bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro and In Vivo Antigen Presentation and Diagnosis Development of Recombinant Overlapping Peptides Corresponding to Mtb ESAT-6/CFP-10
Authors: Zhang Qing , Lu Xiong , Gao Liang , Tao Siyu , Ge Yinghua , Cui Daocheng , Zhu Renying , Lu Wenshu , Wang Jian , Jiang Shisong
Published: June 2022

Cellular immunity in Mycobacteria tuberculosis (Mtb) infection is important for the pathogenesis and final clearance of intracellular Mtb infection. In addition, it is valuable for the diagnosis of tuberculosis. In this pioneering work, we tested in vitro and in vivo antigen presentation and diagnostic application of a recombinant overlapping peptide-protein derived from two Mtb RD1 antigens ESAT-6 and CFP-10 (ROP-TB). The overlapping peptide sequence of ROP-TB is cleaved by the cathepsin S enzyme and covers the entire length of the two proteins. ROP-TB can be expressed and purified from E. coli. Once taken in by antigen-presenting cells, ROP-TB can be cleaved into a peptide pool by cathepsin S within the cells. We found that in dendritic cells, ROP-TB can be processed in 6 hours of co-culture, while the ESAT-6/CFP-10 fusion protein remained in the endosomal compartment. In Mtb-infected mice, ROP-TB stimulated stronger specific T cell responses than pooled synthetic peptides derived from ESAT-6 and CFP-10. With regard to the presentation of in vivo antigens, in a guinea pig model infected with Mtb, ROP-TB induced delayed type hypersensitivity (DTH) responses comparable to those of the tuberculin purified protein derivative (PPD) and ESAT-6/CFP-10 fusion protein. In Mycobacterium bovis (Bovine TB)-infected cattle, ROP-TB elicited DTH responses. Finally, in Mtb infected patients, ROP-TB stimulated cellular immune responses in majority of patients (16/18) of different HLA phenotypes while a single peptide derived from the same proteins did not elicit the immune responses in all patients. In summary, in vitro and in vivo data suggest that ROP-TB stimulates a strong cellular immune response irrespective of HLA phenotypes and is therefore suitable for use in vitro and in vivo diagnostics.
The ‘Danse Macabre’—Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes
Authors: Hadjigol Sara , Shah Bansari A. , O’Brien-Simpson Neil M.
Published: June 2022

Over the past few decades, tremendous advances in the prevention, diagnosis, and treatment of cancer have taken place. However for head and neck cancers, including oral cancer, the overall survival rate is below 50% and they remain the seventh most common malignancy worldwide. These cancers are, commonly, aggressive, genetically complex, and difficult to treat and the delay, which often occurs between early recognition of symptoms and diagnosis, and the start of treatment of these cancers, is associated with poor prognosis. Cancer development and progression occurs in concert with alterations in the surrounding stroma, with the immune system being an essential element in this process. Despite neutrophils having major roles in the pathology of many diseases, they were thought to have little impact on cancer development and progression. Recent studies are now challenging this notion and placing neutrophils as central interactive players with other immune and tumor cells in affecting cancer pathology. This review focuses on how neutrophils and their sub-phenotypes, N1, N2, and myeloid-derived suppressor cells, both directly and indirectly affect the anti-tumor and pro-tumor immune responses. Emphasis is placed on what is currently known about the interaction of neutrophils with myeloid innate immune cells (such as dendritic cells and macrophages), innate lymphoid cells, natural killer cells, and fibroblasts to affect the tumor microenvironment and progression of oral cancer. A better understanding of this dialog will allow for improved therapeutics that concurrently target several components of the tumor microenvironment, increasing the possibility of constructive and positive outcomes for oral cancer patients. For this review, PubMed, Web of Science, and Google Scholar were searched for manuscripts using keywords and combinations thereof of “oral cancer, OSCC, neutrophils, TANs, MDSC, immune cells, head and neck cancer, and tumor microenvironment” with a focus on publications from 2018 to 2021.
Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products
Authors: Silva Daniela Nascimento , Chrobok Michael , Rovesti Giulia , Healy Katie , Wagner Arnika Kathleen , Maravelia Panagiota , Gatto Francesca , Mazza Massimiliano , Mazzotti Lucia , Lohmann Volker , Sällberg Chen Margaret , Sällberg Matti , Buggert Marcus , Pasetto Anna
Published: June 2022

Cellular immunotherapies based on T cell receptor (TCR) transfer are promising approaches for the treatment of cancer and chronic viral infections. The discovery of novel receptors is expanding considerably; however, the clinical development of TCR-T cell therapies still lags. Here we provide a pipeline for process development and clinical-scale manufacturing of TCR-T cells in academia. We utilized two TCRs specific for hepatitis C virus (HCV) as models because of their marked differences in avidity and functional profile in TCR-redirected cells. With our clinical-scale pipeline, we reproduced the functional profile associated with each TCR. Moreover, the two TCR-T cell products demonstrated similar yield, purity, transduction efficiency as well as phenotype. The TCR-T cell products had a highly reproducible yield of over 1.4 × 109 cells, with an average viability of 93%; 97.8–99% of cells were CD3+, of which 47.66 ± 2.02% were CD8+ T cells; the phenotype was markedly associated with central memory (CD62L+CD45RO+) for CD4+ (93.70 ± 5.23%) and CD8+ (94.26 ± 4.04%). The functional assessments in 2D and 3D cell culture assays showed that TCR-T cells mounted a polyfunctional response to the cognate HCV peptide target in tumor cell lines, including killing. Collectively, we report a solid strategy for the efficient large-scale manufacturing of TCR-T cells.
Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era
Authors: Larkin Collin J. , Arrieta Víctor A. , Najem Hinda , Li Gongbo , Zhang Peng , Miska Jason , Chen Peiwen , James Charles David , Sonabend Adam M. , Heimberger Amy B.
Published: June 2022

The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.
Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future
Authors: Saura-Esteller José , de Jong Milon , King Lisa A. , Ensing Erik , Winograd Benjamin , de Gruijl Tanja D. , Parren Paul W. H. I. , van der Vliet Hans J.
Published: June 2022

γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.
Bio-Physical Controls on Wave Transformation in Coastal Reed Beds: Insights From the Razelm-Sinoe Lagoon System, Romania
Authors: Möller Iris , Ionescu Maria Smaranda , Constantinescu Adriana Maria , Evans Ben Richard , Scrieciu Albert , Stanica Adrian , Grosu Dumitru
Published: June 2022

Coastal wetlands are dynamic bio-physical systems in which vegetation affects the movement of water and sediment, which in turn build and maintain the landform and ecosystem. Wetlands are an effective buffer against coastal erosion and flooding, enhance water quality and human health and wellbeing. Numerous field and laboratory experiments have quantified the reduction of waves by coastal ecosystems. Numerical models, however, are only able to capture observed reduction in wave energy when calibration coefficients are obtained by comparison with measured dissipation rates. A deeper understanding of how wave attenuation varies over time, with local flow conditions and ecosystem properties, is still lacking and should be acquired from a greater range of ecosystem types and geographical settings. Few studies have observed the detailed seasonal variations in how coastal wetlands function as wave buffers and how such seasonal variations might be explained. Equally, few studies have focused on the effect of coastal reed beds on wave dynamics. This study addresses both: i) seasonal variability in wave dissipation through reed vegetation and ii) intricate connections between reed vegetation and the physical context (meteorological and topographical) that might explain such variability. We present observations of wind generated wave transformation through two Phragmites australis reed beds in the Razelm-Sinoe Lagoon System, Danube Delta, Romania. We find that seasonal changes in vegetation density and biomass, as well as meteorological conditions, affect observed wave conditions within the first few meters of the reed beds. Our results also show a preferential reduction of higher frequency waves, irrespective of reed stem diameter or density and suggest the potential importance of seasonal vegetation debris to observed wave dissipation. Such complex and non-linear biogeomorphic effects on wave dissipation are not currently well understood or captured in the parameterisation of vegetation-induced wave dissipation. Our study highlights the importance of an accurate and temporally granular quantification of nearshore bathymetry, wetland topography, and vegetation to fully understand, model, and manage bio-physical interactions in coastal wetlands. More specifically, our results point towards the need for spatially and temporally explicit wave decay functions in emergent reed vegetation. This is particularly critical where the accurate evaluation of the flood and erosion risk contribution of any wetland is required as part of nature-based coastal protection solutions.
Setting Performance Indicators for Coastal Marine Protected Areas: An Expert-Based Methodology
Authors: Cardoso-Andrade Mariana , Queiroga Henrique , Rangel Mafalda , Sousa Inês , Belackova Adela , Bentes Luís , Oliveira Frederico , Monteiro Pedro , Sales Henriques Nuno , Afonso Carlos M. L. , Silva Ana F. , Quintella Bernardo R. , Costa José L. , Pais Miguel P. , Henriques Sofia , Batista Marisa I. , Franco Gustavo , Gonçalves Emanuel J. , Henriques Miguel , Leonardo Teresa , Coelho Paula , Comas-González Robert , Fernández Laura P. , Quiles-Pons Carla , Costa André , Espírito-Santo Cristina , Castro João J. , Arenas Francisco , Ramos Sandra , Ferreira Vasco , Gonçalves Jorge M. S. , Horta e Costa Bárbara
Published: June 2022

Marine Protected Areas (MPAs) require effective indicators to assess their performance, in compliance with the goals of relevant national and international commitments. Achieving and prioritizing shortlists of multidisciplinary indicators demands a significant effort from specialists to depict the multiple conservation and socioeconomic interests, and the large complexity of natural systems. The present paper describes a structured expert-based methodology (process and outputs) to co-define a list of multidisciplinary MPA performance indicators. This work was promoted by the management authority of coastal MPAs in mainland Portugal to gather a consensual and feasible list of indicators that would guide the design of a future national monitoring program. Hence, Portuguese coastal MPAs served as a case study to develop such a process between 2019 and 2020. In the end, participants (1) agreed on a shortlist of prioritized indicators (i.e., environmental, governance, and socioeconomic indicators) and (2) defined minimum monitoring frequencies for the indicators in this list, compatible with the potential replicability of the associated survey methods. The present approach recommends that management plans incorporate monitoring procedures and survey methods, with a validated list of indicators and associated monitoring periodicity, agreed among researchers, MPA managers and governance experts. The proposed methodology, and the lessons learned from it, can support future processes aiming to define and prioritize MPA performance indicators.
Seasonal Enzyme Activities of Sympatric Calanus glacialis and C. finmarchicus in the High-Arctic
Authors: Hatlebakk Maja , Niehoff Barbara , Choquet Marvin , Hop Haakon , Wold Anette , Hoarau Galice , Søreide Janne E.
Published: June 2022

In the Arctic shelf seas, the mesozooplankton biomass is dominated by the arctic copepod Calanus glacialis, but its boreal congeneric C. finmarchicus is expanding northwards. Even though it is already there, C. finmarchicus may not be able to truly establish itself in the Arctic seas and potentially replace C. glacialis. We compared metabolic and digestive enzyme activities of sympatric C. glacialis and C. finmarchicus from Isfjorden, Svalbard and off-shelf north of Svalbard. The seasonal regulation of anabolic and catabolic enzyme activities was generally similar for the two species, but with some interspecific differences corresponding to their ontogeny. Wake-up from overwintering started earlier in adults of C. glacialis than in C. finmarchicus, while the onset of dormancy started early in the overwintering stages of both species. Furthermore, C. glacialis showed an earlier and higher mobilization of lipase enzyme activities, indicating higher efficiency in assimilating dietary lipids compared to C. finmarchicus. Similar population sizes and population structures for C. finmarchicus off-shelf north of Svalbard and in Isfjorden support a similar origin. Still, C. finmarchicus was able to match regulation of enzyme activities to the bloom even though the bloom peaked approximately a month later off-shelf north of Svalbard, indicating that food availability is an important signal for the final step of termination of diapause. Even though the two species largely follow the same patterns of metabolic enzyme activities, the more efficient lipid anabolism of C. glacialis may give it an advantage over C. finmarchicus in high-Arctic unpredictable environments with short-pulsed primary production regimes.
Effects of Spartina alterniflora Invasion on Soil Organic Carbon Storage in the Beihai Coastal Wetlands of China
Authors: Huang Xing , Duan Yitao , Tao Yuhua , Wang Xueping , Long Haili , Luo Changsheng , Lai Yufei
Published: June 2022

The invasion of Spartina alterniflora (S. alterniflora) has changed the carbon cycle process of local ecosystems. In order to clarify the effect of S. alterniflora invasion on coastal soil carbon pool in Northern Beibu Gulf, the distribution characteristics and influencing factors of soil organic carbon (SOC) and SOC storage (SOCS) at different intrusion stages were investigated and analyzed. The results showed that the SOC content in S. alterniflora wetlands (2.65–21.54 g/kg) was higher than that in mudflats (0.85–1.19 g/kg). SOC content in 0–20 cm depth was highest than that in 20–40 cm and 40–60 cm depth. The total SOCS increased by 72.11%, 78.45%, 77.56%, 80.42%, and 90.63% in 3a, 12a, 15a, 16–19a, and 26a compared with mudflats, respectively. S. alterniflora invasion increased SOC and SOCS both in surface soil and deep soil. SOCS increased rapidly during the initial stage of invasion, and remained in a relatively stable and continuous growth state after 12–15 years. The distributions and accumulation of SOC and SOCS were affected mainly by soil texture, soil bulk density, moisture content, total nitrogen and total phosphorus. The source of SOC from S. alterniflora was increasing with invasion ages and would be mainly input in 26a, while marine sources was mainly imported in other invasion ages. Our data indicated that S. alterniflora continuously enhances the SOC sequestration over the years in coastal wetland ecosystems.
A Prediction Model of Significant Wave Height in the South China Sea Based on Attention Mechanism
Authors: Hao Peng , Li Shuang , Yu Chengcheng , Wu Gengkun
Published: June 2022

Significant wave height (SWH) prediction plays an important role in marine engineering fields such as fishery, exploration, power generation, and ocean transportation. Traditional SWH prediction methods based on numerical models cannot achieve high accuracy. In addition, the current SWH prediction methods are largely limited to single-point SWH prediction, without considering regional SWH prediction. In order to explore a new SWH prediction method, this paper proposes a deep neural network model for regional SWH prediction based on the attention mechanism, namely CBA-Net. In this study, the wind and wave height of the ERA5 data set in the South China Sea from 2011 to 2018 were used as input features to train the model to evaluate the SWH prediction performance at 1 h, 12 h, and 24 h. The results show that the single use of a convolutional neural network cannot accurately predict SWH. After adding the Bi-LSTM layer and attention mechanism, the prediction of SWH is greatly improved. In the 1 h SWH prediction using CBA-Net, SARMSE, SAMAPE, SACC are 0.299, 0.136, 0.971 respectively. Compared with the CNN + Bi-LSTM method that does not use the attention mechanism, SARMSE and SAMAPE are reduced by 43.4% and 48.7%, respectively, while SACC is increased by 5%. In the 12 h SWH prediction, SARMSE, SAMAPE, and SACC of CBA-Net are 0.379, 0.177, 0.954 respectively. In the 24 h SWH prediction, SARMSE, SAMAPE, and SACC of CBA-Net are 0.500, 0.236, 0.912 respectively. Although with the increase of prediction time, the performance is slightly lower than that of 12 h, the prediction error is still maintained at a small level, which is still better than other methods.
The Landscape of DNA Methylation Generates Insight Into Epigenetic Regulation of Differences Between Slow-Twitch and Fast-Twitch Muscles in Pseudocaranx dentex
Authors: Li Busu , Wang Huan , Li Ang , An Changting , Zhu Ling , Liu Shufang , Zhuang Zhimeng
Published: June 2022

Skeletal muscles of teleost are mainly composed of slow-twitch muscles (SM) and fast-twitch muscles (FM) differed in contractile properties, metabolic capacities, and regeneration rate. The transcriptional regulatory mechanisms that control different muscle types have been elucidated in teleost according to transcriptome between SM and FM. However, the differences between SM and FM were affected not only by genotype but also by complicated epigenetic effects, including DNA methylation, which usually regulates genes in transcription level. To determine the essential role of DNA methylation in the regulation of different muscle types, we analyzed whole-genome methylation profiles of pelagic migratory fish Pseudocaranx dentex with abundant and well-separated SM and integrated DNA methylation profiles with the previously obtained transcriptome data. A total of 4,217 differentially methylated genes (DMGs) were identified, of which 3,582 were located in the gene body and 635 in the promoter. These DMGs mainly participated in muscle metabolite and cell junction. Enriched cell junction pathway reflected different capillary distribution between SM and FM. Through comprehensive analysis of methylome and transcriptome, 84 differentially expressed genes (DEGs) showed significant methylation variation in promoters between SM and FM, indicating that their expression was regulated by DNA methylation. Hypomethylated and highly expressed oxygen storage protein Myoglobin (myg) in SM indicated demethylation of myg promoter could upregulate its expression, thus increasing O2 supplying and meeting oxygen demands of SM. Hypermethylated and lowly expressed tnn (Troponin) and rlc (myosin regulatory light chain) in SM may be associated with low mobility of myosin cross bridges, which lead to slower and less frequent muscle contraction in SM than in FM. In addition, hypomethylated and highly expressed lbx1 (Ladybird homeobox protein homolog 1) and epo (erythropoietin) may be related to increased satellite cell numbers, and Semaphorin/Plexin genes may be related to higher rate of neuromuscular connection reconstruction, which further promote high muscle regeneration efficiency in SM. Our study elucidated the potential DNA methylation mechanisms that regulate physiological characteristics differences between SM and FM, which could facilitate our understanding of skeletal muscle adaptation in pelagic migratory fishes and further enrich the theoretical basis for the study of physiological characteristics and adaptive evolution in teleost fishes.
Circulating Polyunsaturated Fatty Acids and COVID-19: A Prospective Cohort Study and Mendelian Randomization Analysis
Authors: Sun Yitang , Chatterjee Radhika , Ronanki Akash , Ye Kaixiong
Published: June 2022

Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline (blood samples collected from 2007 to 2010) were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19.
CryoEM Reveals the Complexity and Diversity of ATP Synthases
Authors: Courbon Gautier M. , Rubinstein John L.
Published: June 2022

During respiration, adenosine triphosphate (ATP) synthases harness the electrochemical proton motive force (PMF) generated by the electron transport chain (ETC) to synthesize ATP. These macromolecular machines operate by a remarkable rotary catalytic mechanism that couples transmembrane proton translocation to rotation of a rotor subcomplex, and rotation to ATP synthesis. Initially, x-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and cross-linking were the only ways to gain insights into the three-dimensional (3D) structures of ATP synthases and, in particular, provided ground-breaking insights into the soluble parts of the complex that explained the catalytic mechanism by which rotation is coupled to ATP synthesis. In contrast, early electron microscopy was limited to studying the overall shape of the assembly. However, advances in electron cryomicroscopy (cryoEM) have allowed determination of high-resolution structures, including the membrane regions of ATP synthases. These studies revealed the high-resolution structures of the remaining ATP synthase subunits and showed how these subunits work together in the intact macromolecular machine. CryoEM continues to uncover the diversity of ATP synthase structures across species and has begun to show how ATP synthases can be targeted by therapies to treat human diseases.
Bacterial Enoyl-Reductases: The Ever-Growing List of Fabs, Their Mechanisms and Inhibition
Authors: Hopf Fernanda S. M. , Roth Candida D. , de Souza Eduardo V. , Galina Luiza , Czeczot Alexia M. , Machado Pablo , Basso Luiz A. , Bizarro Cristiano V.
Published: June 2022

Enoyl-ACP reductases (ENRs) are enzymes that catalyze the last step of the elongation cycle during fatty acid synthesis. In recent years, new bacterial ENR types were discovered, some of them with structures and mechanisms that differ from the canonical bacterial FabI enzymes. Here, we briefly review the diversity of structural and catalytic properties of the canonical FabI and the new FabK, FabV, FabL, and novel ENRs identified in a soil metagenome study. We also highlight recent efforts to use the newly discovered Fabs as targets for drug development and consider the complex evolutionary history of this diverse set of bacterial ENRs.
Characterization of Aspergillus terreus Accessory Conidia and Their Interactions With Murine Macrophages
Authors: Henß Isabell , Kleinemeier Christoph , Strobel Lea , Brock Matthias , Löffler Jürgen , Ebel Frank
Published: June 2022

All Aspergillus species form phialidic conidia (PC) when the mycelium is in contact with the air. These small, asexual spores are ideally suited for an airborne dissemination in the environment. Aspergillus terreus and a few closely related species from section Terrei can additionally generate accessory conidia (AC) that directly emerge from the hyphal surface. In this study, we have identified galactomannan as a major surface antigen on AC that is largely absent from the surface of PC. Galactomannan is homogeneously distributed over the entire surface of AC and even detectable on nascent AC present on the hyphal surface. In contrast, β-glucans are only accessible in distinct structures that occur after separation of the conidia from the hyphal surface. During germination, AC show a very limited isotropic growth that has no detectable impact on the distribution of galactomannan. The AC of the strain used in this study germinate much faster than the corresponding PC, and they are more sensitive to desiccation than PC. During infection of murine J774 macrophages, AC are readily engulfed and trigger a strong tumor necrosis factor-alpha (TNFα) response. Both processes are not hampered by the presence of laminarin, which indicates that β-glucans only play a minor role in these interactions. In the phagosome, we observed that galactomannan, but not β-glucan, is released from the conidial surface and translocates to the host cell cytoplasm. AC persist in phagolysosomes, and many of them initiate germination within 24 h. In conclusion, we have identified galactomannan as a novel and major antigen on AC that clearly distinguishes them from PC. The role of this fungal-specific carbohydrate in the interactions with the immune system remains an open issue that needs to be addressed in future research.
Revealing Probiotic Potential of Enterococcus Strains Isolated From Traditionally Fermented Chhurpi and Healthy Human Gut
Authors: Ghatani Kriti , Thapa Subarna , Sha Shankar Prasad , Sarkar Sourav , Modak Debabrata , Bhattacharjee Soumen
Published: June 2022

In this study, the two lactic acid bacterial strains Enterococcus durans and Enterococcus lactis previously isolated from soft chhurpi, a traditionally fermented milk product prepared by the indigenous community of Sikkim Himalayas and healthy human gut were used. In this study, we attempted to investigate the probiotic attributes, safety, and health beneficial role, and hypercholesterolemia of Enterococcus durans and Enterococcus lactis. Both probiotic potential strains showed good hypocholesterolemic activity in vitro along with tolerance to acid pH (2 and 2.5), tolerance to three bile salts, oxbile, cholic acid, and taurocholic acid (0.5 and 1%), presence of BSH enzyme and its activity, and cell surface adherence. On assessing for safety, both LAB strains were sensitive to antibiotics and exhibited no hemolytic activity. The probiotic strains were tested in vivo in the Sprague–Dawley rats which were divided into five experimental groups: Normal Control (ND), probiotic strain Enterococcus durans HS03 (BSH-negative) and high-cholesterol diet (HCD1), probiotic strain Enterococcus lactis YY1 (BSH-positive) and high-cholesterol diet (HCD2), and a combination of both strains and high-cholesterol diet (HCD3) and Negative Control (HCD). The probiotic-treated groups HCD1, HCD2, and HCD3 showed a decrease in serum cholesterol levels up to 22.55, 6.67, and 31.06%; the TG and VLDL concentrations were 25.39, 26.3, and 33.21%; reduction in LDL-cholesterol was 33.66, 28.50, and 35.87%; and increase of HDL was 38.32, 47.9, and 41.92%. Similarly, the effects of total cholesterol and TG in the liver, kidney and liver histopathology, liver and body lipid index, and oxidative stress in rat liver were also studied. The fecal lactobacilli were more in the samples of the probiotic-treated groups and their fecal coliform and E. coli counts decreased relatively as compared to the control groups in 0, 7, 14, and 21 days. This is the first report on the probiotic potential of Enterococcus durans HS03 and Enterococcus lactis YY1 strains that gives a new insight into the cholesterol-lowering and probiotic product development with wide health attributes.
Changes in the Soil Fungal Community Mediated by a Peganum harmala Allelochemical
Authors: Shi Kai , Shao Hua
Published: June 2022

Plants can release phytotoxic allelochemicals into the environment, not only to suppress other plants’ growth, but also alter community structure of soil microbiota, however, the mechanism are often complicated. We designed a consecutive cultivation procedure to evaluate the allelopathic effect of harmaline, the major active allelochemical produced by the desert plant Peganum harmala, on soil microorganisms. Harmaline was added to the soil at 20 μg/g, and after five generations of cultivation, the Chao1, Pielou, Shannon and Simpon indexes changed significantly. In particular, the relative abundances of the dominant fungi, Alternaria sp. and Fusarium sp., declined drastically by 84.90 and 91.90%, respectively. Further in vitro bioassays confirmed that harmaline indeed suppressed growth of 6 Alternaria and Fusarium strains isolated from P. harmala rhizosphere soil. We thus suspect that P. harmala might produce harmaline as an effective carry-on pesticide to defend against general pathogens such as Alternaria sp. and Fusarium sp. and favor itself. Our consecutive cultivation procedure has successfully magnified the core signals from the chaotic data, implying that it can be applied to measure the effects of other allelochemicals on soil microbiota.
Microbiome Impact on Amyloidogenesis
Authors: Seira Curto Jofre , Surroca Lopez Amat , Casals Sanchez Maria , Tic Iva , Fernandez Gallegos Maria Rosario , Sanchez de Groot Natalia
Published: June 2022

Our life is closely linked to microorganisms, either through a parasitic or symbiotic relationship. The microbiome contains more than 1,000 different bacterial species and outnumbers human genes by 150 times. Worryingly, during the last 10 years, it has been observed a relationship between alterations in microbiota and neurodegeneration. Several publications support the hypothesis that amyloid structures formed by microorganisms may trigger host proteins aggregation. In this review, we collect pieces of evidence supporting that the crosstalk between human and microbiota amyloid proteins could be feasible and, probably, a more common event than expected before. The combination of their outnumbers, the long periods of time that stay in our bodies, and the widespread presence of amyloid proteins in the bacteria Domain outline a worrying scenario. However, the identification of the exact microorganisms and the mechanisms through with they can influence human disease also opens the door to developing a new and diverse set of therapeutic strategies.
Exploration of Mutated Genes and Prediction of Potential Biomarkers for Childhood-Onset Schizophrenia Using an Integrated Bioinformatic Analysis
Authors: He Fan , Zhou Yu-ming , Qi Yan-jie , Huang Huan-huan , Guan Lin , Luo Jie , Cheng Yu-hang , Zheng Yi
Published: June 2022

Childhood-onset schizophrenia (COS) is an unusual severe neurodevelopmental disorder of unknown etiology. In this study, we aimed to survey the missense variants in new cases of COS and also identify possible pathology biomarkers for COS. We found one list of mutated genes such as TTN, MUC12, and MUC2, which are the candidates to be involved in the etiology of COS. Next, we used WGSNA to predict COS disease-related genes and identified differential DNA methylation among COS disease groups, COS dangerous groups, and normal groups and found eight methylation sites that can be used as the diagnostic biomarkers. A total of six key genes are obtained through the intersection analysis between weighted correlation network analysis (WGCNA) mode, methylation-related genes, and differentially expressed genes (DGenes). These genes may play important roles in the progression of COS and serve as the potential biomarkers for future diagnosis. Our results might help to design the molecule or gene-targeted drugs for COS.
Retinal Aging in 3× Tg-AD Mice Model of Alzheimer's Disease
Authors: Guimarães Pedro , Serranho Pedro , Martins João , Moreira Paula I. , Ambrósio António Francisco , Castelo-Branco Miguel , Bernardes Rui
Published: June 2022

The retina, as part of the central nervous system (CNS), can be the perfect target for in vivo, in situ, and noninvasive neuropathology diagnosis and assessment of therapeutic efficacy. It has long been established that several age-related brain changes are more pronounced in Alzheimer's disease (AD). Nevertheless, in the retina such link is still under-explored. This study investigates the differences in the aging of the CNS through the retina of 3× Tg-AD and wild-type mice. A dedicated optical coherence tomograph imaged mice's retinas for 16 months. Two neural networks were developed to model independently each group's ages and were then applied to an independent set containing images from both groups. Our analysis shows a mean absolute error of 0.875±1.1 × 10−2 and 1.112±1.4 × 10−2 months, depending on training group. Our deep learning approach appears to be a reliable retinal OCT aging marker. We show that retina aging is distinct in the two classes: the presence of the three mutated human genes in the mouse genome has an impact on the aging of the retina. For mice over 4 months-old, transgenic mice consistently present a negative retina age-gap when compared to wild-type mice, regardless of training set. This appears to contradict AD observations in the brain. However, the ‘black-box” nature of deep-learning implies that one cannot infer reasoning. We can only speculate that some healthy age-dependent neural adaptations may be altered in transgenic animals.
Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?
Authors: Sun Yuanjie , Koyama Yoshihisa , Shimada Shoichi
Published: June 2022

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.
Comparative Severity Assessment of Genetic, Stress-Based, and Pharmacological Mouse Models of Depression
Authors: Mallien Anne Stephanie , Pfeiffer Natascha , Brandwein Christiane , Inta Dragos , Sprengel Rolf , Palme Rupert , Talbot Steven R. , Gass Peter
Published: June 2022

The use of animals in neurosciences is pivotal to gaining insights into complex functions and dysfunctions of behavior. For example, various forms of physical and/or psychological stress are inherent to various animal models for psychiatric disorders, e.g., depression. Regarding animal welfare, it would be mandatory to use models that inflict the least amount of stress necessary to address the underlying scientific question. This study compared the severity of different approaches to induce depression in mice: mutagenesis in GluA1 knockout, immobilization stress, and stress-induction via stress hormone treatment. While genetic alterations potentially represent a lifelong burden, the temporary intervention only affects the animals for a limited time. Therefore, we used home cage-based behavioral and physiological parameters, including nest building, burrowing, body weight, and fecal corticosterone metabolites, to determine the well-being of male and female mice. In addition, we performed an evidence-based estimate of severity using a composite score for relative severity assessment (RELSA) with this data. We found that even though restraint stress and supplementation of corticosterone in the diet both aimed at depression-related precipitating stress effects, the latter affected the well-being much stronger, especially in females. Restraint leads to less noticeable well-being impairments but causes depression-associated anhedonic behavior. Mice of both sexes recovered well from the stress treatment. GluA1 KO and their littermates showed diminished well-being, comparable to the immobilization experiments. However, since this is a lifelong condition, this burden is not reversible and potentially accumulative. In line with the 3Rs (Replacement, Reduction, and Refinement), the process of choosing the most suitable model should ideally include an evidence-based severity assessment to be able to opt for the least severe alternative, which still induces the desired effect. Promoting refinement, in our study, this would be the restraint stress.
Blood–Brain Barrier Dysfunction and the Potential Mechanisms in Chronic Cerebral Hypoperfusion Induced Cognitive Impairment
Authors: Xu WenQing , Bai Qingke , Dong Qiang , Guo Min , Cui Mei
Published: June 2022

Chronic cerebral hypoperfusion (CCH) is a major cause of vascular cognitive impairment and dementia (VCID). Although the underlying mechanisms have not been fully elucidated, the emerging data suggest that blood–brain barrier (BBB) dysfunction is one of the pivotal pathological changes in CCH. BBB dysfunction appears early in CCH, contributing to the deterioration of white matter and the development of cognitive impairment. In this review, we summarize the latest experimental and clinical evidence implicating BBB disruption as a major cause of VCID. We discuss the mechanisms of BBB dysfunction in CCH, focusing on the cell interactions within the BBB, as well as the potential role of APOE genotype. In summary, we provide novel insights into the pathophysiological mechanisms underlying BBB dysfunction and the potential clinical benefits of therapeutic interventions targeting BBB in CCH.
PKAN hiPS-Derived Astrocytes Show Impairment of Endosomal Trafficking: A Potential Mechanism Underlying Iron Accumulation
Authors: Ripamonti Maddalena , Santambrogio Paolo , Racchetti Gabriella , Cozzi Anna , Di Meo Ivano , Tiranti Valeria , Levi Sonia
Published: June 2022

PKAN disease is caused by mutations in the PANK2 gene, encoding the mitochondrial enzyme pantothenate kinase 2, catalyzing the first and key reaction in Coenzyme A (CoA) biosynthetic process. This disorder is characterized by progressive neurodegeneration and excessive iron deposition in the brain. The pathogenic mechanisms of PKAN are still unclear, and the available therapies are only symptomatic. Although iron accumulation is a hallmark of PKAN, its relationship with CoA dysfunction is not clear. We have previously developed hiPS-derived astrocytes from PKAN patients showing iron overload, thus recapitulating the human phenotype. In this work, we demonstrated that PKAN astrocytes presented an increase in transferrin uptake, a key route for cellular iron intake via transferrin receptor-mediated endocytosis of transferrin-bound iron. Investigation of constitutive exo-endocytosis and vesicular dynamics, exploiting the activity-enriching biosensor SynaptoZip, led to the finding of a general impairment in the constitutive endosomal trafficking in PKAN astrocytes. CoA and 4-phenylbutyric acid treatments were found to be effective in partially rescuing the aberrant vesicular behavior and iron intake. Our results demonstrate that the impairment of CoA biosynthesis could interfere with pivotal intracellular mechanisms involved in membrane fusions and vesicular trafficking, leading to an aberrant transferrin receptor-mediated iron uptake.
Case Report: Alzheimer's Dementia Associated With Cerebrospinal Fluid Neurochondrin Autoantibodies
Authors: Hansen Niels , Malchow Berend , Teegen Bianca , Wiltfang Jens , Bartels Claudia
Published: June 2022

Background

Neurochondrin autoimmunity is a rare disorder mainly associated with cerebellar and vestibular syndromes. Our report aims to enlarge its phenotypic spectrum to encompass major cognitive disorder with very late onset never before reported in conjunction with neurochondrin antibodies.

Methods

We describe the case of an 85-year-old woman who presented in our memory clinic. Retrospective analysis of patient records included cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), and neuropsychological testing using the CERAD-plus.

Results

Because of her unknown onset of progressive cognitive dysfunction in conjunction with speech and language problems, we decided to take an extensive differential diagnostic approach including a search for neural autoantibodies potentially involved in cognitive impairment. Our patient presented serum and CSF neurochondrin autoantibodies. Further CSF analysis revealed elevated tau and ptau 181 protein as well as a reduced Aß42/40 ratio in CSF, thus matching a biomarker profile of Alzheimer's disease (AD). Neuropsychological tests revealed predominant and severe deficits in verbal and visual memory. Her MRI showed reduced parietal and cerebellar brain volume.

Discussion

Taken together, this case reveals the novelty of a patient with a CSF-based and typical clinical and imaging profile of AD. She is also likely to have neurochondrin autoimmunity, as we detected neurochondrin autoantibodies in her CSF; we therefore diagnosed AD dementia associated with neurochondrin antibodies. Our case expands the spectrum of neurochondrin autoimmunity to disorders involving major cognitive disorder such as AD dementia. Furthermore, we speculate that neurochondrin autoimmunity might have triggered an acceleration of AD symptoms as its onset was reported only after a short 6-month interval via a synergistic or negatively additive hybrid mechanism of action between neurodegeneration and autoimmunity.
Study Design and Protocol of a Randomized Controlled Trial of the Efficacy of a Smartphone-Based Therapy of Migraine (SMARTGEM)
Authors: Oliveira Gonçalves Ana Sofia , Laumeier Inga , Hofacker Maxi Dana , Raffaelli Bianca , Burow Philipp , Dahlem Markus A. , Heintz Simon , Jürgens Tim Patrick , Naegel Steffen , Rimmele Florian , Scholler Simon , Kurth Tobias , Reuter Uwe , Neeb Lars
Published: June 2022

Background

Digitalization and electronic health (eHealth) offer new treatment approaches for patients with migraine. Current smartphone applications (apps) for migraine patients include a wide spectrum of functions ranging from digital headache diaries to app-based headache treatment by, among others, analysis of the possible triggers, behavioral therapy approaches and prophylactic non-drug treatment methods with relaxation therapy or endurance sport. Additional possibilities arise through the use of modern, location-independent communication methods, such as online consultations. However, there is currently insufficient evidence regarding the benefits and/or risks of these electronic tools for patients. To date, only few randomized controlled trials have assessed eHealth applications.

Methods

SMARTGEM is a randomized controlled trial assessing whether the provision of a new digital integrated form of care consisting of the migraine app M-sense in combination with a communication platform (with online consultations and medically moderated patient forum) leads to a reduction in headache frequency in migraine patients, improving quality of life, reducing medical costs and work absenteeism (DRKS-ID: DRKS00016328).

Discussion

SMARTGEM constitutes a new integrated approach for migraine treatment, which aims to offer an effective, location-independent, time-saving and cost-saving treatment. The design of the study is an example of how to gather high quality evidence in eHealth. Results are expected to provide insightful information on the efficacy of the use of electronic health technology in improving the quality of life in patients suffering from migraine and reducing resource consumption.