bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Serum Levels of Soluble TNF-α Receptor Is Associated With ICU Mortality in COVID-19 Patients
Authors: Mortaz Esmaeil , Tabarsi Payam , Jamaati Hamidreza , Dalil Roofchayee Neda , Dezfuli Neda K. , Hashemian Seyed MohammadReza , Moniri Afshin , Marjani Majid , Malekmohammad Majid , Mansouri Davood , Varahram Mohammad , Folkerts Gert , Adcock Ian M.
Published: April 2021

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm.

Objectives

To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity.

Methods

We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran.

Results

Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR.

Conclusions

The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.
Pro-Resolving Mediator Annexin A1 Regulates Intracellular Ca2+ and Mucin Secretion in Cultured Goblet Cells Suggesting a New Use in Inflammatory Conjunctival Diseases
Authors: Lyngstadaas Anne V. , Olsen Markus V. , Bair Jeffrey A. , Hodges Robin R. , Utheim Tor P. , Serhan Charles N. , Dartt Darlene A.
Published: April 2021

The amount of mucin secreted by conjunctival goblet cells is regulated to ensure the optimal level for protection of the ocular surface. Under physiological conditions lipid specialized pro-resolving mediators (SPM) are essential for maintaining tissue homeostasis including the conjunctiva. The protein Annexin A1 (AnxA1) can act as an SPM. We used cultured rat conjunctival goblet cells to determine if AnxA1 stimulates an increase in intracellular [Ca2+] ([Ca2+]i) and mucin secretion and to identify the signaling pathways. The increase in [Ca2+]i was determined using fura2/AM and mucin secretion was measured using an enzyme-linked lectin assay. AnxA1 stimulated an increase in [Ca2+]i and mucin secretion that was blocked by the cell-permeant Ca2+ chelator BAPTA/AM and the ALX/FPR2 receptor inhibitor BOC2. AnxA1 increased [Ca2+]i to a similar extent as the SPMs lipoxin A4 and Resolvin (Rv) D1 and histamine. The AnxA1 increase in [Ca2+]i and mucin secretion were inhibited by blocking the phospholipase C (PLC) pathway including PLC, the IP3 receptor, the Ca2+/ATPase that causes the intracellular Ca2+ stores to empty, and blockade of Ca2+ influx. Inhibition of protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase also decreased the AnxA1-stimulated increase in [Ca2+]i and mucin secretion. In contrast inhibitors of ERK 1/2, phospholipase A2 (PLA2), and phospholipase D (PLD) did not alter AnxA1-stimulated increase in [Ca2+]i, but did inhibit mucin secretion. Activation of protein kinase A did not decrease either the AnxA1-stimulated rise in [Ca2+]i or secretion. We conclude that in health, AnxA1 contributes to the mucin layer of the tear film and ocular surface homeostasis by activating the PLC signaling pathway to increase [Ca2+]i and stimulate mucin secretion and ERK1/2, PLA2, and PLD to stimulate mucin secretion from conjunctival goblet cells.
Critical Role of Lkb1 in the Maintenance of Alveolar Macrophage Self-Renewal and Immune Homeostasis
Authors: Wang Qianqian , Chen Song , Li Tengda , Yang Qiongmei , Liu Jingru , Tao Yuan , Meng Yuan , Chen Jiadi , Feng Xiaoming , Han Zhongchao , Shi Mingxia , Huang Huifang , Han Mingzhe , Jiang Erlie
Published: April 2021

Alveolar macrophages (AMs) are pivotal for maintaining lung immune homeostasis. We demonstrated that deletion of liver kinase b1 (Lkb1) in CD11c+ cells led to greatly reduced AM abundance in the lung due to the impaired self-renewal of AMs but not the impeded pre-AM differentiation. Mice with Lkb1-deficient AMs exhibited deteriorated diseases during airway Staphylococcus aureus (S. aureus) infection and allergic inflammation, with excessive accumulation of neutrophils and more severe lung pathology. Drug-mediated AM depletion experiments in wild type mice indicated a cause for AM reduction in aggravated diseases in Lkb1 conditional knockout mice. Transcriptomic sequencing also revealed that Lkb1 inhibited proinflammatory pathways, including IL-17 signaling and neutrophil migration, which might also contribute to the protective function of Lkb1 in AMs. We thus identified Lkb1 as a pivotal regulator that maintains the self-renewal and immune function of AMs.
IFNγ Modulates the Immunopeptidome of Triple Negative Breast Cancer Cells by Enhancing and Diversifying Antigen Processing and Presentation
Authors: Goncalves Gabriel , Mullan Kerry A. , Duscharla Divya , Ayala Rochelle , Croft Nathan P. , Faridi Pouya , Purcell Anthony W.
Published: April 2021

Peptide vaccination remains a viable approach to induce T-cell mediated killing of tumors. To identify potential T-cell targets for Triple-Negative Breast Cancer (TNBC) vaccination, we examined the effect of the pro-inflammatory cytokine interferon-γ (IFNγ) on the transcriptome, proteome, and immunopeptidome of the TNBC cell line MDA-MB-231. Using high resolution mass spectrometry, we identified a total of 84,131 peptides from 9,647 source proteins presented by human leukocyte antigen (HLA)-I and HLA-II alleles. Treatment with IFNγ resulted in a remarkable remolding of the immunopeptidome, with only a 34% overlap between untreated and treated cells across the HLA-I immunopeptidome, and expression of HLA-II only detected on treated cells. IFNγ increased the overall number, diversity, and abundance of peptides contained within the immunopeptidome, as well increasing the coverage of individual source antigens. The suite of peptides displayed under conditions of IFNγ treatment included many known tumor associated antigens, with the HLA-II repertoire sampling 17 breast cancer associated antigens absent from those sampled by HLA-I molecules. Quantitative analysis of the transcriptome (10,248 transcripts) and proteome (6,783 proteins) of these cells revealed 229 common proteins and transcripts that were differentially expressed. Most of these represented downstream targets of IFNγ signaling including components of the antigen processing machinery such as tapasin and HLA molecules. However, these changes in protein expression did not explain the dramatic modulation of the immunopeptidome following IFNγ treatment. These results demonstrate the high degree of plasticity in the immunopeptidome of TNBC cells following cytokine stimulation and provide evidence that under pro-inflammatory conditions a greater variety of potential HLA-I and HLA-II vaccine targets are unveiled to the immune system. This has important implications for the development of personalized cancer vaccination strategies.
Primary Immunodeficiency in Children With Autoimmune Cytopenias: Retrospective 154-Patient Cohort
Authors: Westermann-Clark Emma , Meehan Cristina Adelia , Meyer Anna K. , Dasso Joseph F. , Amre Devendra , Ellison Maryssa , Patel Bhumika , Betensky Marisol , Hauk Charles Isaac , Mayer Jennifer , Metts Jonathan , Leiding Jennifer W. , Sriaroon Panida , Kumar Ambuj , Ayala Irmel , Walter Jolan E.
Published: April 2021

Background

Primary immunodeficiency is common among patients with autoimmune cytopenia.

Objective

The purpose of this study is to retrospectively identify key clinical features and biomarkers of primary immunodeficiency (PID) in pediatric patients with autoimmune cytopenias (AIC) so as to facilitate early diagnosis and targeted therapy.

Methods

Electronic medical records at a pediatric tertiary care center were reviewed. We selected 154 patients with both AIC and PID (n=17), or AIC alone (n=137) for inclusion in two cohorts. Immunoglobulin levels, vaccine titers, lymphocyte subsets (T, B and NK cells), autoantibodies, clinical characteristics, and response to treatment were recorded.

Results

Clinical features associated with AIC-PID included splenomegaly, short stature, and recurrent or chronic infections. PID patients were more likely to have autoimmune hemolytic anemia (AIHA) or Evans syndrome than AIC-only patients. The AIC-PID group was also distinguished by low T cells (CD3 and CD8), low immunoglobulins (IgG and IgA), and higher prevalence of autoantibodies to red blood cells, platelets or neutrophils. AIC diagnosis preceded PID diagnosis by 3 years on average, except among those with partial DiGeorge syndrome. AIC-PID patients were more likely to fail first-line treatment.

Conclusions

AIC patients, especially those with Evans syndrome or AIHA, should be evaluated for PID. Lymphocyte subsets and immune globulins serve as a rapid screen for underlying PID. Early detection of patients with comorbid PID and AIC may improve treatment outcomes. Prospective studies are needed to confirm the diagnostic clues identified and to guide targeted therapy.
Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation
Authors: Rajput Charu , Han Mingyuan , Ishikawa Tomoko , Lei Jing , Goldsmith Adam M. , Jazaeri Seyedehzarifeh , Stroupe Claudia C. , Bentley J. Kelley , Hershenson Marc B.
Published: April 2021

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.
Factors Predicting the Presence of Maternal Cells in Cord Blood and Associated Changes in Immune Cell Composition
Authors: Haddad Marina El , Karlmark Karlin R. , Donato Xavier-Côme , Martin Gabriel V. , Bretelle Florence , Lesavre Nathalie , Cocallemen Jean-François , Martin Marielle , Picard Christophe , Roudier Jean , Desbriere Raoul , Lambert Nathalie C.
Published: April 2021

Background

Cord blood (CB) samples are increasingly used as a source of hematopoietic stem cells in transplantation settings. Maternal cells have been detected in CB samples and their presence is associated with a better graft outcome. However, we still do not know what influences the presence of maternal microchimerism (MMc) in CB samples and whether their presence influences CB hematopoietic cell composition.

Patients and Methods

Here we test whether genetic, biological, anthropometric and/or obstetrical parameters influence the frequency and/or quantity of maternal Mc in CB samples from 55 healthy primigravid women. Mc was evaluated by targeting non-shared, non-inherited Human Leukocyte Antigen (HLA)-specific real-time quantitative PCR in whole blood and four cell subsets (T, B lymphocytes, granulocytes and/or hematopoietic progenitor cells). Furthermore CB samples were analyzed for their cell composition by flow cytometry and categorized according to their microchimeric status.

Results

MMc was present in 55% of CB samples in at least one cell subset or whole blood, with levels reaching up to 0.3% of hematopoietic progenitor cells. Two factors were predictive of the presence of MMc in CB samples: high concentrations of maternal serological Pregnancy-Associated-Protein-A at first trimester of pregnancy (p=0.018) and feto-maternal HLA-A and/or –DR compatibility (p=0.009 and p=0.01 respectively). Finally, CB samples positive for MMc were significantly enriched in CD56+ cells compared to CB negative for MMc.

Conclusions

We have identified two factors, measurable at early pregnancy, predicting the presence of maternal cells in CB samples at delivery. We have shown that MMc in CB samples could have an influence on the hematopoietic composition of fetal cells. CD56 is the phenotypic marker of natural killer cells (NK) and NK cells are known to be the main effector for graft versus leukemia reactions early after hematopoietic stem cell transplantation. These results emphasize the importance of MMc investigation for CB banking strategies.
Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response
Authors: Chu Lei , Li Chenhui , Li Yongxing , Yu Qiuya , Yu Huansha , Li Chunhui , Meng Wei , Zhu Juanjuan , Wang Quanyi , Wang Chen , Cui Shufang
Published: April 2021

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.
The Synergistic Effects of Polysaccharides and Ginsenosides From American Ginseng (Panax quinquefolius L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis
Authors: Zhou Rongrong , He Dan , Xie Jing , Zhou Qingyijun , Zeng Hongliang , Li Hongmei , Huang Luqi
Published: April 2021

Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng (Panax quinquefolius L.) has a long history of functional food use for immunological disorder, colitis, cancer, and so on. This study aimed to illustrate the underlying mechanism of American ginseng’s immunomodulatory effect in CTX-induced mice. In this study, all groups of American ginseng (American ginseng polysaccharide [AGP], American ginseng ginsenoside [AGG], co-treated with American ginseng polysaccharide and ginsenoside [AGP_AGG]) have relieve the immune disorder by reversing the lymphocyte subsets ratio in spleen and peripheral blood, as well as stimulating CD4+T cells and IgA-secreting cells in small intestine. These three treatment groups, especially AGP_AGG co-treated group recovered the intestine morphology that up-regulated villus height (VH)/crypt depth (CD) ratio, areas of mucins expression, quantity of goblet cells, and expression of tight junction proteins (ZO-1, occludin). Importantly, the microbiome-metabolomics analysis was applied in this study to illustrate the possible immuno-modulating mechanism. The synergistic effect of polysaccharides and ginsenosides (AGP_AGG group) restored the gut microbiota composition and increased various beneficial mucosa-associated bacterial taxa Clostridiales, Bifidobacterium, and Lachnospiraceae, while decreased harmful bacteria Escherichia-Shigella and Peptococcaceae. Also, AGP_AGG group altered various fecal metabolites such as uric acid, xanthurenic acid, acylcarnitine, 9,10-DHOME, 13-HDoHE, LysoPE15:0, LysoPC 16:0, LysoPI 18:0, and so on, that associated with immunometabolism or protective effect of gut barrier. These results suggest AG, particularly co-treated of polysaccharide and ginsenoside may be used as immunostimulants targeting microbiome-metabolomics axis to prevent CTX-induced side effects in cancer patients.
Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion
Authors: Griessl Marion , Renzaho Angelique , Freitag Kirsten , Seckert Christof K. , Reddehase Matthias J. , Lemmermann Niels A. W.
Published: April 2021

Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8+ T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8+ T cells over time, a phenomenon known as “memory inflation” (MI). The “inflationary” subset of CD8+ T cells has been phenotyped as KLRG1+CD62L- effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The “reactivation hypothesis” proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the “stochastic transcription hypothesis” proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis, that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.
Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains
Authors: Ma Qiuyue , Grigorescu Melissa , Schreiber Adrian , Kettritz Ralph , Lindenmeyer Maja , Anders Hans-Joachim , Steiger Stefanie
Published: April 2021

Calcium oxalate (CaOx) crystal formation, aggregation and growth is a common cause of kidney stone disease and nephrocalcinosis-related chronic kidney disease (CKD). Genetically modified mouse strains are frequently used as an experimental tool in this context but observed phenotypes may also relate to the genetic background or intestinal microbiota. We hypothesized that the genetic background or intestinal microbiota of mice determine CaOx crystal deposition and thus the outcome of nephrocalcinosis. Indeed,Casp1-/-,Cybb-/-orCasp1-/-/Cybb-/-knockout mice on a 129/C57BL/6J (B6J) background that were fed an oxalate-rich diet for 14 days did neither encounter intrarenal CaOx crystal deposits nor nephrocalcinosis-related CKD. To test our assumption, we fed C57BL/6N (B6N), 129, B6J and Balb/c mice an oxalate-rich diet for 14 days. Only B6N mice displayed CaOx crystal deposits and developed CKD associated with tubular injury, inflammation and interstitial fibrosis. Intrarenal mRNA expression profiling of 64 known nephrocalcinosis-related genes revealed that healthy B6N mice had lower mRNA levels of uromodulin (Umod) compared to the other three strains. Feeding an oxalate-rich diet caused an increase in uromodulin protein expression and CaOx crystal deposition in the kidney as well as in urinary uromodulin excretion in B6N mice but not 129, B6J and Balb/c mice. However, backcrossing 129 mice on a B6N background resulted in a gradual increase in CaOx crystal deposits from F2 to F7, of which all B6N/129 mice from the 7thgeneration developed CaOx-related nephropathy similar to B6N mice. Co-housing experiments tested for a putative role of the intestinal microbiota but B6N co-housed with 129 mice or B6N/129 (3rdand 6thgeneration) mice did not affect nephrocalcinosis. In summary, genetic background but not the intestinal microbiome account for strain-specific crystal formation and, the levels of uromodulin secretion may contribute to this phenomenon. Our results imply that only littermate controls of the identical genetic background strain are appropriate when performing knockout mouse studies in this context, while co-housing is optional.
Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity
Authors: Kinashi Yusuke , Hase Koji
Published: April 2021

The intestinal surface is constitutively exposed to diverse antigens, such as food antigens, food-borne pathogens, and commensal microbes. Intestinal epithelial cells have developed unique barrier functions that prevent the translocation of potentially hostile antigens into the body. Disruption of the epithelial barrier increases intestinal permeability, resulting in leaky gut syndrome (LGS). Clinical reports have suggested that LGS contributes to autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and celiac disease. Furthermore, the gut commensal microbiota plays a critical role in regulating host immunity; abnormalities of the microbial community, known as dysbiosis, are observed in patients with autoimmune diseases. However, the pathological links among intestinal dysbiosis, LGS, and autoimmune diseases have not been fully elucidated. This review discusses the current understanding of how commensal microbiota contributes to the pathogenesis of autoimmune diseases by modifying the epithelial barrier.
Rapid Population Decline of the Pillar Coral Dendrogyra cylindrus Along the Florida Reef Tract
Authors: Neely Karen L. , Lewis Cynthia L. , Lunz Kathleen S. , Kabay Lystina
Published: April 2021

Coral reefs worldwide are in a state of decline, but the population status and impacts of stressors for rare species are generally not well documented using broad-scale monitoring protocols. We fate-tracked all known colonies of the pillar coral, Dendrogyra cylindrus, on the Florida Reef Tract (FRT) from 2013 to 2020 to assess population condition and trend, and to document the relative impacts of chronic and acute stressors. Large average colony size, an absence of juveniles, and large geographic distances between genotypes suggest that the Florida D. cylindrus population has been reproductively extinct for decades. During the study period, low-intensity chronic stressors were balanced by regrowth, while back-to-back years of coral bleaching and thermally-exacerbated disease led to declines that the subsequent recovery rates suggest would require 11 uninterrupted years to overcome. The most recent stressor on Florida’s D. cylindrus population is “stony coral tissue loss disease” (SCTLD). Following the appearance of the disease in Florida in 2014, unrecoverable losses occurred within the D. cylindrus population as tissue, colonies, and whole genotypes suffered complete mortality. Losses of 94% of coral tissue, 93% of colonies, and 86% of genotypes between 2014 and the end of 2020 have led to functional extinction of D. cylindrus on the FRT.
Damping Variation Effects in Vehicle Semi-active MR Suspensions: A Stress Concentration Analysis
Authors: Vivas-Lopez Carlos A. , Tudon-Martinez Juan C. , Estrada-Vela Alfonso , de Jesus Lozoya-Santos Jorge , Morales-Menendez Ruben
Published: April 2021

Semi-active vehicle suspensions are used to improve the limited comfort performance of passive vehicle suspensions by varying the damping coefficient according to a control strategy. These benefits have been usually studied in a transient and frequency domain, but rarely in a multi-body dynamic analysis considering the mechanical components and their joints. In this study, the controllability effects of a magnetorheological (MR) damper on the mechanical components of a McPherson automotive suspension are investigated using a stress concentration analysis. Finite element analysis was used with a Quarter of Vehicle (QoV) suspension model configured with an MR damper, and then compared with the passive damper. The simulation results show that an SA damper in the suspension not only improves the dynamic behavior of a road vehicle, but it also has the positive effect of reducing the stress concentrations in a critical suspension element, the knuckle, that are generated by high amplitude road profiles such as rough roads or dangerous street bumps.
Plant-Derived Nanobiomaterials as a Potential Next Generation Dental Implant Surface Modifier
Authors: Jeevanandam Jaison , Danquah Michael K. , Pan Sharadwata
Published: April 2021

Dental implants resemble synthetic materials, mainly designed as teeth-mimics to replace the damaged or irregular teeth. Specifically, they are demarcated as a surgical fixture of artificial implant materials, which are placed into the jawbone, and are allowed to be fused with the bone, similar to natural teeth. Dental implants may be categorized into endosteal, subperiosteal, and zygomatic classes, based on the placement of the implant “in the bone” or on top of the jawbone, under the gum tissue. In general, titanium and its alloys have found everyday applications as common, successful dental implant materials. However, these materials may also undergo corrosion and wear, which can lead to degradation into their ionic states, deposition in the surrounding tissues, as well as inflammation. Consequently, nanomaterials are recently introduced as a potential alternative to replace the conventional titanium-based dental implants. However, nanomaterials synthesized via physical and chemical approaches are either costly, non/less biocompatible, or toxic to the bone cells. Hence, biosynthesized nanomaterials, or bionanomaterials, are proposed in recent studies as potential non-toxic dental implant candidates. Further, nanobiomaterials with plant origins, such as nanocelluloses, nanometals, nanopolymers, and nanocarbon materials, are identified to possess enhanced biocompatibility, bioavailability and no/less cytotoxicity with antimicrobial efficacy at low costs and ease of fabrication. In this minireview, we present an outline of recent nanobiomaterials that are extensively investigated for dental implant applications. Additionally, we discuss their action mechanisms, applicability, and significance as dental implants, shortcomings, and future perspectives.
Dielectric Properties of Upside-Down SrTiO3/Li2MoO4 Composites Fabricated at Room Temperature
Authors: Kuzmić Nina , Škapin Srečo Davor , Nelo Mikko , Jantunen Heli , Spreitzer Matjaž
Published: April 2021

In this paper, ceramic upside-down lithium molybdate-strontium titanate (LMO-ST) composites fabricated at room temperature are described. Room temperature fabrication (RTF) is a promising alternative to the time- and energy-consuming high-temperature sintering of electroceramics, which involves mixing of the initial phases, molding with a steel dye, pressing, and drying, while in the last two phases the action of densification takes place. The LMO-ST composites are based on a high ratio of filler ST, coupled with the corresponding LMO binder. Part of the binder is admixed to the ceramic particles and additional part is added as a saturated aqueous solution, which crystallizes during pressing and drying, leading to its deposition on the surface of the filler particles. As a result, sufficient binding with 76–84% relative density was achieved. The deeper insight into the method was provided by various processing aspects and corresponding microstructural investigations. The particle size distribution, pressure, pressing time, ultrasonic treatment, drying time and processing conditions were optimized to obtain improved functional properties of the LMO-ST composites. The results of this study with relative permittivity in the range of 65–78 and dielectric loss tangent values of 0.002–0.05 can attract considerable attention for the use of LMO-ST composites in the industry of electroceramics.
Production of Mass-Separated Erbium-169 Towards the First Preclinical in vitro Investigations
Authors: Talip Zeynep , Borgna Francesca , Müller Cristina , Ulrich Jiri , Duchemin Charlotte , Ramos Joao P. , Stora Thierry , Köster Ulli , Nedjadi Youcef , Gadelshin Vadim , Fedosseev Valentin N. , Juget Frederic , Bailat Claude , Fankhauser Adelheid , Wilkins Shane G. , Lambert Laura , Marsh Bruce , Fedorov Dmitry , Chevallay Eric , Fernier Pascal , Schibli Roger , van der Meulen Nicholas P.
Published: April 2021

The β−-particle-emitting erbium-169 is a potential radionuclide toward therapy of metastasized cancer diseases. It can be produced in nuclear research reactors, irradiating isotopically-enriched168Er2O3. This path, however, is not suitable for receptor-targeted radionuclide therapy, where high specific molar activities are required. In this study, an electromagnetic isotope separation technique was applied after neutron irradiation to boost the specific activity by separating169Er from168Er targets. The separation efficiency increased up to 0.5% using resonant laser ionization. A subsequent chemical purification process was developed as well as activity standardization of the radionuclidically pure169Er. The quality of the169Er product permitted radiolabeling and pre-clinical studies. A preliminaryin vitroexperiment was accomplished, using a169Er-PSMA-617, to show the potential of169Er to reduce tumor cell viability.
Thrombotic Events in COVID-19 Are Associated With a Lower Use of Prophylactic Anticoagulation Before Hospitalization and Followed by Decreases in Platelet Reactivity
Authors: Clark Chantal C. , Jukema Bernard N. , Barendrecht Arjan D. , Spanjaard Judith S. , Jorritsma Nikita K. N. , Smits Simone , de Maat Steven , Seinen Cor W. , Verhoef Sandra , Parr Naomi M. J. , Sebastian Silvie A. E. , Koekman Arnold C. , van Wesel Annet C. W. , van Goor Harriet M. R. , Spijkerman Roy , Bongers Suzanne H. , van der Vries Erhard , Nierkens Stefan , Boes Marianne , Koenderman Leo , Kaasjager Karin A. H. , Maas Coen
Published: April 2021

Background: Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE).

Objectives: To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality.

Methods: Seventy nine hospitalized COVID-19 patients were enrolled in this retrospective cohort study and provided blood samples in which platelet reactivity in response to stimulation with ADP and TRAP-6 was determined using flow cytometry. Clinical outcomes included thrombotic events, and all-cause mortality.

Results: The incidence of TE in this study was 28% and all-cause mortality 16%. Patients that developed a TE were younger than patients that did not develop a TE [median age of 55 vs. 70 years; adjusted odds ratio (AOR) = 0.96 per 1 year of age, 95% confidence interval (CI) 0.92–1.00; p = 0.041]. Furthermore, patients using preexisting thromboprophylaxis were less likely to develop a thrombotic complication than patients that were not (18 vs. 54%; AOR = 0.19, 95% CI 0.04–0.84; p = 0.029). Conversely, having asthma strongly increased the risk on TE development (AOR = 6.2, 95% CI 1.15–33.7; p = 0.034). No significant differences in baseline P-selectin expression or platelet reactivity were observed between the COVID-19 positive patients (n = 79) and COVID-19 negative hospitalized control patients (n = 21), nor between COVID-19 positive survivors or non-survivors. However, patients showed decreased platelet reactivity in response to TRAP-6 following TE development.

Conclusion: We observed an association between the use of preexisting thromboprophylaxis and a decreased risk of TE during COVID-19. This suggests that these therapies are beneficial for coping with COVID-19 associated hypercoagulability. This highlights the importance of patient therapy adherence. We observed lowered platelet reactivity after the development of TE, which might be attributed to platelet desensitization during thromboinflammation.
Axial Spondyloarthritis: Mimics and Pitfalls of Imaging Assessment
Authors: Caetano António Proença , Mascarenhas Vasco V. , Machado Pedro M.
Published: April 2021

Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder that predominantly involves the axial skeleton. Imaging findings of axSpA can be divided into active changes, which include bone marrow edema, synovitis, enthesitis, capsulitis, and intra-articular effusion, and structural changes, which include erosions, sclerosis, bone fatty infiltration, fat deposition in an erosion cavity, and bone bridging or ankylosis. The ability to distinguish between imaging lesions suggestive of axSpA and artifacts or lesions suggestive of other disorders is critical for the accurate diagnosis of axSpA. Diagnosis may be challenging, particularly in early-stage disease and magnetic resonance imaging (MRI) plays a key role in the detection of subtle or inflammatory changes. MRI also allows the detection of structural changes in the subchondral bone marrow that are not visible on conventional radiography and is of prognostic and monitoring value. However, bone structural changes are more accurately depicted using computed tomography. Conventional radiography, on the other hand, has limitations, but it is easily accessible and may provide insight on gross changes as well as rule out other pathological features of the axial skeleton. This review outlines the imaging evaluation of axSpA with a focus on imaging mimics and potential pitfalls when assessing the axial skeleton.
High Diversity and Functional Potential of Undescribed “Acidobacteriota” in Danish Wastewater Treatment Plants
Authors: Kristensen Jannie Munk , Singleton Caitlin , Clegg Lee-Ann , Petriglieri Francesca , Nielsen Per Halkjaer
Published: April 2021

Microbial communities in water resource recovery facilities encompass a large diversity of poorly characterized lineages that could have undescribed process-critical functions. Recently, it was shown that taxa belonging to “Acidobacteriota” are abundant in Danish full-scale activated sludge wastewater treatment plants (WWTP), and here we investigated their diversity, distribution, and functional potential. “Acidobacteriota” taxa were identified using a comprehensive full-length 16S rRNA gene reference dataset and amplicon sequencing surveys across 37 WWTPs. Members of this phylum were diverse, belonging to 14 families, eight of which are completely uncharacterized and lack type strains. Several lineages were abundant, with relative abundances of up to 5% of the microbial community. Genome annotation and metabolic reconstruction of 50 high-quality “Acidobacteriota” metagenome-assembled genomes (MAGs) from 19 WWTPs showed high metabolic diversity and potential involvement in nitrogen and phosphorus removal and iron reduction. Fluorescence in situ hybridization (FISH) using newly-designed probes revealed cells with diverse morphologies, predominantly located inside activated sludge flocs. FISH in combination with Raman microspectroscopy revealed ecophysiological traits in probe-defined cells from the families Holophagaceae, Thermoanaerobaculaceae, and Vicinamibacteraceae, and families with the placeholder name of midas_f_502, midas_f_973, and midas_f_1548. Members of these lineages had the potential to be polyphosphate-accumulating organisms (PAOs) as intracellular storage was observed for the key compounds polyphosphate and glycogen.
Virus Prevalence and Genetic Diversity Across a Wild Bumblebee Community
Authors: Pascall David J. , Tinsley Matthew C. , Clark Bethany L. , Obbard Darren J. , Wilfert Lena
Published: April 2021

Viruses are key population regulators, but we have limited knowledge of the diversity and ecology of viruses. This is even the case in wild host populations that provide ecosystem services, where small fitness effects may have major ecological impacts in aggregate. One such group of hosts are the bumblebees, which have a major role in the pollination of food crops and have suffered population declines and range contractions in recent decades. In this study, we investigate the diversity of four recently discovered bumblebee viruses (Mayfield virus 1, Mayfield virus 2, River Liunaeg virus, and Loch Morlich virus), and two previously known viruses that infect both wild bumblebees and managed honeybees (Acute bee paralysis virus and Slow bee paralysis virus) from isolates in Scotland. We investigate the ecological and environmental factors that determine viral presence and absence. We show that the recently discovered bumblebee viruses were more genetically diverse than the viruses shared with honeybees. Coinfection is potentially important in shaping prevalence: we found a strong positive association between River Liunaeg virus and Loch Morlich virus presence after controlling for host species, location and other relevant ecological variables. We tested for a relationship between environmental variables (temperature, UV radiation, wind speed, and prevalence), but as we had few sampling sites, and thus low power for site-level analyses, we could not conclude anything regarding these variables. We also describe the relationship between the bumblebee communities at our sampling sites. This study represents a first step in the description of predictors of bumblebee infection in the wild.
Interactions Between Microplastics and Heavy Metals in Aquatic Environments: A Review
Authors: Liu Sitong , Shi Jiafu , Wang Jiao , Dai Yexin , Li Hongyu , Li Jiayao , Liu Xianhua , Chen Xiaochen , Wang Zhiyun , Zhang Pingping
Published: April 2021

Microplastics (MPs), tiny particles broken down from larger pieces of plastics, have accumulated everywhere on the earth. As an inert carbon stream in aquatic environment, they have been reported as carriers for heavy metals and exhibit diverse interactive effects. However, these interactions are still poorly understood, especially mechanisms driving these interactions and how they pose risks on living organisms. In this mini review, a bibliometric analysis in this field was conducted and then the mechanisms driving these interactions were examined, especially emphasizing the important roles of microorganisms on the interactions. Their combined toxic effects and the potential hazards to human health were also discussed. Finally, the future research directions in this field were suggested. This review summarized the recent research progress in this field and highlighted the essential roles of the microbes on the interactions between MPs and heavy metals with the hope to promote more studies to unveil action mechanisms and reduce/eliminate the risks associated with MP presence.
Anti-Bacterial Properties of Cannabigerol Toward Streptococcus mutans
Authors: Aqawi Muna , Sionov Ronit Vogt , Gallily Ruth , Friedman Michael , Steinberg Doron
Published: April 2021

Streptococcus mutans (S. mutans) is a gram-positive facultatively anaerobic bacterium and the most common pathogen associated with tooth caries. The organism is acid tolerant and can undergo physiological adaptation to function effectively in acid environments such as carious dental plaque. Some cannabinoids have been found to have potent anti-microbial activity against gram-positive bacteria. One of these is the non-psychoactive, minor phytocannabinoid Cannabigerol (CBG). Here we show that CBG exhibits anti-bacterial activities against S. mutans. CBG halts the proliferation of planktonic growing S. mutans, which is affected by the initial cell density. High-resolution scanning electron microscopy showed that the CBG-treated bacteria become swollen with altered membrane structures. Transmission electron microscopy provided data showing that CBG treatment leads to intracellular accumulation of membrane structures. Nile red, DiOC2(3) and laurdan staining demonstrated that CBG alters the membrane properties, induces membrane hyperpolarization, and decreases the membrane fluidity. CBG-treated bacteria showed increased propidium iodide uptake and reduced calcein AM staining, suggesting that CBG increases the membrane permeability and reduces the metabolic activity. Furthermore, CBG prevented the drop in pH caused by the bacteria. In summary, we present here data showing the mechanisms by which CBG exerts its anti-bacterial effect against S. mutans.
Multiple CheY Proteins Control Surface-Associated Lifestyles of Azospirillum brasilense
Authors: Ganusova Elena E. , Vo Lam T. , Mukherjee Tanmoy , Alexandre Gladys
Published: April 2021

Bacterial chemotaxis is the directed movement of motile bacteria in gradients of chemoeffectors. This behavior is mediated by dedicated signal transduction pathways that couple environment sensing with changes in the direction of rotation of flagellar motors to ultimately affect the motility pattern. Azospirillum brasilense uses two distinct chemotaxis pathways, named Che1 and Che4, and four different response regulators (CheY1, CheY4, CheY6, and CheY7) to control the swimming pattern during chemotaxis. Each of the CheY homologs was shown to differentially affect the rotational bias of the polar flagellum and chemotaxis. The role, if any, of these CheY homologs in swarming, which depends on a distinct lateral flagella system or in attachment is not known. Here, we characterize CheY homologs’ roles in swimming, swarming, and attachment to abiotic and biotic (wheat roots) surfaces and biofilm formation. We show that while strains lacking CheY1 and CheY6 are still able to navigate air gradients, strains lacking CheY4 and CheY7 are chemotaxis null. Expansion of swarming colonies in the presence of gradients requires chemotaxis. The induction of swarming depends on CheY4 and CheY7, but the cells’ organization as dense clusters in productive swarms appear to depend on functional CheYs but not chemotaxis per se. Similarly, functional CheY homologs but not chemotaxis, contribute to attachment to both abiotic and root surfaces as well as to biofilm formation, although these effects are likely dependent on additional cell surface properties such as adhesiveness. Collectively, our data highlight distinct roles for multiple CheY homologs and for chemotaxis on swarming and attachment to surfaces.
Phenotypic Characterization of Sulfolobus islandicus Strains Lacking the B-Family DNA Polymerases PolB2 and PolB3 Individually and in Combination
Authors: Bohall Peter B. , Bell Stephen D.
Published: April 2021

Across the three domains of life, B-family DNA polymerases play a variety of roles in both DNA repair and DNA replication processes. We examine the phenotypic consequences of loss of the putative repair polymerases PolB2 and/or PolB3 in the crenarchaeon Sulfolobus islandicus. We detect a modest growth advantage when cells lacking the polymerase are grown in unperturbed conditions. Further, we observe a striking insensitivity of the mutant lines to acute treatment with the oxidizing agent, hydrogen peroxide. In addition, cells lacking PolB3 show enhanced sensitivity to the DNA damaging agent 4-NQO. Our data therefore suggest that these non-essential DNA polymerases may influence DNA repair pathway choice in these hyperthermophilic aerobes.
Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae
Authors: Wang Zijing , Cai Ruopeng , Wang Gang , Guo Zhimin , Liu Xiao , Guan Yuan , Ji Yalu , Zhang Hao , Xi Hengyu , Zhao Rihong , Bi Lanting , Liu Shanshan , Yang Li , Feng Xin , Sun Changjiang , Lei Liancheng , Han Wenyu , Gu Jingmin
Published: April 2021

Klebsiella pneumoniae (K. pneumoniae) is an important nosocomial and community acquired opportunistic pathogen which causes various infections. The emergence of multi-drug resistant (MDR) K. pneumoniae and carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) has brought more severe challenge to the treatment of K. pneumoniae infection. In this study, a novel bacteriophage that specifically infects K. pneumoniae was isolated and named as vB_KpnM_P-KP2 (abbreviated as P-KP2). The biological characteristics of P-KP2 and the bioinformatics of its genome were analyzed, and then the therapeutic effect of P-KP2 was tested by animal experiments. P-KP2 presents high lysis efficiency in vitro. The genome of P-KP2 shows homology with nine phages which belong to “KP15 virus” family and its genome comprises 172,138 bp and 264 ORFs. Besides, P-KP2 was comparable to gentamicin in the treatment of lethal pneumonia caused by K. pneumoniae W-KP2 (K47 serotype). Furthermore, the combined treatment of P-KP2 and gentamicin completely rescued the infected mice. Therefore, this study not only introduces a new member to the phage therapeutic library, but also serves as a reference for other phage-antibiotic combinations to combat MDR pathogens.