combination group [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31–0.81,p= 0.004] and that participants in the TGC group had a lower risk of 28-day mortality than in the PMB/TGC combination group but without statistical significance. The incidence of AKI in the PMB group (52.5%) and the PMB/TGC combination group (53.3%) was significantly higher than that in the TGC group (33.5%,p= 0.001).

Conclusion

The appropriate PMB/TGC combination was not superior to appropriate PMB therapy in the treatment of HAP caused by carbapenem-resistantEnterobacteriaceae/carbapenem-resistantAcinetobacter baumannii(CRE/CRAB) in terms of 28-day mortality.
Classification-Based Approaches to Myopia Control in a Taiwanese Cohort
Authors: Hsieh Meng-Wei , Chang Hsu-Chieh , Chen Yi-Hao , Chien Ke-Hung
Published: June 2022

Purpose

Myopia is a disorder of growing prevalence in school-aged children worldwide, especially in Asia. Although low-dose atropine is recognized as an effective treatment to slow myopia progression, different studies have reported varying efficacies of treatment, and the optimal concentration of low-dose atropine remains an open question.

Methods

A two-stage approach was conducted in this study. First, an observational study was conducted to plot the axial length growth curve for Taiwanese children. Second, an interventional 2-year study was performed in which different concentrations of low-dose atropine were applied based upon the risk-level status from the first stage.

Results

A total of 4,091 subjects, consisting of 2,105 boys (51.5%) and 1,986 girls (48.5%), were enrolled in the first stage to plot the axial growth curve for Taiwanese children aged between 3 and 16 years. The percentage of children with myopia increased from 2.3% in 4-year-olds to 88.0% in 16-year-olds. At the second stage, a total of 886 subjects [307 (34.65%) at low risk, 358 (40.41%) at moderate risk and 221 (24.94%) at high risk] were enrolled to receive low-dose atropine based upon the risk level (0.02, 0.03, and 0.05%, respectively). With this approach, the mean annual myopia progression was −0.33, −0.57, and −0.82 D in the low-risk, moderate-risk and high-risk groups, respectively. Applying annual myopic progression < -1.0 D as a criterion for responder, the responder rates were 95.77, 83.52, and 70.59% in the low-risk, moderate-risk, and high-risk groups, respectively.

Conclusions

We proposed a classification-based approach involving different concentrations of low-dose atropine based upon an individual's risk-level status. With this approach, myopic progression can be effectively controlled in patients without exposure to atropine side effects due to exposure to a higher dose than actually needed.
Operationalization of the Clinical Frailty Scale in Korean Community-Dwelling Older People
Authors: Jung Hee-Won , Baek Ji Yeon , Jang Il-Young , Lee Eunju
Published: June 2022

Background

The Clinical Frailty Scale (CFS) is a simple measure of global fitness validated in various populations in real-world settings. In this study, we aimed to assess the characteristics and validities of the CFS in community-dwelling older people in Korea, with the original classification tree (oCFS) and a culturally modified tree (mCFS).

Methods

The comprehensive geriatric assessment records of 1,064 individuals of the Aging Study of the Pyeongchang Rural Area were used for this study. For mCFS, we considered the dependency of the food preparations and household chores not to be deficits in the male population. The frailty index was used as a reference for construct validity. We used a composite outcome of death and institutionalization for outcome validity.

Results

The correlation coefficients with frailty index were higher in mCFS (.535) than in oCFS (.468). The mean frailty index was lower in individuals reclassified by mCFS (5 to 4) than people who stayed in mCFS 5. The classification coefficient of mCFS was significantly higher than that of oCFS (p <0.001) in determining people with frailty (frailty index.25 or higher). Trends of a higher incidence of the composite outcome were observed in both higher oCFS and mCFS, in which oCFS and mCFS did not differ significantly in predicting the risk of the outcome.

Conclusion

The classification tree of CFS could be culturally adopted in a community-dwelling population of Korea and considered valid in detecting the vulnerable population.
Stopping of Mycophenolic Acid in Kidney Transplant Recipients for 2 Weeks Peri-Vaccination Does Not Increase Response to SARS-CoV-2 Vaccination—A Non-randomized, Controlled Pilot Study
Authors: Regele Florina , Heinzel Andreas , Hu Karin , Raab Lukas , Eskandary Farsad , Faé Ingrid , Zelzer Sieglinde , Böhmig Georg A. , Bond Gregor , Fischer Gottfried , Oberbauer Rainer , Reindl-Schwaighofer Roman
Published: June 2022

Introduction

Kidney transplant recipients (KTR) are at high risk of developing severe COVID-19. However, vaccine response in this population is severely impaired with humoral response rates of 36–54 and 55–69% after two or three doses of SARS-COV-2 vaccines, respectively. Triple immunosuppression and specifically the use of anti-proliferative agents such as mycophenolic acid (MPA) or azathioprine (AZA) have been identified as risk factors for vaccine hypo-responsiveness.

Methods

We hypothesized that in vaccine non-responders to at least three previous vaccine doses, pausing of MPA or AZA for 1 week before and 1 week after an additional vaccination would improve humoral response rates. We conducted an open-label, non-randomized controlled pilot study including 40 KTR with no detectable humoral response after three or four previous vaccine doses. Primary endpoint was seroconversion following SARS-CoV-2 vaccination. MPA and AZA was paused in 18 patients 1 week before until 1 week after an additional vaccine dose while immunosuppression was continued in 22 patients.

Results

There was no difference in the humoral response rate between the MPA/AZA pause group and the control group (29 vs. 32%, p > 0.99). Absolute antibody levels were also not statistically significantly different between the two groups (p = 0.716).Renal function in the MPA/AZA pause group remained stable and there was no detection of new onset donor-specific antibodies or an increase of donor-derived cell-free DNA serving as a marker of allograft damage throughout the study period.

Conclusion

Pausing of MPA/AZA for 2 weeks peri-vaccination did not increase the rate of seroconversion in kidney transplant. However, one in three KTR without humoral immune response to at least three previous vaccinations developed antibodies after an additional vaccine dose supporting continued vaccination in non-responders.
Living and Dead Microorganisms in Mediating Soil Carbon Stocks Under Long-Term Fertilization in a Rice-Wheat Rotation
Authors: Chen Jie , Song Dali , Luan Haoan , Liu Donghai , Wang Xiubin , Sun Jingwen , Zhou Wei , Liang Guoqing
Published: June 2022

Although soil microorganism is an active area of research, we are still in the early stages of understanding how living microorganisms influence the accumulations of soil microbial residues under different agricultural practices. Based on a 39-year fertilization experiment, we characterized the soil microbiota and correlated their compositions to soil microbial residues, which are indicated by amino sugars under a rice-wheat rotation. In the present study, fertilization regimes and crop season all exerted significant impacts on the compositions of soil microbial communities and their residues, although no significant difference in the microbial residues was found between soil depth (0–10 cm vs. 10–20 cm). Compared within fertilization regimes, the long-term fertilization, especially the application of organic manure, stimulated the accumulations of carbon (C) and nitrogen in soils and microbial residues. Upland soils in wheat season accumulated more microbial residues, particularly in fungal residues, than paddy soils in rice season. Our results suggested that the long-term application of organic manure favored the growth of soil microbial communities, and then increased the contents of microbial residues, particularly in fungal residues, leading to an enlargement of soil C pools. The keystone taxa Pseudaleuria identified by network analysis showed a significantly positive potential in soil C sequestration by increasing the accumulation of fungal residues. Thus, this study revealed the strong and close connections between microbial communities and their residues, and provided evidence about the critical role of keystone taxa in regulating C sequestration.
Long-Term Warming of Baltic Sea Coastal Waters Affects Bacterial Communities in Bottom Water and Sediments Differently
Authors: Seidel Laura , Broman Elias , Ståhle Magnus , Nilsson Emelie , Turner Stephanie , Hendrycks Wouter , Sachpazidou Varvara , Forsman Anders , Hylander Samuel , Dopson Mark
Published: June 2022

Coastal marine ecosystems are some of the most diverse natural habitats while being highly vulnerable in the face of climate change. The combination of anthropogenic influence from land and ongoing climate change will likely have severe effects on the environment, but the precise response remains uncertain. This study compared an unaffected “control” Baltic Sea bay to a “heated” bay that has undergone artificial warming from cooling water release from a nuclear power plant for ~50 years. This heated the water in a similar degree to IPCC SSP5-8.5 predictions by 2100 as natural systems to study temperature-related climate change effects. Bottom water and surface sediment bacterial communities and their biogeochemical processes were investigated to test how future coastal water warming alters microbial communities; shifts seasonal patterns, such as increased algae blooming; and influences nutrient and energy cycling, including elevated respiration rates. 16S rRNA gene amplicon sequencing and geochemical parameters demonstrated that heated bay bottom water bacterial communities were influenced by increased average temperatures across changing seasons, resulting in an overall Shannon's H diversity loss and shifts in relative abundances. In contrast, Shannon's diversity increased in the heated surface sediments. The results also suggested a trend toward smaller-sized microorganisms within the heated bay bottom waters, with a 30% increased relative abundance of small size picocyanobacteria in the summer (June). Furthermore, bacterial communities in the heated bay surface sediment displayed little seasonal variability but did show potential changes of long-term increased average temperature in the interplay with related effects on bottom waters. Finally, heated bay metabolic gene predictions from the 16S rRNA gene sequences suggested raised anaerobic processes closer to the sediment-water interface. In conclusion, climate change will likely alter microbial seasonality and diversity, leading to prolonged and increased algae blooming and elevated respiration rates within coastal waters.
Canopy and Understory Nitrogen Addition Alters Organic Soil Bacterial Communities but Not Fungal Communities in a Temperate Forest
Authors: Liu Yang , Tan Xiangping , Fu Shenglei , Shen Weijun
Published: June 2022

Atmospheric nitrogen (N) deposition is known to alter soil microbial communities, but how canopy and understory N addition affects soil bacterial and fungal communities in different soil layers remains poorly understood. Conducting a 6-year canopy and understory N addition experiment in a temperate forest, we showed that soil bacterial and fungal communities in the organic layer exhibited different responses to N addition. The main effect of N addition decreased soil bacterial diversity and altered bacterial community composition in the organic layer, but not changed fungal diversity and community composition in all layers. Soil pH was the main factor that regulated the responses of soil bacterial diversity and community composition to N addition, whereas soil fungal diversity and community composition were mainly controlled by soil moisture and nutrient availability. In addition, compared with canopy N addition, the understory N addition had stronger effects on soil bacterial Shannon diversity and community composition but had a weaker effect on soil bacteria richness in the organic soil layer. Our study demonstrates that the bacterial communities in the organic soil layer were more sensitive than the fungal communities to canopy and understory N addition, and the conventional method of understory N addition might have skewed the effects of natural atmospheric N deposition on soil bacterial communities. This further emphasizes the importance of considering canopy processes in future N addition studies and simultaneously evaluating soil bacterial and fungal communities in response to global environmental changes.
Ectopic Colonization and Immune Landscapes of Periodontitis Microbiota in Germ-Free Mice With Streptozotocin-Induced Type 1 Diabetes Mellitus
Authors: Shen Xin , Wei Hong , Li Jian , Wei Wei , Zhang Bo , Lu Changqing , Yan Caixia , Li Shuzhen , Bao Lirong , Zhang Jinmei , Zhang Cheng , Li Yan
Published: June 2022

A two-way relationship between diabetes and periodontitis has been discussed recently. Periodontitis microbiota might affect the immune homeostasis of diabetes, but the molecular mechanism of their interactions is still not clear. The aims of this study were to clarify the possible immune regulatory effects of periodontitis microbiota on diabetes and the correlation between immunomodulation and ectopic colonization. A model of germ-free mice with streptozotocin-induced type 1 diabetes mellitus (T1D), which was orally inoculated with mixed saliva samples for 2 weeks, was used in this study. Those mice were randomly divided into two groups, namely, SP (where the T1D mice were orally inoculated with mixed saliva samples from periodontitis patients) and SH (where the T1D mice were orally inoculated with mixed saliva samples from healthy subjects). Ectopic colonization of saliva microbiota was assessed using culture-dependent method and Sanger sequencing, and the composition of gut microbiota was analyzed using 16S rRNA gene sequencing. Changes in 15 types of immune cells and six cytokines either from the small intestine or spleen were detected by multicolor flow cytometry. The correlation between gut microbiota and immune cells was evaluated by redundancy analysis. Although periodontitis microbiota minorly colonized the lungs, spleens, and blood system, they predominantly colonized the gut, which was mainly invaded by Klebsiella. SH and SP differed in beta diversity of the gut bacterial community. Compared to SH, microbial alteration in small intestine occurred with an increase of Lacticaseibacillus, Bacillus, Agathobacter, Bacteroides, and a decrease of Raoultella in SP. More types of immune cells were disordered in the spleen than in the small intestine by periodontitis microbiota, mainly with a dramatical increase in the proportion of macrophages, plasmacytoid dendritic cells (pDCs), monocytes, group 3 innate lymphoid cells, CD4-CD8- T cells and Th17 cells, as well as a decline of αβT cells in SP. Cytokines of IFNγ, IL17, and IL22 produced by CD4 + T cells as well as IL22 produced by ILCs of small intestine rose in numbers, and the intestinal and splenic pDCs were positively regulated by gut bacterial community in SP. In conclusion, periodontitis microbiota invasion leads to ectopic colonization of the extra-oral sites and immune cells infiltration, which might cause local or systemic inflammation. Those cells are considered to act as a “bridge” between T1D and periodontitis.
A Flagella Hook Coding Gene flgE Positively Affects Biofilm Formation and Cereulide Production in Emetic Bacillus cereus
Authors: Li Yangfu , Chen Nuo , Wu Qingping , Liang Xinmin , Yuan Xiaoming , Zhu Zhenjun , Zheng Yin , Yu Shubo , Chen Moutong , Zhang Jumei , Wang Juan , Ding Yu
Published: June 2022

Bacillus cereus, an important foodborne pathogen, poses a risk to food safety and quality. Robust biofilm formation ability is one of the key properties that is responsible for the food contamination and food poisoning caused by B. cereus, especially the emetic strains. To investigate the mechanism of biofilm formation in emetic B. cereus strains, we screened for the mutants that fail to form biofilms by using random mutagenesis toward B. cereus 892-1, an emetic strain with strong biofilm formation ability. When knocking out flgE, a flagellar hook encoding gene, the mutant showed disappearance of flagellar structure and swimming ability. Further analysis revealed that both pellicle and ring presented defects in the null mutant compared with the wild-type and complementary strains. Compared with the flagellar paralytic strains ΔmotA and ΔmotB, the inhibition of biofilm formation by ΔflgE is not only caused by the inhibition of motility. Interestingly, ΔflgE also decreased the synthesis of cereulide. To our knowledge, this is the first report showing that a flagellar component can both affect the biofilm formation and cereulide production in emetic B. cereus, which can be used as the target to control the biohazard of emetic B. cereus.
Analysis of Microbial Community, Volatile Flavor Compounds, and Flavor of Cigar Tobacco Leaves From Different Regions
Authors: Zheng Tianfei , Zhang Qianying , Li Pinhe , Wu Xinying , Liu Yi , Yang Zhen , Li Dongliang , Zhang Juan , Du Guocheng
Published: June 2022

Despite the booming international trade in cigar tobacco leaves (CTLs), the main characteristics of tobacco leaves from different producing areas are rarely reported. This study aimed to characterize the microbial community, volatile flavor compounds (VFCs), and flavor of CTLs from four famous cigar-producing areas, including Dominica, Brazil, Indonesia, and China. High-throughput sequencing results showed that the dominant genera in CTLs wereStaphylococcus, Pseudomonas, Aspergillus, Sampaiozyma, andAlternaria. Sensory analysis revealed that Indonesian and Chinese CTLs were characterized by leathery, peppery, and baked aroma. Brazilian CTLs were dominated by caramel and herb aroma. Dominican CTLs had aromas of milk, fruity, sour, cream, flower, nutty, and honey. Supplemented with the determination of volatile flavor compounds (VFCs), the flavor of CTLs could be scientifically quantified. Most of these VFCs were aldehydes and ketones, and 20 VFCs showed significant differences in CTLs from different regions. The microbial community, VFCs, and flavor of CTLs vary widely due to geographic differences. Network analysis revealed the microbial community was closely related to most VFCs, but the relationships between the fungal community and VFCs were less than the bacterial community, and most of them were negative. Furthermore, it also found that the bacterial community had a greater contribution to the flavor of CTLs than the fungal community. This study obtained essential information on CTLs, which laid a foundation for deeply excavating the relationship between microbes and VFCs and flavor, and establishing a tobacco information database.
Genome-Scale Mutational Analysis of Cathode-Oxidizing Thioclava electrotropha ElOx9T
Authors: Sackett Joshua D. , Kamble Nitin , Leach Edmund , Schuelke Taruna , Wilbanks Elizabeth , Rowe Annette R.
Published: June 2022

Extracellular electron transfer (EET) – the process by which microorganisms transfer electrons across their membrane(s) to/from solid-phase materials – has implications for a wide range of biogeochemically important processes in marine environments. Though EET is thought to play an important role in the oxidation of inorganic minerals by lithotrophic organisms, the mechanisms involved in the oxidation of solid particles are poorly understood. To explore the genetic basis of oxidative EET, we utilized genomic analyses and transposon insertion mutagenesis screens (Tn-seq) in the metabolically flexible, lithotrophic Alphaproteobacterium Thioclava electrotropha ElOx9T. The finished genome of this strain is 4.3 MB, and consists of 4,139 predicted ORFs, 54 contain heme binding motifs, and 33 of those 54 are predicted to localize to the cell envelope or have unknown localizations. To begin to understand the genetic basis of oxidative EET in ElOx9T, we constructed a transposon mutant library in semi-rich media which was comprised of >91,000 individual mutants encompassing >69,000 unique TA dinucleotide insertion sites. The library was subjected to heterotrophic growth on minimal media with acetate and autotrophic oxidative EET conditions on indium tin oxide coated glass electrodes poised at –278 mV vs. SHE or un-poised in an open circuit condition. We identified 528 genes classified as essential under these growth conditions. With respect to electrochemical conditions, 25 genes were essential under oxidative EET conditions, and 29 genes were essential in both the open circuit control and oxidative EET conditions. Though many of the genes identified under electrochemical conditions are predicted to be localized in the cytoplasm and lack heme binding motifs and/or homology to known EET proteins, we identified several hypothetical proteins and poorly characterized oxidoreductases that implicate a novel mechanism(s) for EET that warrants further study. Our results provide a starting point to explore the genetic basis of novel oxidative EET in this marine sediment microbe.