bluuebunny/crossref_metadata_2025 huggingface dataset:
Controls on Gas Emission Distribution on the Continental Slope of the Western Black Sea
Authors: Riedel Michael , Hähnel Line , Bialas Jörg , Bachmann Anna Katharina , Gaide Stefanie , Wintersteller Paul , Klaucke Ingo , Bohrmann Gerhard
Published: February 2021

The continental slopes of the Black Sea show abundant manifestations of gas seepage in water depth of <720 m, but underlying controls are still not fully understood. Here, we investigate gas seepage along the Bulgarian and Romanian Black Sea margin using acoustic multibeam water column, bathymetry, backscatter, and sub-bottom profiler data to determine linkages between sub-seafloor structures, seafloor gas seeps, and gas discharge into the water column. More than 10,000 seepage sites over an area of ∼3,000 km2were identified. The maximum water depth of gas seepage is controlled by the onset of the structure I gas hydrate stability zone in ∼720 m depth. However, gas seepage is not randomly distributed elsewhere. We classify three factors controlling on gas seepage locations into depositional, erosional, and tectonic factors. Depositional factors are associated with regionally occurring sediment waves forming focusing effects and mass-transport deposits (MTDs) with limited sediment drape. Elongated seafloor depressions linked to faulting and gas seepage develop at the base between adjacent sediment waves. The elongated depressions become progressively wider and deeper toward shallow water depths and culminate in some locations into clusters of pockmarks. MTDs cover larger regions and level out paleo-topography. Their surface morphology results in fault-like deformation patterns of the sediment drape on top of the MTDs that is locally utilized for gas migration. Erosional factors are seen along channels and canyons as well as slope failures, where gas discharge occurs along head-scarps and ridges. Sediment that was removed by slope failures cover larger regions down-slope. Those regions are devoid of gas seepage either by forming impermeable barriers to gas migration or by removal of the formerly gas-rich sediments. Deep-rooted tectonic control on gas migration is seen in the eastern study region with wide-spread normal faulting promoting gas migration. Overall, gas seepage is widespread along the margin. Gas migration appears more vigorous in shallow waters below ∼160 m water depth, but the number of flare sites is not necessarily an indicator of the total volume of gas released.
Advancing School Professionals’ Dyslexia Knowledge Through Neuroscience: Bridging the Science-Education Gap Through Developmental Psychology
Authors: Anderson Alida
Published: February 2021

This review presents a summary of the research on advancing dyslexia knowledge among school professionals. It contributes to the literature with a proposed solution for professional development and teacher training through the field of developmental psychology. The article outlines what has been done to address the science-education gap owing to misunderstandings about dyslexia, proposing a solution to advance school professionals’ knowledge of dyslexia through developmental psychology coursework aimed at the neuroscience of dyslexia, including basic and cognitive neuroscience concepts. The review outlines the legislative and research support for this proposal as well as the candidate knowledge focused on the neuroscience of dyslexia to address gaps in professional knowledge and practice. The review includes a discussion section with implications for research and practice.
L-T4 Therapy in Enteric Malabsorptive Disorders
Authors: Fallahi Poupak , Ferrari Silvia Martina , Elia Giusy , Ragusa Francesca , Paparo Sabrina Rosaria , Antonelli Alessandro
Published: February 2021

Levothyroxine (L-T4) absorption can be impaired by various causes: a) L-T4 ingestion during breakfast, or with food; b) conditions of reduced gastric acidity; c) intestinal procedures and diseases such as bariatric surgery, lactose intolerance (LI), celiac disease (CD), inflammatory bowel disease; d) drugs that alter L-T4 absorption, increasing the gastric pH, or preventing the dissolution of tablets. The development of new oral formulations, i.e. the liquid preparation and the soft gel capsule, represents the most recent advance regarding L-T4 therapy. Treating hypothyroidism with L-T4 tablets can lead to an improper control of thyroid-stimulating hormone (TSH) in ~10%–15% of patients. The improperly elevated TSH is usually managed by increasing the L-T4 daily dose, and revaluating TSH upon 2-6 months. The increase of the L-T4 dosage may cause iatrogenic hyperthyroidism, especially when the underlying disorders are cured. Liquid L-T4 can be administered in patients unable to swallow capsules or tablets, and this is one of its major benefits. Liquid L-T4 can: 1- overcome food and beverages interference; 2- bypass the malabsorption associated with an increased gastric pH; 3- circumvent the issue of malabsorption in patients who underwent bariatric surgery; 4-maintain TSH values under control better than L-T4 tablets in hypothyroid patients with typical or atypical CD, or in patients with LI. Few clinical studies evaluated soft gel L-T4 with encouraging findings in patients with gastric- or coffee-related malabsorption, or hypothyroid patients without malabsorption. Additional research is necessary to investigate liquid L-T4, or soft gel capsule, in other conditions of altered L-T4 absorption.
A Test for the Underlying State-Structure of Hidden Markov Models: Partially Observed Capture-Recapture Data
Authors: Jeyam Anita , McCrea Rachel S. , Pradel Roger
Published: February 2021

Hidden Markov models (HMMs) are being widely used in the field of ecological modeling, however determining the number of underlying states in an HMM remains a challenge. Here we examine a special case of capture-recapture models for open populations, where some animals are observed but it is not possible to ascertain their state (partial observations), whilst the other animals' states are assigned without error (complete observations). We propose a mixture test of the underlying state structure generating the partial observations, which assesses whether they are compatible with the set of states observed in the complete observations. We demonstrate the good performance of the test using simulation and through application to a data set of Canada Geese.
Morphology, Life Cycle, Environmental Factors and Fitness – a Machine Learning Analysis in Kissing Bugs (Hemiptera, Reduviidae, Triatominae)
Authors: Rabinovich Jorge E.
Published: February 2021

Populations are permanently evolving and their evolution will influence their survival and reproduction, which will then alter demographic parameters. Several phenotypic, life history and environmental variables are known to be related to fitness measures. The goal of this article was to look into the possible types of those relationships in insects of the subfamily Triatominae, vectors ofTrypanosoma cruzi, the causative agent of Chagas disease. After an exhaustive literature review of 7,207 records of publications referring exclusively to all possible features of the triatomines, using 15 keywords those records were reduced to 2,968 publications, that were analyzed individually; after deleting those publications that did not have the data in quantitative form as needed for the objective of this article, I found that 171 papers were adequate for the present analysis. From them I compiled a dataset of 11 variables and 90 cases from 36 triatomine species. Those variables included four environmental, two life cycle, and four morphological variables, and one demographic parameter: a fitness measure (the population intrinsic rate of natural increase,r0), used as dependent variable. However, the relationship betweenT. cruziand its vector host was not included in this analysis despite triatomine-T. cruziinteractions constitute an important factor in the evolution of triatomine’s life history. I resorted to the Random Forest method as a machine learning approach for the analysis of this dataset, and found that –in addition to the triatomine species themselves– only the two life cycle variables (mean development time from egg to adult, and mean fecundity, expressed as the average number of female eggs laid per female per day) were statistically significant in determining fitness (r0). The machine learning approach used in the analysis provided a similar but deeper insight into these relationships than classical regression. Except for an analysis on senescence, this is the first study in triatomines addressing these questions. These results will be useful for other theoretical optimization approaches (frequency-dependence, density-dependence, evolutionary game theory, and adaptive dynamics), thus contributing to the theoretical framework for interpreting the succession of stages in insect adaptations, a framework yet to be constructed.
Process Development of Sj-p80: A Low-Cost Transmission-Blocking Veterinary Vaccine for Asiatic Schistosomiasis
Authors: Molehin Adebayo J. , Gray Sean A. , Turner Cheri , Davis Jennifer , Zhang Weidong , Khatoon Sabiha , Rattan Madison , Kernen Rebecca , Peterson Christopher , Sennoune Souad R. , Carter Darrick , Siddiqui Afzal A.
Published: February 2021

Asiatic schistosomiasis caused bySchistosoma japonicumis a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) fromS. japonicum(Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4–51.4%) and intestines (1.9–55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.
Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers
Authors: Sadik Christian D. , Langan Ewan A. , Gutzmer Ralf , Fleischer Maria Isabel , Loquai Carmen , Reinhardt Lydia , Meier Friedegund , Göppner Daniela , Herbst Rudolf A. , Zillikens Detlef , Terheyden Patrick
Published: February 2021

Immune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3–74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms.
CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance
Authors: Montamat Guillem , Leonard Cathy , Poli Aurélie , Klimek Ludger , Ollert Markus
Published: February 2021

Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.
Frequencies of CD8 and DN MAIT Cells Among Children Diagnosed With Type 1 Diabetes Are Similar to Age-Matched Controls
Authors: Harms Robert Z. , Ostlund Katie R. , Cabrera Monina , Edwards Earline , Smith Victoria B. , Smith Lynette M. , Sarvetnick Nora
Published: February 2021

Mucosal-associated invariant T (MAIT) cells have been implicated in various forms of autoimmunity, including type 1 diabetes (T1D). Here, we tested the hypothesis that CD8 and double negative (DN) MAIT cell frequencies were altered among diagnosed T1D subjects compared to controls. To do this, we analyzed cryopreserved peripheral blood mononuclear cells (PBMCs) from age-matched T1D and control children using flow cytometry. We observed that CD8 and DN MAIT cell frequencies were similarly abundant between the two groups. We tested for associations between MAIT cell frequency and T1D-associated parameters, which could reveal a pathogenic role for MAIT cells in the absence of changes in frequency. We found no significant associations between CD8 and DN MAIT cell frequency and levels of islet cell autoantibodies (ICA), glutamate decarboxylase 65 (GAD65) autoantibodies, zinc transporter 8 (ZNT8) autoantibodies, and insulinoma antigen 2 (IA-2) autoantibodies. Furthermore, CD8 and DN MAIT cell frequencies were not significantly associated with time since diagnosis, c-peptide levels, HbA1c, and BMI. As we have examined this cohort for multiple soluble factors previously, we tested for associations between relevant factors and MAIT cell frequency. These could help to explain the broad range of MAIT frequencies we observed and/or indicate disease-associated processes. Although we found nothing disease-specific, we observed that levels of IL-7, IL-18, 25 (OH) vitamin D, and the ratio of vitamin D binding protein to 25 (OH) vitamin D were all associated with MAIT cell frequency. Finally, previous cytomegalovirus infection was associated with reduced CD8 and DN MAIT cells. From this evaluation, we found no connections between CD8 and DN MAIT cells and children with T1D. However, we did observe several intrinsic and extrinsic factors that could influence peripheral MAIT cell abundance among all children. These factors may be worth consideration in future experimental design.
Sending Out Alarms: A Perspective on Intercellular Communications in Insect Antiviral Immune Response
Authors: Wang Fei
Published: February 2021

Viral infection triggers insect immune response, including RNA interference, apoptosis and autophagy, and profoundly changes the gene expression profiles in infected cells. Although intracellular degradation is crucial for restricting viral infection, intercellular communication is required to mount a robust systemic immune response. This review focuses on recent advances in understanding the intercellular communications in insect antiviral immunity, including protein-based and virus-derived RNA based cell-cell communications, with emphasis on the signaling pathway that induces the production of the potential cytokines. The prospects and challenges of future work are also discussed.
Phenotypic and Functional Characterization of Double Negative B Cells in the Blood of Individuals With Obesity
Authors: Frasca Daniela , Diaz Alain , Romero Maria , Blomberg Bonnie B.
Published: February 2021

We have previously shown that obesity is associated with increased secretion of IgG antibodies with anti-self-reactivity. In this paper, we confirm and extend our previous findings. We show that the plasma of individuals with obesity is enriched in autoimmune antibodies whose levels are positively associated with blood frequencies of the subset of Double Negative (DN) B cells, which is the most pro-inflammatory B cell subset. We also show that DN B cells, significantly increased in the blood of obese versus lean individuals, are characterized by higher expression of immune activation markers and of the transcription factor T-bet, both associated with autoimmunity. The removal of DN B cells from the peripheral B cell pool significantly decreases in vitro secretion of anti-self IgG antibodies. These results altogether confirm the crucial role of DN B cells in the secretion of anti-self IgG antibodies in individuals with obesity.
New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries
Authors: Jain Tejeshwar , Sharma Prateek , Are Abhi C. , Vickers Selwyn M. , Dudeja Vikas
Published: February 2021

The past decade has witnessed groundbreaking advances in the field of microbiome research. An area where immense implications of the microbiome have been demonstrated is tumor biology. The microbiome affects tumor initiation and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. It can also determine response to cancer therapies and predict disease progression and survival. Modulation of the microbiome can be harnessed to potentiate the efficacy of immunotherapies and decrease their toxicity. In this review, we comprehensively dissect recent evidence regarding the interaction of the microbiome and anti-tumor immune machinery and outline the critical questions which need to be addressed as we further explore this dynamic colloquy.
Natural Killer Anti-Tumor Activity Can Be Achieved by In Vitro Incubation With Heat-Killed BCG
Authors: Esteso Gloria , Aguiló Nacho , Julián Esther , Ashiru Omodele , Ho Mei. M. , Martín Carlos , Valés-Gómez Mar
Published: February 2021

Natural Killer cell receptors allow this heterogeneous immune population to efficiently fight both tumors and infection, so their use as immunotherapy agents is an active field of research. Cytokine activation, particularly by myeloid cell-derived IL15, can induce potent NK anti-tumor responses. While studying the mechanism of action of intravesical instillations of Bacille Calmette-Guérin (BCG) as therapy for patients with high risk non-muscle invasive bladder cancer, we showed that BCG can activate a cytotoxic CD56bright NK cell population which efficiently recognized bladder cancer cells. This pioneer immunotherapy provides an invaluable model to understand the role of different immune populations in tumor elimination. However, during the propagation of BCG worldwide a large number of genetically diverse BCG substrains developed. Here, we investigated the capacity of different BCG substrains to promote NK cell activation and confirmed that they were able to activate lymphocytes. Tice, Connaught and Moreau were the substrains with a stronger NK activation effect as measured by CD56 upregulation. Surprisingly, dead mycobacteria also stimulated PBMC cultures and we further demonstrate here that subcellular fractions of BCG-Tice, in the absence of live mycobacteria, could also induce an NK cell response. Lipids from BCG-Tice, but not from Mycobacterium bovis, stimulated NK cell activation and degranulation, whereas the aqueous fraction of either bacteria did not activate lymphocytes. However, delipidated BCG-Tice bacteria were able to activate effector cells (CD3+CD56+ and NK, CD3-CD56+). These data demonstrate that different components of mycobacteria can stimulate different immune subpopulations resulting in phenotypes suitable for cancer elimination.
Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial
Authors: Abbade Luciana P. F. , Barraviera Silvia Regina Catharino Sartori , Silvares Maria Regina Cavariani , Lima Ana Beatriz B. de C. O. , Haddad Gabriela R. , Gatti Márcia A. N. , Medolago Natália Bronzatto , Rigotto Carneiro Márcia Tonin , dos Santos Lucilene Delazari , Ferreira Rui Seabra , Barraviera Benedito
Published: February 2021

Background

Heterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom. This study evaluated the safety and immunogenicity of HFS, estimated the best dose, and assessed its preliminary efficacy in the treatment of chronic venous ulcers (CVU).

Methods

A phase I/II non-randomized, single-arm clinical trial was performed on 31 participants, accounting for a total of 69 active CVUs. All ulcers were treated with HFS, essential fatty acid, and Unna boot for 12 weeks. The outcomes assessed were: (1) primary safety, immunogenicity analyses, and confirmation of the lowest safe dose; (2) secondary promising efficacy by analyzing the healing process. Immunogenicity was evaluated using the serum-neutralizing (IgM and IgG) and non-neutralizing (IgA and IgE) antibody techniques against the product. The immuno-detection of IgE class antibodies was assessed using dot-blot assay before and at the end of treatment. Positive samples on dot-blot assays were subsequently analyzed by western blotting to verify the results.

Results

No severe systemic adverse events related to the use of HFS were observed. Local adverse events potentially related to treatment include ulcer pain (52%), peri-ulcer maceration (16%), peri-ulcer pruritus (12%), critical colonization (8%), peri-ulcer eczema (4%), the opening of new ulcers (4%), and increased ulcerated area 4%). Neutralizing and non-neutralizing antibodies did not show significant deviations at any of the evaluated time points. Blot assays showed that all patients presented negative immunological reactions, either before or after treatment, with the thrombin-like enzyme component. In addition, two participants showed a positive immunological reaction to the cryoprecipitate component, while another two were positive before and during treatment. Regarding the secondary outcomes of preliminary efficacy, a total healing and significant reduction of the area was observed in 47.5 and 22%, respectively. A qualitative improvement was observed in the wound beds of unhealed ulcers.

Conclusions

The investigational HFS bioproduct proved to be safe and non-immunogenic with a good preliminary efficacy for the treatment of CVU, according to the protocol and doses proposed. A multicentric phase III clinical trial will be necessary to verify these findings.
An Abnormally High Neutrophil-to-Lymphocyte Ratio Is Not an Independent Outcome Predictor in AQP4-IgG-Positive NMOSD
Authors: Carnero Contentti Edgar , Delgado-García Guillermo , Criniti Juan , López Pablo A. , Pettinicchi Juan Pablo , Cristiano Edgardo , Miguez Jimena , Correa-Díaz Edgar Patricio , Álvarez Pucha Marcelo Oswaldo , Miño Zambrano Joselyn Elizabeth , Gómez-Figueroa Enrique , Rivas-Alonso Verónica , Flores-Rivera José , Tkachuk Verónica , Caride Alejandro , Rojas Juan Ignacio
Published: February 2021

Background

The neutrophil-to-lymphocyte ratio (NLR) has been investigated in many autoimmune conditions as a biomarker of inflammation and/or disease activity. The role of NLR in AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) is far from clear. In this study, NLR was evaluated in patients with AQP4-IgG-positive NMOSD at disease onset and its prognostic impact was subsequently assessed.

Methods

In this multicenter study, we retrospectively included all recent/newly diagnosed treatment-naïve patients with AQP4-IgG-positive NMOSD (n=90) from three different countries in Latin America (LATAM): Argentina, Ecuador, and Mexico. NLR was compared between AQP4-IgG-positive NMOSD and healthy controls (HC, n = 365). Demographic, clinical, paraclinical (including imaging), and prognostic data at 12 and 24 months were also evaluated. Multivariate regression analysis was used to describe and identify independent associations between the log-transformed NLR and clinical (relapses and EDSS) and imaging (new/enlarging and/or contrast-enhancing MRI lesions) outcomes.

Results

NLR was higher in NMOSD patients during the first attack compared with HC (2.9 ± 1.6 vs 1.8 ± 0.6; p<0.0001). Regardless of immunosuppressant’s initiation at disease onset, NLR remained higher in NMOSD patients at 12 (2.8 ± 1.3; p<0.0001) and 24 (3.1 ± 1.6; p<0.0001) months. No association was found at 12 and 24 months between the log-transformed NLR and the presence of relapses, new/enlarging and/or contrast-enhancing MRI lesions, and/or physical disability.

Conclusions

In this cohort of LATAM patients with AQP4-IgG-positive NMOSD, NLR was abnormally high in attacks but also during follow-up. However, a high NLR was not an independent predictor of clinical or imaging outcomes in our models.
Rapid Induction of Pulmonary Inflammation, Autoimmune Gene Expression, and Ectopic Lymphoid Neogenesis Following Acute Silica Exposure in Lupus-Prone Mice
Authors: Chauhan Preeti S. , Wagner James G. , Benninghoff Abby D. , Lewandowski Ryan P. , Favor Olivia K. , Wierenga Kathryn A. , Gilley Kristen N. , Ross Elizabeth A. , Harkema Jack R. , Pestka James J.
Published: February 2021

Occupational exposure to crystalline silica (cSiO2) is etiologically associated with systemic lupus erythematosus (lupus) and other autoimmune diseases. cSiO2's autoimmune effects in humans can be mimicked chronically in female lupus-prone NZBWF1 mice following repeated exposure to the particle. However, the immediate and short-term effects of cSiO2 in this widely used model of autoimmune disease are not well-understood. In the present study, we tested the hypothesis that a single acute cSiO2 dose triggers early presentation of cellular, histopathological, transcriptomic, and protein biomarkers of inflammation and autoimmunity in lupus-prone mice. Eight-week old female NZBWF1 mice were intranasally instilled once with 2.5 mg cSiO2 or saline vehicle and necropsied at 1, 7, 14, 21, and 28 d post-instillation (PI). Analyses of bronchoalveolar lavage fluid (BALF) and lung tissue revealed that by 7 d PI, acute cSiO2 exposure persistently provoked: (i) robust recruitment of macrophages, neutrophils, and lymphocytes into the alveoli, (ii) cell death as reflected by increased protein, double-stranded DNA, and lactate dehydrogenase activity, (iii) elevated secretion of the cytokines IL-1α, IL-1β, IL-18, TNF-α, IL-6, MCP-1, and B cell activation factor (BAFF), and (iv) upregulation of genes associated with chemokines, proinflammatory cytokines, lymphocyte activation, and type I interferon signaling. The appearance of these endpoints was subsequently followed by the emergence in the lung of organized CD3+ T cells (14 d PI) and CD45R+ B cells (21 d PI) that were indicative of ectopic lymphoid structure (ELS) development. Taken together, acute cSiO2 exposure triggered a rapid onset of autoimmune disease pathogenesis that was heralded in the lung by unresolved inflammation and cell death, proinflammatory cytokine production, chemokine-driven recruitment of leukocytes, an interferon response signature, B and T cell activation, and ELS neogenesis. This short-term murine model provides valuable new insight into potential early mechanisms of cSiO2-induced lupus flaring and, furthermore, offers a rapid venue for evaluating interventions against respirable particle-triggered inflammation and autoimmunity.
Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO
Authors: Kim Minah , Tomek Petr
Published: February 2021

Blockade of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) holds enormous promise for sensitising cancer patients to immune checkpoint blockade. Yet, only IDO1 inhibitors had entered clinical trials so far, and those agents have generated disappointing clinical results. Improved understanding of molecular mechanisms involved in the immune-regulatory function of the tryptophan catabolism is likely to optimise therapeutic strategies to block this pathway. The immunosuppressive role of tryptophan metabolite kynurenine is becoming increasingly clear, but it remains a mystery if tryptophan exerts functions beyond serving as a precursor for kynurenine. Here we hypothesise that tryptophan acts as a rheostat of kynurenine-mediated immunosuppression by competing with kynurenine for entry into immune T-cells through the amino acid transporter called System L. This hypothesis stems from the observations that elevated tryptophan levels in TDO-knockout mice relieve immunosuppression instigated by IDO1, and that the vacancy of System L transporter modulates kynurenine entry into CD4+ T-cells. This hypothesis has two potential therapeutic implications. Firstly, potent TDO inhibitors are expected to indirectly inhibit IDO1 hence development of TDO-selective inhibitors appears advantageous compared to IDO1-selective and dual IDO1/TDO inhibitors. Secondly, oral supplementation with System L substrates such as leucine represents a novel potential therapeutic modality to restrain the immunosuppressive kynurenine and restore anti-tumour immunity.
Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement
Authors: Morini Raffaella , Bizzotto Matteo , Perrucci Fabio , Filipello Fabia , Matteoli Michela
Published: February 2021

The role of microglia in controlling synapse homeostasis is becoming increasingly recognized by the scientific community. In particular, the microglia-mediated elimination of supernumerary synapses during development lays the basis for the correct formation of neuronal circuits in adulthood, while the possible reactivation of this process in pathological conditions, such as schizophrenia or Alzheimer's Disease, provides a promising target for future therapeutic strategies. The methodological approaches to investigate microglial synaptic engulfment include differentin vitroandin vivosettings. Basicin vitroassays, employing isolated microglia and microbeads, apoptotic membranes, liposomes or synaptosomes allow the quantification of the microglia phagocytic abilities, while co-cultures of microglia and neurons, deriving from either WT or genetically modified mice models, provide a relatively manageable setting to investigate the involvement of specific molecular pathways. Further detailed analysis in mice brain is then mandatory to validate thein vitroassays as representative for thein vivosituation. The present review aims to dissect the main technical approaches to investigate microglia-mediated phagocytosis of neuronal and synaptic substrates in critical developmental time windows.
Disentangling the Influence of Three Major Threats on the Demography of an Albatross Community
Authors: Cleeland Jaimie B. , Pardo Deborah , Raymond Ben , Tuck Geoffrey N. , McMahon Clive R. , Phillips Richard A. , Alderman Rachael , Lea Mary-Anne , Hindell Mark A.
Published: February 2021

Climate change, fisheries and invasive species represent three pervasive threats to seabirds, globally. Understanding the relative influence and compounding nature of marine and terrestrial threats on the demography of seabird communities is vital for evidence-based conservation. Using 20 years of capture-mark-recapture data from four sympatric species of albatross (black-browedThalassarche melanophris, gray-headedT. chrysostoma, light-mantledPhoebetria palpebrataand wanderingDiomedea exulans) at subantarctic Macquarie Island, we quantified the temporal variability in survival, breeding probability and success. In three species (excluding the wandering albatross because of their small population), we also assessed the influence of fisheries, oceanographic and terrestrial change on these rates. The Southern Annular Mode (SAM) explained 20.87–29.38% of the temporal variability in survival in all three species and 22.72–28.60% in breeding success for black-browed and gray-headed albatross, with positive SAM events related to higher success. The El Niño Southern Oscillation (ENSO) Index explained 21.14–44.04% of the variability in survival, with higher survival rates following La Niña events. For black-browed albatrosses, effort in south-west Atlantic longline fisheries had a negative relationship with survival and explained 22.75–32.21% of the variability. Whereas increased effort in New Zealand trawl fisheries were related to increases in survival, explaining 21.26–28.29 % of variability. The inclusion of terrestrial covariates, reflecting extreme rainfall events and rabbit-driven habitat degradation, explained greater variability in trends breeding probability than oceanographic or fisheries covariates for all three species. These results indicate managing drivers of demographic trends that are most easily controlled, such as fisheries and habitat degradation, will be a viable option for some species (e.g., black-browed albatross) but less effective for others (e.g., light-mantled albatross). Our results illustrate the need to integrate fisheries, oceanographic and terrestrial processes when assessing demographic variability and formulating the appropriate management response.
Multi-Model Approach on Growth Estimation and Association With Life History Trait for Elasmobranchs
Authors: Liu Kwang-Ming , Wu Chiao-Bin , Joung Shoou-Jeng , Tsai Wen-Pei , Su Kuan-Yu
Published: February 2021

Age and growth information is essential for stock assessment of fish, and growth model selection may influence the accuracy of stock assessment and subsequent fishery management decision making. Previous descriptions of the age and growth of elasmobranchs relied mainly on the von Bertalanffy growth model (VBGM). However, it has been noted that sharks, skates and rays exhibit significant variety in size, shape, and life history traits. Given this variation, the VBGM may not necessarily provide the best fit for all elasmobranchs. This study attempts to improve the growth estimates by using multi-model approach to test four growth models—the VBGM, the two-parameter VBGM, the Robertson (Logistic) and the Gompertz models to fit observed or simulated length-at-age data for 38 species (44 cases) of elasmobranchs. The best-fit growth model was selected based on the bias corrected Akaike’s Information Criterion (AICc), the AICcdifference, the AICcweight, the Bayesian Information Criterion (BIC), and the Leave-one-out cross-validation (LOOCV). The VBGM and two-parameter VBGM provide the best fit for species with slow growth and extended longevity (L∞> 100 cm TL, 0.02 < k < 0.25 yr–1), such as pelagic sharks. For fast-growing small sharks (L∞< 100 cm TL, kror kg> 0.2 yr–1) in deep waters and for small-sized demersal skates/rays, the Robertson and the Gompertz models provide the best fit. The best-fit growth models for small sharks in shallow waters are the two-parameter VBGM and the Robertson model. Although it was found that the best-fit growth models for elasmobranchs were associated with their life history trait, exceptions were also noted. Therefore, a multi-model approach incorporating with the best-fit model selected for each group in this study was recommended in growth estimation for elasmobranchs.
Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study
Authors: Wang Ling , Wang Li-ning , Zhou Ji-fang , Gao Wen-hui , Jiang Chuan-he , Tang Wei , Zhao Wei-li , Hu Jiong , Jiang Jie-ling
Published: February 2021

T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6–8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3–22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Gut Microbiota Variation With Short-Term Intake of Ginger Juice on Human Health
Authors: Wang Xiaolong , Zhang Dan , Jiang Haiqiang , Zhang Shuo , Pang Xiaogang , Gao Shijie , Zhang Huimin , Zhang Shanyu , Xiao Qiuyue , Chen Liyuan , Wang Shengqi , Qi Dongmei , Li Yunlun
Published: February 2021

Ginger, a widely used functional food and food additive, little is known about the effect of ginger juice, which is rich in many healthful agents, on healthy humans or on its relationship with gut microbiota composition variation. The aim of this study was to investigate the changes in the gut microbial communities that occur following the supplementation of fresh ginger-derived juice in healthy adults and its potential associations with function. A crossover intervention study in which 123 healthy subjects (63 men and 60 women) consumed fresh ginger juice from Zingiber officinale Rosc. or sterile 0.9% sodium chloride was conducted. 16S rRNA sequencing analyses were applied to characterize gut microbiota variation. We found that ginger juice intervention increased the species number of intestinal flora. A decreased relative abundance of the Prevotella-to-Bacteroides ratio and pro-inflammatory Ruminococcus_1 and Ruminococcus_2 while a tendency toward an increased Firmicutes-to-Bacteroidetes ratio, Proteobacteria and anti-inflammatory Faecalibacterium were found. When we did not consider gender, we found differences in bacterial diversity both in community evenness and in richness caused by ginger intervention. In fact, there were different changes in bacterial α-diversity induced by the ginger juice in men and women. We identified 19 bacterial genera with significant differences between the control group (women) and ginger group (women) and 15 significant differences between the control group (men) and ginger group (men) at the genus level. Our results showed that short-term intake of ginger juice had substantial effects on the composition and function of gut microbiota in healthy people. Moreover, our findings underscored the importance of analyzing both male and female individuals to investigate the effects of ginger on gut microbiota. Additional studies are necessary to confirm these findings.
Rhizodegradation of Pyrene by a Non-pathogenic Klebsiella pneumoniae Isolate Applied With Tagetes erecta L. and Changes in the Rhizobacterial Community
Authors: Rajkumari Jina , Choudhury Yashmin , Bhattacharjee Kasturi , Pandey Piyush
Published: February 2021

The non-clinical Klebsiella pneumoniae variants, isolated from different environments, are now well acknowledged for their role in plant-growth promotion and biodegradation of pollutants. In the present study, a non-clinical environmental isolate K. pneumoniae AWD5 is being described for rhizoremediation of pyrene, applied through the rhizosphere of an ornamental plant, Tagetes erecta L (marigold). The non-pathogenic nature of AWD5 was established using an in vivo mouse model experiment, where AWD5 was unable to cause lung infection in tested mice. Degradation of pyrene, in the presence of succinate as co-substrate, was observed to be 87.5% by AWD5, after 21 days of incubation in minimal (Bushnell–Hass) medium in vitro conditions. Consequently, the bacterial inoculation through the rhizosphere of T. erecta L. plants resulted in 68.61% degradation of pyrene, which was significantly higher than control soil. Inoculation of AWD5 also improved plant growth and exhibited an increase in root length (14.64%), dry root weight (80.56%), shoot length (3.26%), and dry shoot weight (45.35%) after 60 days of incubation. T. erecta L., an ornamental plant, was also found to be suitable for bioremediation of pyrene. The effect of AWD5 application, and rhizoremediation process, on rhizosphere bacterial diversity and community structure has been studied using the metagenomic analysis of the 16S (V3–V4) region of rRNA. 37 bacterial phyla constituted the core microbiome, which was dominated by Proteobacteria followed by Actinobacteria, Actinobacteria, and Planctomycetes for all the treatments. AWD5 inoculation enhanced the relative abundance of Firmicutes and Acidobacteria as compared with other treatments. Genus Kaistobacter and Verrucomicrobia were found to be an abundant indigenous population in pyrene-spiked soils. Bacterial richness and diversity were analyzed using the Shannon–Wiener (H) index. A lower diversity index was observed in pyrene-spiked soils. Canonical correspondence analysis (CCA) showed a possible linkage with plant growth attributes and available nitrogen content that influences diversity and abundance of the bacterial community.
Toward Best Practice in Livestock Microbiota Research: A Comprehensive Comparison of Sample Storage and DNA Extraction Strategies
Authors: Wegl Gertrude , Grabner Nikolaus , Köstelbauer Andreas , Klose Viviana , Ghanbari Mahdi
Published: February 2021

Understanding the roles of microorganisms in the animal gastrointestinal microenvironment is highly important for the development of effective strategies to manage and manipulate these microbial communities. In order to guide future animal gut microbiota research projects and standardization efforts, we have conducted a systematic comparison of 10 currently used sample preservation and DNA extraction approaches for pig and chicken microbiota samples and quantified their effects on bacterial DNA yield, quality, integrity, and on the resulting sequence-based bacterial composition estimates. The results showed how key stages of conducting a microbiota study, including the sample storage and DNA extraction, can substantially affect DNA recovery from the microbial community, and therefore, biological interpretation in a matrix-dependent manner. Our results highlight the fact that the influence of storage and extraction methods on the resulting microbial community structure differed by sample type, even within the same species. As the effects of these technical steps are potentially large compared with the real biological variability to be explained, standardization is crucial for accelerating progress in the area of livestock microbiota research. This study provided a framework to assist future animal gut microbiota research projects and standardization efforts.