bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal Stem/Progenitor Cells Derived From Adult Müller Glia for the Treatment of Retinal Degeneration
Authors: Too Lay Khoon , Simunovic Matthew P.
Published: September 2021

Over the past two decades, progress in our understanding of glial function has been revolutionary. Within the retina, a subset of glial cells termed the “Müller glia (MG),” have been demonstrated to play key roles in retinal homeostasis, structure and metabolism. Additionally, MG have also been shown to possess the regenerative capacity that varies across species. In teleost fish, MG respond to injury by reprogramming into stem-like cells capable of regenerating lost tissue. The expression of stem/progenitor cell markers has been demonstrated broadly in mammalian MG, including human MG, but their in vivo regenerative capacity appears evolutionarily limited. Advances in stem cell therapy have progressively elucidated critical mechanisms underlying innate MG reprogramming in teleost fish, which have shown promising results when applied to rodents. Furthermore, when cultured ex vivo, MG from mammals can differentiate into several retina cell types. In this review, we will explore the reparative and regenerative potential of MG in cellular therapy approaches, and outline our current understanding of embryonic retinal development, the stem-cell potential of MG in adult vertebrate retina (including human), and microenvironmental cues that guide MG reprogramming.
Sex Steroid Hormones as a Balancing Factor in Oral Host Microbiome Interactions
Authors: Cornejo Ulloa Pilar , Krom Bastiaan P. , van der Veen Monique H.
Published: September 2021

Sex steroid hormones (SSH) are cholesterol-derived molecules. They are secreted into saliva and enter the oral cavity, triggering physiological responses from oral tissues, with possible clinical implications, such as gingival inflammation and bleeding. SSH and hormonal changes affect not only oral host cells but also oral microorganisms.

Historically, most research has focused on the effect of hormonal changes on specific bacteria and yeasts. Recently a broader effect of SSH on oral microorganisms was suggested. In order to assess the role of SSH in host-microbe interactions in the oral cavity, this review focuses on how and up to what extent SSH can influence the composition and behavior of the oral microbiome. The available literature was reviewed and a comprehensive hypothesis about the role of SSH in host-microbiome interactions is presented. The limited research available indicates that SSH may influence the balance between the host and its microbes in the oral cavity.
Characterization, Biological Activity, and Mechanism of Action of a Plant-Based Novel Antifungal Peptide, Cc-AFP1, Isolated From Carum carvi
Authors: Seyedjavadi Sima Sadat , Khani Soghra , Goudarzi Mehdi , Zare-Zardini Hadi , Shams-Ghahfarokhi Masoomeh , Jamzivar Fatemehsadat , Razzaghi-Abyaneh Mehdi
Published: September 2021

Due to the increasing rate of invasive fungal infections and emerging antifungal resistance, development of novel antifungal drugs has been an urgent necessity. Antifungal peptides (AFPs) have recently attracted attention due to their unique ability to evade drug-resistant fungal pathogens. In this study, a novel AFP, Cc-AFP1, with a molecular weight of ~3.759 kDa, was isolated from Carum carvi L., purified by ammonium sulfate precipitation and reversed-phase HPLC and finally identified by sequence analysis using Edman degradation. Peptide sequence analysis revealed a fragment of 36 amino acid residues as RVCFRPVAPYLGVGVSGAVRDQIGVKLGSVYKGPRG for Cc-AFP1 with a net charge of +5 and a hydrophobicity ratio of 38%. The antifungal activity of Cc-AFP1 was confirmed against Aspergillus species with MIC values in the range of 8–16 µg/ml. Cc-AFP1 had less than 5% hemolytic activity at 8–16 µg/ml on human red blood cells with no obvious cytotoxicity against the HEK293 cell line. Stability analysis showed that the activity of Cc-AFP1 was maintained at different temperatures (20°C to 80°C) and pH (8 to 10). The results of a propidium iodide uptake and transmission electron microscopy showed that the antifungal activity of Cc-AFP1 could be attributed to alteration in the fungal cell membrane permeability. Taken together, these results indicate that Cc-AFP1 may be an attractive molecule to develop as a novel antifungal agent combating fungal infections cause by Aspergillus species.
Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation
Authors: Chen Zhi-Teng , Gao Qing-Yuan , Wu Mao-Xiong , Wang Meng , Sun Run-Lu , Jiang Yuan , Guo Qi , Guo Da-Chuan , Liu Chi-Yu , Chen Si-Xu , Liu Xiao , Wang Jing-Feng , Zhang Hai-Feng , Chen Yang-Xin
Published: September 2021

Objective: To explore the role of glycolysis in cardiac fibroblast (CF) activation and cardiac fibrosis after myocardial infarction (MI).

Method:In vivo: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was injected into the abdominal cavity of the MI or sham mice every day. On the 28th day, cardiac function was measured by ultrasonic cardiography, and the hearts were harvested. Masson staining and immunofluorescence (IF) were used to evaluate the fibrosis area, and western blot was used to identify the glycolytic level. In vitro, we isolated the CF from the sham, MI and MI with 2-DG treatment mice, and we also activated normal CF with transforming growth factor-β1 (TGF-β1) and block glycolysis with 2-DG. We then detected the glycolytic proteins, fibrotic proteins, and the concentrations of lactate and glucose in the culture medium. At last, we further detected the fibrotic and glycolytic markers in human fibrotic and non-fibrotic heart tissues with masson staining, IF and western blot.

Result: More collagen and glycolytic protein expressions were observed in the MI mice hearts. The mortality increased when mice were treated with 2-DG (100 mg/kg/d) after the MI surgery (Log-rank test, P < 0.05). When the dosage of 2-DG declined to 50 mg/kg/d, and the treatment was started on the 4th day after MI, no statistical difference of mortality between the two groups was observed (Log-rank test, P = 0.98). The collagen volume fraction was smaller and the fluorescence signal of α-smooth muscle actin (α-SMA) was weaker in mice treated with 2-DG than PBS. In vitro, 2-DG could significantly inhibit the increased expression of both the glycolytic and fibrotic proteins in the activated CF.

Conclusion: Cardiac fibrosis is along with the enhancement of CF activation and glycolysis. Glycolysis inhibition can alleviate cardiac fibroblast activation and cardiac fibrosis after myocardial infarction.
Immune Checkpoint Inhibitors and the Heart
Authors: Mocan-Hognogi Diana Larisa , Trancǎ Sebastian , Farcaş Anca Daniela , Mocan-Hognogi Radu Florin , Pârvu Andrada Viorica , Bojan Anca Simona
Published: September 2021

Immune checkpoint inhibitors (ICIs) represent a break-through treatment for a large number of cancer types. This treatment is increasingly being recommended. ICIs are prescribed for primary tumours and for metastases, adjuvant/neo-adjuvant therapy. Thus, there is an increased need for expertise in the field, including the ways of response and toxicities related to them. ICIs become toxic because of the removal of self-tolerance, which in turn induces autoimmune processes that affect every organ. However, when relating to the heart, it has been noticed to be leading to acute heart failure and even death caused by various mechanisms, such as: myocarditis, pericarditis, arrhythmia, and Takotsubo cardiomyopathy. This review aims to address the above issues by focusing on the latest findings on the topic, by adding some insights on the mechanism of action of ICIs with a special focus on the myocardial tissue, by providing information on clinical manifestations, diagnosis and (wherever possible) treatment of the cardiotoxic events related to this therapy. The information is expanding and in many cases, the articles we found refer mainly to case-presentations and studies conducted on small populations. However, we consider that it is worthwhile to raise awareness of this new treatment, especially since it is widely now and it provides a significant increase in the survival rate in patients who receive it.
Implementing and Evaluating Growth Mindset Pedagogy – A Study of Finnish Elementary School Teachers
Authors: Rissanen Inkeri , Laine Sonja , Puusepp Ita , Kuusisto Elina , Tirri Kirsi
Published: September 2021

This article presents a study of five teachers at a Finnish elementary school who implemented and evaluated growth mindset pedagogy (GMP). The teachers received GMP training and conducted student interventions in their classrooms. We analyzed the impact of GMP on the teacher’s pedagogical thinking and practices and found significant differences between fixed-mindset and growth-mindset teachers in the ways they internalized and applied GMP principles. The most important value of GMP was seen in its impact on emotion regulation through the normalization of hardship in learning. We discuss the dangers of a superficial understanding of growth mindsets in education.
Evolution and Potential Function in Molluscs of Neuropeptide and Receptor Homologues of the Insect Allatostatins
Authors: Li Zhi , Cardoso João C. R. , Peng Maoxiao , Inácio João P. S. , Power Deborah M.
Published: September 2021

The allatostatins (ASTs), AST-A, AST-B and AST-C, have mainly been investigated in insects. They are a large group of small pleotropic alloregulatory neuropeptides that are unrelated in sequence and activate receptors of the rhodopsin G-protein coupled receptor family (GPCRs). The characteristics and functions of the homologue systems in the molluscs (Buccalin, MIP and AST-C-like), the second most diverse group of protostomes after the arthropods, and of high interest for evolutionary studies due to their less rearranged genomes remains to be explored. In the present study their evolution is deciphered in molluscs and putative functions assigned in bivalves through meta-analysis of transcriptomes and experiments. Homologues of the three arthropod AST-type peptide precursors were identified in molluscs and produce a larger number of mature peptides than in insects. The number of putative receptors were also distinct across mollusc species due to lineage and species-specific duplications. Our evolutionary analysis of the receptors identified for the first time in a mollusc, the cephalopod, GALR-like genes, which challenges the accepted paradigm that AST-AR/buccalin-Rs are the orthologues of vertebrate GALRs in protostomes. Tissue transcriptomes revealed the peptides, and their putative receptors have a widespread distribution in bivalves and in the bivalve Mytilus galloprovincialis, elements of the three peptide-receptor systems are highly abundant in the mantle an innate immune barrier tissue. Exposure of M. galloprovincialis to lipopolysaccharide or a marine pathogenic bacterium, Vibrio harveyi, provoked significant modifications in the expression of genes of the peptide precursor and receptors of the AST-C-like system in the mantle suggesting involvement in the immune response. Overall, our study reveals that homologues of the arthropod AST-systems in molluscs are potentially more complex due to the greater number of putative mature peptides and receptor genes. In bivalves they have a broad and varying tissue distribution and abundance, and the elements of the AST-C-like family may have a putative function in the immune response.
Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia
Authors: Asadi Farzad , Dhanvantari Savita
Published: September 2021

Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus.
Green Food Industry in China: Spatial Pattern and Production Concentration Drivers
Authors: Sun Chuanzhun , Huang Diejun , Li Hua , Chen Cheng , Wang Chao , Li Minting , Wang Zichen
Published: September 2021

China is the largest manufacturing country globally and currently faces severe environmental problems. China needs to identify a new mode of economic growth to contribute towards environmental protection. Developing the green industry is China’s national strategy to achieve a sustainable path and prevent further degradation of the environment. This study used China’s green food certification enterprise location data to investigate the green food industry’s spatial patterns in 2018 at the agricultural district, provincial, and city levels. Then, using the geographically weighted regression (GWR) method, we evaluated the factors impacting the green food industry’s concentration. Fourteen impact factors were selected from three aspects: socioeconomic, natural, and other factors corresponding to the regional food production potential. Our results showed the following: 1) the structure and species of green food enterprises are simple, and most enterprises are plant products upstream of the industrial chain, with low additional value. There is a large potential to increase the ratio of livestock, poultry, and fishery products; 2) the regional development of the green food industry is not uniform. The green food industry tends to concentrate along the eastern coastline and Yangtze River, and the middle-lower Yangtze Plain, Huang-Huai-Hai Plain, and North East Plain account for 76% of the total production capacity. However, northern China has the highest production ability among single enterprises; 3) regional economies, natural resource conditions, and environmental quality largely impact the concentration of the green food industry. In particular, the green food industry is concentrated in regions with high gross economic levels, highly advantageous natural conditions, and high proportion of cultivated land, except cereal planting areas. Better air quality has a positive influence on the food industry’s concentration.
Mosses are Important for Soil Carbon Sequestration in Forested Peatlands
Authors: Kasimir Å. , He H. , Jansson P.-E. , Lohila A. , Minkkinen K.
Published: September 2021

Nutrient-rich peat soils have previously been demonstrated to lose carbon despite higher photosynthesis and litter production compared to nutrient-poor soils, where instead carbon accumulates. To understand this phenomenon, we used a process-oriented model (CoupModel) calibrated on data from two closely located drained peat soil sites in boreal forests in Finland, Kalevansuo and Lettosuo, with different soil C/N ratios. Uncertainty-based calibrations were made using eddy-covariance data (hourly values of net ecosystem exchange) and tree growth data. The model design used two forest scenarios on drained peat soil, one nutrient-poor with dense moss cover and another with lower soil C/N ratio with sparse moss cover. Three vegetation layers were assumed: conifer trees, other vascular plants, and a bottom layer with mosses. Adding a moss layer was a new approach, because moss has a modified physiology compared to vascular plants. The soil was described by three separate soil organic carbon (SOC) pools consisting of vascular plants and moss litter origin and decomposed organic matter. Over 10 years, the model demonstrated a similar photosynthesis rate for the two scenarios, 903 and 1,034 g C m−2 yr−1, for the poor and rich site respectively, despite the different vegetation distribution. For the nutrient-rich scenario more of the photosynthesis produce accumulated as plant biomass due to more trees, while the poor site had abundant moss biomass which did not increase living aboveground biomass to the same degree. Instead, the poor site showed higher litter inputs, which compared with litter from vascular plants had low turnover rates. The model calibration showed that decomposition rate coefficients for the three SOC pools were similar for the two scenarios, but the high quantity of moss litter input with low decomposability for the nutrient poor scenario explained the major difference in the soil carbon balance. Vascular plant litter declined with time, while SOC pools originating from mosses accumulated with time. Large differences between the scenarios were obtained during dry spells where soil heterotrophic respiration doubled for the nutrient-rich scenario, where vascular plants dominated, owing to a larger water depletion by roots. Where moss vegetation dominated, the heterotrophic respiration increased by only 50% during this dry period. We suggest moss vegetation is key for carbon accumulation in the poor soil, adding large litter quantities with a resistant quality and less water depletion than vascular plants during dry conditions.
From Paris to Switzerland: Four Pathways to a Forest Reference Level
Authors: Stadelmann Golo , Portier Jeanne , Didion Markus , Rogiers Nele , Thürig Esther
Published: September 2021

Introduction: Among terrestrial ecosystems, forests represent large carbon stocks threatened by changing climatic conditions, deforestation, overexploitation, and forest degradation. Close to nature forestry may help forests to continue to acting as carbon sinks by promoting their resilience against disturbances. The EU decided to carry out carbon accounting of emissions and removals from managed forests under the Paris Agreement (PA) by using a projected Forest Reference Level (FRL) based on the continuation of recent management practices.

Methods: We developed four conceptual scenarios that could build the Swiss Forest Reference Level and performed simulations over 50 years using Swiss National Forest Inventory (NFI) data and the empirical forest model MASSIMO. To improve MASSIMO, we further developed a new tree species-specific model for small scale mortality that accounts for the Swiss NFI design. Then, using projected biomass and mortality from MASSIMO, carbon budgets of mineral soil, litter, and dead wood were estimated using the Yasso07 model.

Results: The U-shaped mortality model performed well (AUC 0.7). Small as well as large trees had the highest mortality probabilities, reflecting both young trees dying due to self-thinning and old trees from age, pests or abiotic influences. All scenarios matched their given harvesting and growing stock targets, whereby the share of broadleaves increased in all regions of Switzerland. This resulted in decreasing biomass growth, possibly due to a species shift from typically fast growing and more shade tolerant conifers to broadleaves. The CO2-balance of the conceptual scenarios ranged from 1.06 to −3.3 Mt CO2 a–1 under Increased Harvesting and Recent Management Practices (RMP), respectively. Rotation periods are shortened under Increased Harvesting, which is an important climate adaptive management strategy, but forests were predicted to become a net carbon source. In contrast, RMP resulted in similar harvesting amounts and forests as carbon sinks, as reported in the past. Further, the RMP scenario does not involve political assumptions and reflects the idea of the CMP approach used by the EU member states, which makes it comparable to other countries. Therefore, we propose the scenario RMP as a suitable and ideal candidate for the Swiss FRL.
Health Effects Associated With Pre- and Perinatal Exposure to Arsenic
Authors: Martinez Victor D. , Lam Wan L.
Published: September 2021

Inorganic arsenic is a well-established human carcinogen, able to induce genetic and epigenetic alterations. More than 200 million people worldwide are exposed to arsenic concentrations in drinking water exceeding the recommended WHO threshold (10μg/l). Additionally, chronic exposure to levels below this threshold is known to result in long-term health effects in humans. The arsenic-related health effects in humans are associated with its biotransformation process, whereby the resulting metabolites can induce molecular damage that accumulates over time. The effects derived from these alterations include genomic instability associated with oxidative damage, alteration of gene expression (including coding and non-coding RNAs), global and localized epigenetic reprogramming, and histone posttranslational modifications. These alterations directly affect molecular pathways involved in the onset and progression of many conditions that can arise even decades after the exposure occurs. Importantly, arsenic metabolites generated during its biotransformation can also pass through the placental barrier, resulting in fetal exposure to this carcinogen at similar levels to those of the mother. As such, more immediate effects of the arsenic-induced molecular damage can be observed as detrimental effects on fetal development, pregnancy, and birth outcomes. In this review, we focus on the genetic and epigenetic damage associated with exposure to low levels of arsenic, particularly those affecting early developmental stages. We also present how these alterations occurring during early life can impact the development of certain diseases in adult life.
Shared Genetics Between Age at Menopause, Early Menopause, POI and Other Traits
Authors: Louwers Yvonne V. , Visser Jenny A.
Published: September 2021

Reproductive ageing leading to menopause is characterized by depletion of follicles and its regulating mechanisms are only partly understood. Early age at menopause and premature ovarian insufficiency (POI) are associated with several other traits such as cardiovascular disease, dyslipidemia, osteoporosis and diabetes. In large cohorts of Northern European women hundreds of Single Nucleotide Polymorphisms (SNPs) have been identified to be associated with age at menopause. These SNPs are located in genes enriched for immune and mitochondrial function as well as DNA repair and maintenance processes. Genetic predisposition to earlier menopause might also increase the risk of other associated traits. Increased risk for cardiovascular disease in women has been associated with age at menopause lowering SNPs. Pleiotropy between early age at menopause and increased mortality from coronary artery disease has been observed, implicating that genetic variants affecting age at menopause also affect the risk for coronary deaths. This review will discuss the shared genetics of age at menopause with other traits. Mendelian Randomization studies implicate causal genetic association between age at menopause and age at menarche, breast cancer, ovarian cancer, BMD and type 2 diabetes. Although the shared biological pathways remain to be determined, mechanisms that regulate duration of estrogen exposure remain an important focus.
WVMDA: Predicting miRNA–Disease Association Based on Weighted Voting
Authors: Zhang Zhen-Wei , Gao Zhen , Zheng Chun-Hou , Li Lei , Qi Su-Min , Wang Yu-Tian
Published: September 2021

An increasing number of experiments had verified that miRNA expression is related to human diseases. The miRNA expression profile may be an indicator of clinical diagnosis and provides a new direction for the prevention and treatment of complex diseases. In this work, we present a weighted voting-based model for predicting miRNA–disease association (WVMDA). To reasonably build a network of similarity, we established credibility similarity based on the reliability of known associations and used it to improve the original incomplete similarity. To eliminate noise interference as much as possible while maintaining more reliable similarity information, we developed a filter. More importantly, to ensure the fairness and efficiency of weighted voting, we focus on the design of weighting. Finally, cross-validation experiments and case studies are undertaken to verify the efficacy of the proposed model. The results showed that WVMDA could efficiently identify miRNAs associated with the disease.
Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei
Authors: D’haeseleer Patrik , Collette Nicole M. , Lao Victoria , Segelke Brent W. , Branda Steven S. , Franco Magdalena
Published: September 2021

Peptide-based subunit vaccines are coming to the forefront of current vaccine approaches, with safety and cost-effective production among their top advantages. Peptide vaccine formulations consist of multiple synthetic linear epitopes that together trigger desired immune responses that can result in robust immune memory. The advantages of linear compared to conformational epitopes are their simple structure, ease of synthesis, and ability to stimulate immune responses by means that do not require complex 3D conformation. Prediction of linear epitopes through use of computational tools is fast and cost-effective, but typically of low accuracy, necessitating extensive experimentation to verify results. On the other hand, identification of linear epitopes through experimental screening has been an inefficient process that requires thorough characterization of previously identified full-length protein antigens, or laborious techniques involving genetic manipulation of organisms. In this study, we apply a newly developed generalizable screening method that enables efficient identification of B-cell epitopes in the proteomes of pathogenic bacteria. As a test case, we used this method to identify epitopes in the proteome of Francisella tularensis (Ft), a Select Agent with a well-characterized immunoproteome. Our screen identified many peptides that map to known antigens, including verified and predicted outer membrane proteins and extracellular proteins, validating the utility of this approach. We then used the method to identify seroreactive peptides in the less characterized immunoproteome of Select Agent Burkholderia pseudomallei (Bp). This screen revealed known Bp antigens as well as proteins that have not been previously identified as antigens. Although B-cell epitope prediction tools Bepipred 2.0 and iBCE-EL classified many of our seroreactive peptides as epitopes, they did not score them significantly higher than the non-reactive tryptic peptides in our study, nor did they assign higher scores to seroreactive peptides from known Ft or Bp antigens, highlighting the need for experimental data instead of relying on computational epitope predictions alone. The present workflow is easily adaptable to detecting peptide targets relevant to the immune systems of other mammalian species, including humans (depending upon the availability of convalescent sera from patients), and could aid in accelerating the discovery of B-cell epitopes and development of vaccines to counter emerging biological threats.
Interplay Between Non-Canonical NF-κB Signaling and Hepatitis B Virus Infection
Authors: Lu Xinyu , Chen Qianhui , Liu Hongyan , Zhang Xiaoyong
Published: September 2021

The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex. Activation of this pathway mediates the development and function of host immune system involved in inflammation and viral infection. During hepatitis B virus (HBV) infection, there is a complex interaction between infected hepatocytes and the immune cells, which can hinder antiviral immune responses and is associated with pathological changes in liver tissue. Consistently, the host immune system is closely related to the severity of liver damage and the level of viral replication. Previous studies indicated that the non-canonical NF-κB signaling pathway was affected by HBV and might play an important regulatory role in the antiviral immunity. Therefore, systematically elucidating the interplay between HBV and non-canonical NF-κB signaling will contribute the discovery of more potential therapeutic targets and novel drugs to treat HBV infection.
Apelin Promotes Endothelial Progenitor Cell Angiogenesis in Rheumatoid Arthritis Disease via the miR-525-5p/Angiopoietin-1 Pathway
Authors: Chang Ting-Kuo , Zhong You-Han , Liu Shan-Chi , Huang Chien-Chung , Tsai Chun-Hao , Lee Hsiang-Ping , Wang Shih-Wei , Hsu Chin-Jung , Tang Chih-Hsin
Published: September 2021

Angiogenesis is a critical process in the formation of new capillaries and a key participant in rheumatoid arthritis (RA) pathogenesis. The adipokine apelin (APLN) plays critical roles in several cellular functions, including angiogenesis. We report that APLN treatment of RA synovial fibroblasts (RASFs) increased angiopoietin-1 (Ang1) expression. Ang1 antibody abolished endothelial progenitor cell (EPC) tube formation and migration in conditioned medium from APLN-treated RASFs. We also found significantly higher levels of APLN and Ang1 expression in synovial fluid from RA patients compared with those with osteoarthritis. APLN facilitated Ang1-dependent EPC angiogenesis by inhibiting miR-525-5p synthesis via phospholipase C gamma (PLCγ) and protein kinase C alpha (PKCα) signaling. Importantly, infection with APLN shRNA mitigated EPC angiogenesis, articular swelling, and cartilage erosion in ankle joints of mice with collagen-induced arthritis. APLN is therefore a novel therapeutic target for RA.
A Review of Cyclophosphamide-Induced Transplantation Tolerance in Mice and Its Relationship With the HLA-Haploidentical Bone Marrow Transplantation/Post-Transplantation Cyclophosphamide Platform
Authors: Mayumi Hisanori
Published: September 2021

The bone marrow transplantation (BMT) between haplo-identical combinations (haploBMT) could cause unacceptable bone marrow graft rejection and graft-versus-host disease (GVHD). To cross such barriers, Johns Hopkins platform consisting of haploBMT followed by post-transplantation (PT) cyclophosphamide (Cy) has been used. Although the central mechanism of the Johns Hopkins regimen is Cy-induced tolerance with bone marrow cells (BMC) followed by Cy on days 3 and 4, the mechanisms of Cy-induced tolerance may not be well understood. Here, I review our studies in pursuing skin-tolerance from minor histocompatibility (H) antigen disparity to xenogeneic antigen disparity through fully allogeneic antigen disparity. To overcome fully allogeneic antigen barriers or xenogeneic barriers for skin grafting, pretreatment of the recipients with monoclonal antibodies (mAb) against T cells before cell injection was required. In the cells-followed-by-Cy system providing successful skin tolerance, five mechanisms were identified using the correlation between super-antigens and T-cell receptor (TCR) Vβ segments mainly in the H-2-identical murine combinations. Those consist of: 1) clonal destruction of antigen-stimulated-thus-proliferating mature T cells with Cy; 2) peripheral clonal deletion associated with immediate peripheral chimerism; 3) intrathymic clonal deletion associated with intrathymic chimerism; 4) delayed generation of suppressor T (Ts) cells; and 5) delayed generation of clonal anergy. These five mechanisms are insufficient to induce tolerance when the donor-recipient combinations are disparate in MHC antigens plus minor H antigens as is seen in haploBMT. Clonal destruction is incomplete when the antigenic disparity is too strong to establish intrathymic mixed chimerism. Although this incomplete clonal destruction leaves the less-proliferative, antigen-stimulated T cells behind, these cells may confer graft-versus-leukemia (GVL) effects after haploBMT/PTCy.
Type 3 Innate Lymphoid Cells as Regulators of the Host-Pathogen Interaction
Authors: Valle-Noguera Ana , Ochoa-Ramos Anne , Gomez-Sánchez Maria José , Cruz-Adalia Aranzazu
Published: September 2021

Type 3 Innate lymphoid cells (ILC3s) have been described as tissue-resident cells and characterized throughout the body, especially in mucosal sites and classical first barrier organs such as skin, gut and lungs, among others. A significant part of the research has focused on their role in combating pathogens, mainly extracellular pathogens, with the gut as the principal organ. However, some recent discoveries in the field have unveiled their activity in other organs, combating intracellular pathogens and as part of the response to viruses. In this review we have compiled the latest studies on the role of ILC3s and the molecular mechanisms involved in defending against different microbes at the mucosal surface, most of these studies have made use of conditional transgenic mice. The present review therefore attempts to provide an overview of the function of ILC3s in infections throughout the body, focusing on their specific activity in different organs.
Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis
Authors: Li Yan , Ma Yiqi , Wu Zijun , Zeng Fanxin , Song Bin , Zhang Yanrong , Li Jinxing , Lui Su , Wu Min
Published: September 2021

Objectives

For colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint inhibitors (ICIs). Recent years, researchers considered tumor mutation burden (TMB) as another predictive biomarker which means the number of nonsynonymous mutations in cancer cells. Several studies have proven that TMB can evaluate the efficacy of ICI therapy in diverse types of cancer, especially in non-small cell lung cancer and melanoma. However, studies on the association between TMB and the response to ICI therapy in colorectal cancer alone are still lacking. In this study, we aim to verify the effect of TMB as a biomarker in predicting the efficacy of ICIs in colorectal cancer.

Methods

We searched the PubMed and Ovid MEDLINE databases up to May 1, 2021 and screened studies for eligibility. Thirteen studies published from 2015 to 2021 with 5062 patients were included finally. We extracted and calculated hazard ratios (HRs) and odds ratios (ORs) of overall survival (OS) and objective response rates (ORRs) and their 95% confidence intervals (95% CIs). Pooled HR and OR were evaluated to compare OS and ORR between TMB-high and TMB-low groups in colorectal cancer patients. Meanwhile, we assessed heterogeneity with the I2 statistic and p-values and performed publication bias assessments, sensitivity analyses, and subgroup analyses to search the cause of heterogeneity.

Results

The TMB-high patient group had a longer OS than the TMB-low patient group (HR = 0.68, 95% CI: 0.51, 0.92, p = 0.013) among colorectal cancer patients receiving ICIs. In addition, the TMB-high patient group was superior in terms of ORR (OR = 19.25, 95% CI: 10.06, 36.82, p < 0.001) compared to the TMB-low patient group.

Conclusions

In conclusion, this meta-analysis revealed that TMB can be used as a potential predictive biomarker of colorectal cancer patients receiving ICI therapy. Nevertheless, this finding is not stable enough. Therefore, many more randomized controlled trials are needed to prove that TMB is reliable enough to be used clinically to predict the efficacy of immunotherapy in colorectal cancer. And the most relevant biomarker remains to be determined when TMB high overlaps with other biomarkers like MSI and TILs.
Immune Phenomena in Myeloid Neoplasms: An “Egg or Chicken” Question
Authors: Barcellini Wilma , Fattizzo Bruno
Published: September 2021

Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings.
Academic Publication of Anesthesiology From a Bibliographic Perspective From 1999 to 2018: Comparative Analysis Using Subject-Field Dataset and Department Dataset
Authors: Chen Sy-Yuan , Wei Ling-Fang , Huang Mu-Hsuan , Ho Chiu-Ming
Published: September 2021

Background: Publication activity in the field of anesthesiology informs decisions that enhance academic advancement. Most previous bibliometric studies on anesthesiology examined data limited to journals focused on anesthesiology rather than data answerable to authors in anesthesia departments. This study comprehensively explored publication trends in the field of anesthesiology and their impact. We hypothesized that anesthesiology's bibliometric scene would differ based on whether articles in the same study period were published in anesthesiology-focused journals or were produced by authors in anesthesia departments but published in non-specialty journals.

Methods: This cross-sectional study used bibliometric data from the Science Citation Index Expanded database between 1999 and 2018. Two datasets were assembled. The first dataset was a subject-dataset (articles published in 31 journals in the anesthesiology category of InCites Journal Citation Reports in 2018); the second dataset was the department-dataset (articles published in the Science Citation Index Expanded by authors in anesthesia departments). We captured the bibliographical record of each article in both datasets and noted each article's Institute for Scientific Information code, publication year, title, abstract, author addresses, subject category, and references for further study.

Results: A total of 69,593 articles were published—cited 1,497,932 times—in the subject-dataset; a total of 167,501 articles were published—cited 3,731,540 times—in the department-dataset. The results demonstrate differences between the two datasets. First, the number of articles was stagnant, with little growth (average annual growth rate = 0.31%) in the subject-dataset; whereas there was stable growth (average annual growth rate = 4.50%) in articles in the department-dataset. Second, only 30.4% of anesthesia department articles were published in anesthesiology journals. Third, journals related to “pain” had the lowest department-subject ratio, which was attributable to a large portion of non-anesthesia department researchers' participation in related research.

Conclusions: This study showed that articles published in anesthesiology-focused and non-specialty journals demonstrate fundamentally different trends. Thus, it not only helps researchers develop a more comprehensive understanding of the current publication status and trends in anesthesiology, but also provides a basis for national academic organizations to frame relevant anesthesiology development policies and rationalize resource allocation.
Narrative Review of Neurologic Complications in Adults on ECMO: Prevalence, Risks, Outcomes, and Prevention Strategies
Authors: Zhang Hongling , Xu Jiqian , Yang Xiaobo , Zou Xiaojing , Shu Huaqing , Liu Zhengdong , Shang You
Published: September 2021

Extracorporeal membrane oxygenation (ECMO), a life-saving technique for patients with severe respiratory and cardiac diseases, is being increasingly utilized worldwide, particularly during the coronavirus disease 2019(COVID-19) pandemic, and there has been a sharp increase in the implementation of ECMO. However, due to the presence of various complications, the survival rate of patients undergoing ECMO remains low. Among the complications, the neurologic morbidity significantly associated with venoarterial and venovenous ECMO has received increasing attention. Generally, failure to recognize neurologic injury in time is reportedly associated with poor outcomes in patients on ECMO. Currently, multimodal monitoring is increasingly utilized in patients with devastating neurologic injuries and has been advocated as an important approach for early diagnosis. Here, we highlight the prevalence and outcomes, risk factors, current monitoring technologies, prevention, and treatment of neurologic complications in adult patients on ECMO. We believe that an improved understanding of neurologic complications presumably offers promising therapeutic solutions to prevent and treat neurologic morbidity.
Clinical Characteristics and Prognoses of Patients With Systemic Lupus Erythematosus Hospitalized for Pulmonary Infections
Authors: Yang Yanli , Jiang Hui , Wang Chuhan , Jiang Nan , Wu Chanyuan , Zhang Shangzhu , Jiang Wei , Peng Jinmin , Weng Li , Zhao Jiuliang , Wang Qian , Li Mengtao , Du Bin , Zhao Yan , Zeng Xiaofeng
Published: September 2021

Objective: To identify factors associated with mortality in SLE patients who were hospitalized for pulmonary infections (PIs).

Methods: This single-center retrospective study analyzed the characteristics and risk factors for mortality in 95 SLE patients hospitalized for PIs.

Results: Ninety-five SLE patients had 97 episodes of hospitalization for PIs, and 33 of these episodes (34.02%) led to death. Death from PI was associated with a higher neutrophil count (6.30 vs. 4.201 × 109/L, p < 0.01), immunoglobulin G (6.20 vs. 9.82 g/L, p = 0.01), serum creatinine (126.00 vs. 73.00 μmol/L, p = 0.01), proteinuria (2.99 vs. 0.54 g/day, p < 0.01), cardiopulmonary involvement (57.58 vs. 34.38%, p < 0.05), SLE disease activity index (SLEDAI; 11.00 vs. 6.00, p < 0.05), and opportunistic infections (78.79 vs. 45.31%, p < 0.05). Demographic characteristics, antibody/complements, bacterial infection, and primary treatment before infection (including corticosteroid and immunosuppressants) had no effect. Multivariate analysis indicated cardiopulmonary involvement (HR: 2.077; 95%CI: 1.022–4.220; p = 0.043) and opportunistic infection (HR: 2.572; 95%CI: 1.104–5.993; p = 0.029) were independent risk factors for mortality. High-dose steroid pulse therapy (HR: 0.982; 95%CI: 0.410–2.350; p = 0.982) and first-line immunosuppressant therapy (HR: 1.635; 95%CI: 0.755–3.542, p = 0.212) had no effect on mortality.

Conclusion: Cardiopulmonary involvement and opportunistic infection were independent risk factors for mortality for SLE patients hospitalized for PIs. Use of high-dose pulse steroids and or immunosuppressants before hospitalization had no significant effects.
Machine Learning Predicts the Presence of 2,4,6-Trinitrotoluene in Sediments of a Baltic Sea Munitions Dumpsite Using Microbial Community Compositions
Authors: Janßen René , Beck Aaron J. , Werner Johannes , Dellwig Olaf , Alneberg Johannes , Kreikemeyer Bernd , Maser Edmund , Böttcher Claus , Achterberg Eric P. , Andersson Anders F. , Labrenz Matthias
Published: September 2021

Bacteria are ubiquitous and live in complex microbial communities. Due to differences in physiological properties and niche preferences among community members, microbial communities respond in specific ways to environmental drivers, potentially resulting in distinct microbial fingerprints for a given environmental state. As proof of the principle, our goal was to assess the opportunities and limitations of machine learning to detect microbial fingerprints indicating the presence of the munition compound 2,4,6-trinitrotoluene (TNT) in southwestern Baltic Sea sediments. Over 40 environmental variables including grain size distribution, elemental composition, and concentration of munition compounds (mostly at pmol⋅g–1 levels) from 150 sediments collected at the near-to-shore munition dumpsite Kolberger Heide by the German city of Kiel were combined with 16S rRNA gene amplicon sequencing libraries. Prediction was achieved using Random Forests (RFs); the robustness of predictions was validated using Artificial Neural Networks (ANN). To facilitate machine learning with microbiome data we developed the R package phyloseq2ML. Using the most classification-relevant 25 bacterial genera exclusively, potentially representing a TNT-indicative fingerprint, TNT was predicted correctly with up to 81.5% balanced accuracy. False positive classifications indicated that this approach also has the potential to identify samples where the original TNT contamination was no longer detectable. The fact that TNT presence was not among the main drivers of the microbial community composition demonstrates the sensitivity of the approach. Moreover, environmental variables resulted in poorer prediction rates than using microbial fingerprints. Our results suggest that microbial communities can predict even minor influencing factors in complex environments, demonstrating the potential of this approach for the discovery of contamination events over an integrated period of time. Proven for a distinct environment future studies should assess the ability of this approach for environmental monitoring in general.
The Fecal Microbiota of Dogs Switching to a Raw Diet Only Partially Converges to That of Wolves
Authors: Xu Jia , Becker Anne A. M. J. , Luo Yu , Zhang Wenfu , Ge Bingqian , Leng Chunqing , Wang Guyue , Ding Limin , Wang Jianmei , Fu Xiaoyu , Janssens Geert P. J.
Published: September 2021

The genomic signature of dog domestication reveals adaptation to a starch-rich diet compared with their ancestor wolves. Diet is a key element to shape gut microbial populations in a direct way as well as through coevolution with the host. We investigated the dynamics in the gut microbiota of dogs when shifting from a starch-rich, processed kibble diet to a nature-like raw meat diet, using wolves as a wild reference. Six healthy wolves from a local zoo and six healthy American Staffordshire Terriers were included. Dogs were fed the same commercial kibble diet for at least 3 months before sampling at day 0 (DC), and then switched to a raw meat diet (the same diet as the wolves) for 28 days. Samples from the dogs were collected at day 1 (DR1), week 1 (DR7), 2 (DR14), 3 (DR21), and 4 (DR28). The data showed that the microbial population of dogs switched from kibble diet to raw diet shifts the gut microbiota closer to that of wolves, yet still showing distinct differences. At phylum level, raw meat consumption increased the relative abundance of Fusobacteria and Bacteroidetes at DR1, DR7, DR14, and DR21 (q < 0.05) compared with DC, whereas no differences in these two phyla were observed between DC and DR28. At genus level, Faecalibacterium, Catenibacterium, Allisonella, and Megamonas were significantly lower in dogs consuming the raw diet from the first week onward and in wolves compared with dogs on the kibble diet. Linear discriminant analysis effect size (LEfSe) showed a higher abundance of Stenotrophomonas, Faecalibacterium, Megamonas, and Lactobacillus in dogs fed kibble diet compared with dogs fed raw diet for 28 days and wolves. In addition, wolves had greater unidentified Lachnospiraceae compared with dogs irrespective of the diets. These results suggested that carbohydrate-fermenting bacteria give way to protein fermenters when the diet is shifted from kibble to raw diet. In conclusion, some microbial phyla, families, and genera in dogs showed only temporary change upon dietary shift, whereas some microbial groups moved toward the microbial profile of wolves. These findings open the discussion on the extent of coevolution of the core microbiota of dogs throughout domestication.