bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Septoria Nodorum Blotch (SNB) Resistance in Glumes of Wheat (Triticum aestivum L.) and the Genetic Relationship With Foliar Disease Response
Authors: Francki Michael G. , Walker Esther , McMullan Christopher J. , Morris W. George
Published: June 2021

Septoria nodorum blotch (SNB) is a necrotrophic disease of wheat prominent in some parts of the world, including Western Australia (WA) causing significant losses in grain yield. The genetic mechanisms for resistance are complex involving multiple quantitative trait loci. In order to decipher comparable or independent regulation, this study identified the genetic control for glume compared to foliar resistance across four environments in WA against 37 different isolates. High proportion of the phenotypic variation across environments was contributed by genotype (84.0% for glume response and 82.7% for foliar response) with genotype-by-environment interactions accounting for a proportion of the variation for both glume and foliar response (14.7 and 16.2%, respectively). Despite high phenotypic correlation across environments, most of the eight and 14 QTL detected for glume and foliar resistance using genome wide association analysis (GWAS), respectively, were identified as environment-specific. QTL for glume and foliar resistance neither co-located nor were in LD in any particular environment indicating autonomous genetic mechanisms control SNB response in adult plants, regulated by independent biological mechanisms and influenced by significant genotype-by- environment interactions. Known Snn and Tsn loci and QTL were compared with 22 environment-specific QTL. None of the eight QTL for glume or the 14 for foliar response were co-located or in linkage disequilibrium with Snn and only one foliar QTL was in LD with Tsn loci on the physical map. Therefore, glume and foliar response to SNB in wheat is regulated by multiple environment-specific loci which function independently, with limited influence of known NE-Snn interactions for disease progression in Western Australian environments. Breeding for stable resistance would consequently rely on recurrent phenotypic selection to capture and retain favorable alleles for both glume and foliar resistance relevant to a particular environment.
Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions
Authors: Robinson Natassia , Bergen Sarah E.
Published: June 2021

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic and environmental factors. It is well-established that they are highly heritable disorders, and considerable progress has been made identifying their shared and distinct genetic risk factors. However, the 15–40% of risk that is derived from environmental sources is less definitively known. Environmental factors that have been repeatedly investigated and often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, and cannabis use. There is evidence that childhood adversity and some types of infections are also associated with BD. Evidence for other risk factors in BD is weaker due to fewer studies and often smaller sample sizes. Relatively few environmental exposures have ever been examined for SZ or BD, and additional ones likely remain to be discovered. A complete picture of how genetic and environmental risk factors confer risk for these disorders requires an understanding of how they interact. Early gene-by-environment interaction studies for both SZ and BD often involved candidate genes and were underpowered. Larger samples with genome-wide data and polygenic risk scores now offer enhanced prospects to reveal genetic interactions with environmental exposures that contribute to risk for these disorders. Overall, although some environmental risk factors have been identified for SZ, few have been for BD, and the extent to which these account for the total risk from environmental sources remains unknown. For both disorders, interactions between genetic and environmental risk factors are also not well understood and merit further investigation. Questions remain regarding the mechanisms by which risk factors exert their effects, and the ways in which environmental factors differ by sex. Concurrent investigations of environmental and genetic risk factors in SZ and BD are needed as we work toward a more comprehensive understanding of the ways in which these disorders arise.
Integrative Analysis of Human Macrophage Inflammatory Response Related to Mycobacterium tuberculosis Virulence
Authors: Bade Pauline , Simonetti Fabrizio , Sans Stephanie , Laboudie Patricia , Kissane Khadija , Chappat Nicolas , Lagrange Sophie , Apparailly Florence , Roubert Christine , Duroux-Richard Isabelle
Published: June 2021

Mycobacterium tuberculosis(Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. The ability of Mtb to hinder phagolysosome maturation and acidification, and to escape the phagosome into the cytosol, is closely linked to its virulence. The modulation of the host inflammatory response relies on Mtb virulence factors, but remains poorly studied. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence. Using human macrophages infected with two different live strains of mycobacteria (live or heat-inactivated Mtb H37Rv andM. marinum), we quantified and analyzed 184 inflammatory mRNAs and 765 micro(mi)RNAs. Transcripts and miRNAs differently modulated by H37Rv in comparison with the two other conditions were analyzed using in silico approaches. We identified 30 host inflammatory response genes and 37 miRNAs specific for H37Rv virulence, and highlight evidence suggesting that Mtb intracellular-linked virulence depends on the inhibition of IL-1β-dependent pro-inflammatory response, the repression of apoptosis and the delay of the recruitment and activation of adaptive immune cells. Our findings provide new potential targets for the development of macrophage-based therapeutic strategies against TB.
Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy
Authors: Renaude Elodie , Kroemer Marie , Borg Christophe , Peixoto Paul , Hervouet Eric , Loyon Romain , Adotévi Olivier
Published: June 2021

Evidences highlight the role of various CD4+ helper T cells (CD4+ Th) subpopulations in orchestrating the immune responses against cancers. Epigenetics takes an important part in the regulation of CD4+ Th polarization and plasticity. In this review, we described the epigenetic factors that govern CD4+ T cells differentiation and recruitment in the tumor microenvironment and their subsequent involvement in the antitumor immunity. Finally, we discussed how to manipulate tumor reactive CD4+ Th responses by epigenetic drugs to improve anticancer immunotherapy.
CD206 Expression in Induced Microglia-Like Cells From Peripheral Blood as a Surrogate Biomarker for the Specific Immune Microenvironment of Neurosurgical Diseases Including Glioma
Authors: Tanaka Shunya , Ohgidani Masahiro , Hata Nobuhiro , Inamine Shogo , Sagata Noriaki , Shirouzu Noritoshi , Mukae Nobutaka , Suzuki Satoshi O. , Hamasaki Hideomi , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Takigawa Kosuke , Funakoshi Yusuke , Iwaki Toru , Hosoi Masako , Iihara Koji , Mizoguchi Masahiro , Kato Takahiro A.
Published: June 2021

Targeting the unique glioma immune microenvironment is a promising approach in developing breakthrough immunotherapy treatments. However, recent advances in immunotherapy, including the development of immune checkpoint inhibitors, have not improved the outcomes of patients with glioma. A way of monitoring biological activity of immune cells in neural tissues affected by glioma should be developed to address this lack of sensitivity to immunotherapy. Thus, in this study, we sought to examine the feasibility of non-invasive monitoring of glioma-associated microglia/macrophages (GAM) by utilizing our previously developed induced microglia-like (iMG) cells. Primary microglia (pMG) were isolated from surgically obtained brain tissues of 22 patients with neurological diseases. iMG cells were produced from monocytes extracted from the patients’ peripheral blood. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant correlation of the expression levels of representative markers for M1 and M2 microglia phenotypes between pMG and the corresponding iMG cells in each patient (Spearman’s correlation coefficient = 0.5225, P <0.0001). Synchronous upregulation of CD206 expression levels was observed in most patients with glioma (6/9, 66.7%) and almost all patients with glioblastoma (4/5, 80%). Therefore, iMG cells can be used as a minimally invasive tool for monitoring the disease-related immunological state of GAM in various brain diseases, including glioma. CD206 upregulation detected in iMG cells can be used as a surrogate biomarker of glioma.
T Cell Specificity: A Great Challenge in Chagas Disease
Authors: Ferragut Fátima , Acevedo Gonzalo R. , Gómez Karina A.
Published: June 2021

The CD4+and CD8+T cell immune response againstT. cruzi, the parasite causing Chagas disease, are relevant for both parasite control and disease pathogenesis. Several studies have been focused on their phenotype and functionally, but only a few have drilled down to identify the parasite proteins that are processed and presented to these cells, especially to CD4+T lymphocytes. Although approximately 10,000 proteins are encoded per haploidT. cruzigenome, fewer than 200 T cell epitopes from 49T. cruziproteins have been identified so far. In this context, a detailed knowledge of the specific targets of T cell memory response emerges as a prime tool for the conceptualization and development of prophylactic or therapeutic vaccines, an approach with great potential to prevent and treat this chronic disease. Here, we review the available information about this topic in a comprehensive manner and discuss the future challenges in the field.
Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design
Authors: Ellis Daniel , Brunette Natalie , Crawford Katharine H. D. , Walls Alexandra C. , Pham Minh N. , Chen Chengbo , Herpoldt Karla-Luise , Fiala Brooke , Murphy Michael , Pettie Deleah , Kraft John C. , Malone Keara D. , Navarro Mary Jane , Ogohara Cassandra , Kepl Elizabeth , Ravichandran Rashmi , Sydeman Claire , Ahlrichs Maggie , Johnson Max , Blackstone Alyssa , Carter Lauren , Starr Tyler N. , Greaney Allison J. , Lee Kelly K. , Veesler David , Bloom Jesse D. , King Neil P.
Published: June 2021

The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.
Seasonal Changes in the Drivers of Water Physico-Chemistry Variability of a Small Freshwater Tidal River
Authors: Indivero Julia , Myers-Pigg Allison N. , Ward Nicholas D.
Published: June 2021

Where rivers meet the sea, tides can exert a physical and chemical influence on the lower reaches of a river. How tidal dynamics in these tidal river reaches interact with upstream hydrological drivers such as storm rainfall, which ultimately determines the quantity and composition of material transferred from watersheds to estuaries, is currently unknown. We monitored a small freshwater tidal river in the Pacific Northwest, United States in high resolution over 1 year to evaluate the relative importance of tides vs. upstream hydrological flows (i.e., base flow and precipitation events) on basic physico-chemical parameters (pH, dissolved oxygen, turbidity, specific conductivity, and temperature), and how these interactions relate to the downstream estuary. Tidal variability and diurnal cycles (i.e., solar radiation) dominated water physico-chemical variability in the summer, but the influence of these drivers was overshadowed by storm-driven sharp pulses in river physico-chemistry during the remainder of the year. Within such events, we found incidences of counterclockwise hysteresis of pH, counterclockwise hysteresis of dissolved oxygen, and clockwise hysteresis of turbidity, although systematic trends were not observed across events. The dominance of storm rainfall in the river’s physico-chemistry dynamics, and similar pulses of decreased pH observed in adjacent estuarine waters, suggest that the linkage between tidal streams and the broader system is variable throughout the year. High-frequency monitoring of tidal river biogeochemistry is therefore crucial to enable the assessment of how the relative strength of these drivers may change with future sea level rise and altered precipitation patterns to modulate biogeochemical dynamics across the land-ocean-atmosphere continuum.
Synthesis of Monolithic TiO2 Aerogels With Relatively Low Shrinkage and Improved Formability Assisted by CTAB
Authors: Niu Tingting , Zhou Bin , Zhang Zehui , Yang Jianming , Ji Xiujie , Shen Jun , Zhang Zhihua , Du Ai
Published: June 2021

Monolithic TiO2 aerogels without severe shrink were obtained by the sol-gel method with the addition of the surfactant cetyltrimethylammonium bromide (CTAB) to control the hydrolysis and polycondensation process and acetonitrile solvent as the solvent to improve the crystallinity. After CO2 supercritical drying, the shrinkage ratio of monolithic TiO2 aerogels modified by CTAB decreased by up to ∼26.9%, compared with the pure TiO2 aerogel. Their apparent densities were all lower than 300 g/cm3. X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Fourier Transform infrared spectroscopy (FTIR) and BET Specific Surface Area Analysis were used to analyze the as-synthesized samples. The results revealed that all the samples were anatase-TiO2 phase with nanoporous network structures. The specific surface areas reached 250.2 m2/g confirmed by the BET (Brunaur–Emmett–Teller method) analysis. However, TiO2 aerogels without the addition of CTAB showed evident agglomeration and collapse of the network in comparison with CTAB-added samples. To further study the structure-property relationship, the photocatalysis performance of as-synthesized and 300°C-calcined aerogels was carried out contrastively. Interestingly, the influences of the CTAB adding amount of as-synthesized and calcined TiO2 aerogels are negative and positive, respectively, which is probably due to the synergistic effect of CTAB hindrance and grain refinement. Potentially, This kind of TiO2 aerogels assisted by CATB with low density, small shrinkage, improved formability, high specific surface area and fine crystalline grain may be applied in various applications, such as electrochemistry, photocatalysis, etc.
Case Report: Predominant Tubulointerstitial Lupus Nephritis or the Combination With IgG4-Related Disease?
Authors: Tan Ying , Qin Yan , Yu Xiao-juan , Xu Rong , Wang Su-xia , Zhou Fu-de , Zhao Ming-hui
Published: June 2021

Isolated or dominant tubulointerstitial lupus nephritis is rare. Here, we reported a 67-year-old man diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria, who was showing impaired renal function and non-nephrotic range proteinuria in the past 2 years. Renal biopsy showed almost normal glomeruli, but the tubulointerstitium showed “storiform” pattern with interstitial infiltration of IgG3 predominant plasma cells. Immunofluorescence showed linear and granular staining of IgG and C1q along TBM and interstitium. He started on medium dose of oral steroids and mycophenolate mofetil, which were gradually tapered. As a result, his renal function improved over a few days. Now, he continued on low dose steroids and mycophenolate mofetil with no evidence of relapse.
Assessing the Diversity and Biomedical Potential of Microbes Associated With the Neptune’s Cup Sponge, Cliona patera
Authors: Ho Xin Yi , Katermeran Nursheena Parveen , Deignan Lindsey Kane , Phyo Ma Yadanar , Ong Ji Fa Marshall , Goh Jun Xian , Ng Juat Ying , Tun Karenne , Tan Lik Tong
Published: June 2021

Marine sponges are known to host a complex microbial consortium that is essential to the health and resilience of these benthic invertebrates. These sponge-associated microbes are also an important source of therapeutic agents. The Neptune’s Cup sponge, Cliona patera, once believed to be extinct, was rediscovered off the southern coast of Singapore in 2011. The chance discovery of this sponge presented an opportunity to characterize the prokaryotic community of C. patera. Sponge tissue samples were collected from the inner cup, outer cup and stem of C. patera for 16S rRNA amplicon sequencing. C. patera hosted 5,222 distinct OTUs, spanning 26 bacterial phyla, and 74 bacterial classes. The bacterial phylum Proteobacteria, particularly classes Gammaproteobacteria and Alphaproteobacteria, dominated the sponge microbiome. Interestingly, the prokaryotic community structure differed significantly between the cup and stem of C. patera, suggesting that within C. patera there are distinct microenvironments. Moreover, the cup of C. patera had lower diversity and evenness as compared to the stem. Quorum sensing inhibitory (QSI) activities of selected sponge-associated marine bacteria were evaluated and their organic extracts profiled using the MS-based molecular networking platform. Of the 110 distinct marine bacterial strains isolated from sponge samples using culture-dependent methods, about 30% showed quorum sensing inhibitory activity. Preliminary identification of selected QSI active bacterial strains revealed that they belong mostly to classes Alphaproteobacteria and Bacilli. Annotation of the MS/MS molecular networkings of these QSI active organic extracts revealed diverse classes of natural products, including aromatic polyketides, siderophores, pyrrolidine derivatives, indole alkaloids, diketopiperazines, and pyrone derivatives. Moreover, potential novel compounds were detected in several strains as revealed by unique molecular families present in the molecular networks. Further research is required to determine the temporal stability of the microbiome of the host sponge, as well as mining of associated bacteria for novel QS inhibitors.
Differential Bacteriophage Efficacy in Controlling Salmonella in Cattle Hide and Soil Models
Authors: Xie Yicheng , Thompson Tyler , O’Leary Chandler , Crosby Stephen , Nguyen Quang X. , Liu Mei , Gill Jason J.
Published: June 2021

AsymptomaticSalmonellacarriage in beef cattle is a food safety concern and the beef feedlot environment and cattle hides are reservoirs of this pathogen. Bacteriophages present an attractive non-antibiotic strategy for control ofSalmonellain beef. In this study, four diverse and genetically unrelatedSalmonellaphages, Sergei, Season12, Sw2, and Munch, were characterized and tested alone and in combination for their ability to controlSalmonellain cattle hide and soil systems, which are relevant models forSalmonellacontrol in beef production. Phage Sergei is a member of the genusSashavirus, phage Season12 was identified as a member of theChivirusgenus, Sw2 was identified as a member of the T5-likeEpseptimavirusgenus, and Munch was found to be a novel “jumbo” myovirus. Observed pathogen reductions in the model systems ranged from 0.50 to 1.75 log10CFU/cm2in hides and from 0.53 to 1.38 log10CFU/g in soil, with phages Sergei and Sw2 producing greater reductions (∼1 log10CFU/cm2or CFU/g) than Season12 and Munch. These findings are in accordance with previous observations of phage virulence, suggesting the simple ability of a phage to form plaques on a bacterial strain is not a strong indicator of antimicrobial activity, but performance in liquid culture assays provides a better predictor. The antimicrobial efficacies of phage treatments were found to be phage-specific across model systems, implying that a phage capable of achieving bacterial reduction in one model is more likely to perform well in another. Phage combinations did not produce significantly greater efficacy than single phages even after 24 h in the soil model, and phage-insensitive colonies were not isolated from treated samples, suggesting that the emergence of phage resistance was not a major factor limiting efficacy in this system.
Microbial Communities and Interactions of Nitrogen Oxides With Methanogenesis in Diverse Peatlands of the Amazon Basin
Authors: Buessecker Steffen , Zamora Zacary , Sarno Analissa F. , Finn Damien Robert , Hoyt Alison M. , van Haren Joost , Urquiza Muñoz Jose D. , Cadillo-Quiroz Hinsby
Published: June 2021

Tropical peatlands are hotspots of methane (CH4) production but present high variation and emission uncertainties in the Amazon region. This is because the controlling factors of methane production in tropical peats are not yet well documented. Although inhibitory effects of nitrogen oxides (NOx) on methanogenic activity are known from pure culture studies, the role of NOx in the methane cycling of peatlands remains unexplored. Here, we investigated the CH4 content, soil geochemistry and microbial communities along 1-m-soil profiles and assessed the effects of soil NOx and nitrous oxide (N2O) on methanogenic abundance and activity in three peatlands of the Pastaza-Marañón foreland basin. The peatlands were distinct in pH, DOC, nitrate pore water concentrations, C/N ratios of shallow soils, redox potential, and 13C enrichment in dissolved inorganic carbon and CH4 pools, which are primarily contingent on H2-dependent methanogenesis. Molecular 16S rRNA and mcrA gene data revealed diverse and novel methanogens varying across sites. Importantly, we also observed a strong stratification in relative abundances of microbial groups involved in NOx cycling, along with a concordant stratification of methanogens. The higher relative abundance of ammonia-oxidizing archaea (Thaumarchaeota) in acidic oligotrophic peat than ammonia-oxidizing bacteria (Nitrospira) is noteworthy as putative sources of NOx. Experiments testing the interaction of NOx species and methanogenesis found that the latter showed differential sensitivity to nitrite (up to 85% reduction) and N2O (complete inhibition), which would act as an unaccounted CH4 control in these ecosystems. Overall, we present evidence of diverse peatlands likely differently affected by inhibitory effects of nitrogen species on methanogens as another contributor to variable CH4 fluxes.
Abnormal Tryptophan Metabolism in HIV and Mycobacterium tuberculosis Infection
Authors: Wang Xiaolei , Mehra Smriti , Kaushal Deepak , Veazey Ronald S. , Xu Huanbin
Published: June 2021

Host metabolism has recently gained more attention for its roles in physiological functions and pathologic conditions. Of these, metabolic tryptophan disorders generate a pattern of abnormal metabolites that are implicated in various diseases. Here, we briefly highlight the recent advances regarding abnormal tryptophan metabolism in HIV and Mycobacterium tuberculosis infection and discuss its potential impact on immune regulation, disease progression, and neurological disorders. Finally, we also discuss the potential for metabolic tryptophan interventions toward these infectious diseases.
Exploring the Potential of Micrococcus luteus Culture Supernatant With Resuscitation-Promoting Factor for Enhancing the Culturability of Soil Bacteria
Authors: Lopez Marin Marco Antonio , Strejcek Michal , Junkova Petra , Suman Jachym , Santrucek Jiri , Uhlik Ondrej
Published: June 2021

A bacterial species is best characterized after its isolation in a pure culture. This is an arduous endeavor for many soil microorganisms, but it can be simplified by several techniques for improving culturability: for example, by using growth-promoting factors. We investigated the potential of a Micrococcus luteus culture supernatant containing resuscitation-promoting factor (SRpf) to increase the number and diversity of cultured bacterial taxa from a nutrient-rich compost soil. Phosphate-buffered saline and inactivated SRpf were included as controls. After agitation with SRpf at 28°C for 1 day, the soil suspension was diluted and plated on two different solid, oligotrophic media: tenfold diluted Reasoner’s 2A agar (R2A) and soil extract-based agar (SA). Colonies were collected from the plates to assess the differences in diversity between different treatments and cultivation media. The diversity on both R2A and SA was higher in the SRpf-amended extracts than the controls, but the differences on R2A were higher. Importantly, 51 potentially novel bacterial species were isolated on R2A and SA after SRpf treatment. Diversity in the soil extracts was also determined by high-throughput 16S rRNA amplicon sequencing, which showed an increase in the abundance of specific taxa before their successful cultivation. Conclusively, SRpf can effectively enhance the growth of soil bacterial species, including those hitherto uncultured.
Unlimited Cooperativity of Betatectivirus SSB, a Novel DNA Binding Protein Related to an Atypical Group of SSBs From Protein-Primed Replicating Bacterial Viruses
Authors: Lechuga Ana , Kazlauskas Darius , Salas Margarita , Redrejo-Rodríguez Modesto
Published: June 2021

Bam35 and related betatectiviruses are tail-less bacteriophages that prey on members of the Bacillus cereus group. These temperate viruses replicate their linear genome by a protein-primed mechanism. In this work, we have identified and characterized the product of the viral ORF2 as a single-stranded DNA binding protein (hereafter B35SSB). B35SSB binds ssDNA with great preference over dsDNA or RNA in a sequence-independent, highly cooperative manner that results in a non-specific stimulation of DNA replication. We have also identified several aromatic and basic residues, involved in base-stacking and electrostatic interactions, respectively, that are required for effective protein–ssDNA interaction. Although SSBs are essential for DNA replication in all domains of life as well as many viruses, they are very diverse proteins. However, most SSBs share a common structural domain, named OB-fold. Protein-primed viruses could constitute an exception, as no OB-fold DNA binding protein has been reported. Based on databases searches as well as phylogenetic and structural analyses, we showed that B35SSB belongs to a novel and independent group of SSBs. This group contains proteins encoded by protein-primed viral genomes from unrelated viruses, spanning betatectiviruses and Φ29 and close podoviruses, and they share a conserved pattern of secondary structure. Sensitive searches and structural predictions indicate that B35SSB contains a conserved domain resembling a divergent OB-fold, which would constitute the first occurrence of an OB-fold-like domain in a protein-primed genome.
Evolutionary Modifications Are Moderate in the Astroglial System of Actinopterygii as Revealed by GFAP Immunohistochemistry
Authors: Kálmán Mihály , Matuz Vanessza , Sebők Olivér M. , Lőrincz Dávid
Published: June 2021

The present paper is the first comparative study on the astroglia of several actinopterygian species at different phylogenetical positions, teleosts (16 species), and non-teleosts (3 species), based on the immunohistochemical staining of GFAP (glial fibrillary acidic protein), the characteristic cytoskeletal intermediary filament protein, and immunohistochemical marker of astroglia. The question was, how the astroglial architecture reflexes the high diversity of this largest vertebrate group. The actinopterygian telencephalon has a so-called ‘eversive’ development in contrast to the ‘evagination’ found in sarcopterygii (including tetrapods). Several brain parts either have no equivalents in tetrapod vertebrates (e.g., torus longitudinalis, lobus inferior, lobus nervi vagi), or have rather different shapes (e.g., the cerebellum). GFAP was visualized applying DAKO polyclonal anti-GFAP serum. The study was focused mainly on the telencephalon (eversion), tectum (visual orientation), and cerebellum (motor coordination) where the evolutionary changes were most expected, but the other areas were also investigated. The predominant astroglial elements were tanycytes (long, thin, fiber-like cells). In the teleost telencephala a ‘fan-shape’ re-arrangement of radial glia reflects the eversion. In bichir, starlet, and gar, in which the eversion is less pronounced, the ‘fan-shape’ re-arrangement did not form. In the tectum the radial glial processes were immunostained, but in Ostariophysi and Euteleostei it did not extend into their deep segments. In the cerebellum Bergmann-like glia was found in each group, including non-teleosts, except for Cyprinidae. The vagal lobe was uniquely enlarged and layered in Cyprininae, and had a corresponding layered astroglial system, which left almost free of GFAP the zones of sensory and motor neurons. In conclusion, despite the diversity and evolutionary alterations of Actinopterygii brains, the diversity of the astroglial architecture is moderate. In contrast to Chondrichthyes and Amniotes; in Actinopterygii true astrocytes (stellate-shaped extraependymal cells) did not appear during evolution, and the expansion of GFAP-free areas was limited.
Classification of Microglial Morphological Phenotypes Using Machine Learning
Authors: Leyh Judith , Paeschke Sabine , Mages Bianca , Michalski Dominik , Nowicki Marcin , Bechmann Ingo , Winter Karsten
Published: June 2021

Microglia are the brain’s immunocompetent macrophages with a unique feature that allows surveillance of the surrounding microenvironment and subsequent reactions to tissue damage, infection, or homeostatic perturbations. Thereby, microglia’s striking morphological plasticity is one of their prominent characteristics and the categorization of microglial cell function based on morphology is well established. Frequently, automated classification of microglial morphological phenotypes is performed by using quantitative parameters. As this process is typically limited to a few and especially manually chosen criteria, a relevant selection bias may compromise the resulting classifications. In our study, we describe a novel microglial classification method by morphological evaluation using a convolutional neuronal network on the basis of manually selected cells in addition to classical morphological parameters. We focused on four microglial morphologies, ramified, rod-like, activated and amoeboid microglia within the murine hippocampus and cortex. The developed method for the classification was confirmed in a mouse model of ischemic stroke which is already known to result in microglial activation within affected brain regions. In conclusion, our classification of microglial morphological phenotypes using machine learning can serve as a time-saving and objective method for post-mortem characterization of microglial changes in healthy and disease mouse models, and might also represent a useful tool for human brain autopsy samples.
Double-Sine-Wave Quadri-Pulse Theta Burst Stimulation of Precentral Motor Hand Representation Induces Bidirectional Changes in Corticomotor Excitability
Authors: Jung Nikolai H. , Gleich Bernhard , Gattinger Norbert , Kalb Anke , Fritsch Julia , Asenbauer Elisabeth , Siebner Hartwig R. , Mall Volker
Published: June 2021

Neuronal plasticity is considered to be the neurophysiological correlate of learning and memory and changes in corticospinal excitability play a key role in the normal development of the central nervous system as well as in developmental disorders. In a previous study, it was shown that quadri-pulse theta burst stimulation (qTBS) can induce bidirectional changes in corticospinal excitability (1). There, a quadruple burst consisted of four single-sine-wave (SSW) pulses with a duration of 160 μs and inter-pulse intervals of 1.5 ms to match I-wave periodicity (666 Hz). In the present study, the pulse shape was modified applying double-sine-waves (DSW) rather than SSW pulses, while keeping the pulse duration at 160 μs. In two separate sessions, we reversed the current direction of the DSW pulse, so that its second component elicited either a mainly posterior-to-anterior (DSW PA-qTBS) or anterior-to-posterior (DSW AP-qTBS) directed current in the precentral gyrus. The after-effects of DSW qTBS on corticospinal excitability were examined in healthy individuals (n = 10) with single SSW TMS pulses. For single-pulse SSW TMS, the second component produced the same preferential current direction as DSW qTBS but had a suprathreshold intensity, thus eliciting motor evoked potentials (PA-MEP or AP-MEP). Single-pulse SSW TMS revealed bidirectional changes in corticospinal excitability after DSW qTBS, which depended on the preferentially induced current direction. DSW PA-qTBS at 666 Hz caused a stable increase in PA-MEP, whereas AP-qTBS at 666 Hz induced a transient decrease in AP-MEP. The sign of excitability following DSW qTBS at I-wave periodicity was opposite to the bidirectional changes after SSW qTBS. The results show that the pulse configuration and induced current direction determine the plasticity-effects of ultra-high frequency SSW and DSW qTBS at I-wave periodicity. These findings may offer new opportunities for short non-invasive brain stimulation protocols that are especially suited for stimulation in children and patients with neurological or neurodevelopmental disorders.
Neurofeedback Learning Is Skill Acquisition but Does Not Guarantee Treatment Benefit: Continuous-Time Analysis of Learning-Curves From a Clinical Trial for ADHD
Authors: Veilahti Antti Veikko Petteri , Kovarskis Levas , Cowley Benjamin Ultan
Published: June 2021

Neurofeedback for attention deficit/hyperactivity disorder (ADHD) has long been studied as an alternative to medication, promising non-invasive treatment with minimal side-effects and sustained outcome. However, debate continues over the efficacy of neurofeedback, partly because existing evidence for efficacy is mixed and often non-specific, with unclear relationships between prognostic variables, patient performance when learning to self-regulate, and treatment outcomes. We report an extensive analysis on the understudied area of neurofeedback learning. Our data comes from a randomised controlled clinical trial in adults with ADHD (registered trial ISRCTN13915109; N = 23; 13:10 female:male; age 25–57). Patients were treated with either theta-beta ratio or sensorimotor-rhythm regimes for 40 one-hour sessions. We classify 11 learners vs 12 non-learners by the significance of random slopes in a linear mixed growth-curve model. We then analyse the predictors, outcomes, and processes of learners vs non-learners, using these groups as mutual controls. Significant predictive relationships were found in anxiety disorder (GAD), dissociative experience (DES), and behavioural inhibition (BIS) scores obtained during screening. Low DES, but high GAD and BIS, predicted positive learning. Patterns of behavioural outcomes from Test Of Variables of Attention, and symptoms from adult ADHD Self-Report Scale, suggested that learning itself is not required for positive outcomes. Finally, the learning process was analysed using structural-equations modelling with continuous-time data, estimating the short-term and sustained impact of each session on learning. A key finding is that our results support the conceptualisation of neurofeedback learning as skill acquisition, and not merely operant conditioning as originally proposed in the literature.
When Is Simultaneous Recording Necessary? A Guide for Researchers Considering Combined EEG-fMRI
Authors: Scrivener Catriona L.
Published: June 2021

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) provide non-invasive measures of brain activity at varying spatial and temporal scales, offering different views on brain function for both clinical and experimental applications. Simultaneous recording of these measures attempts to maximize the respective strengths of each method, while compensating for their weaknesses. However, combined recording is not necessary to address all research questions of interest, and experiments may have greater statistical power to detect effects by maximizing the signal-to-noise ratio in separate recording sessions. While several existing papers discuss the reasons for or against combined recording, this article aims to synthesize these arguments into a flow chart of questions that researchers can consider when deciding whether to record EEG and fMRI separately or simultaneously. Given the potential advantages of simultaneous EEG-fMRI, the aim is to provide an initial overview of the most important concepts and to direct readers to relevant literature that will aid them in this decision.
A Study on Mesoporous Silica Loaded With Novel Photosensitizers HCE6 and Oxaliplatin for the Treatment of Cholangiocarcinoma
Authors: Zhang Pei-Jian , Liu Meng-Dong , Fan Fang-Yong , Liu Ke-Xia
Published: June 2021

Purpose

Cholangiocarcinoma (CCA) is a malignant tumor with a high incidence. The therapeutic effect of conventional chemotherapy and radiotherapy is not obvious. Photodynamic therapy (PDT) is an ideal modality to fight cancer, and the nature of photosensitizer limits its application in clinical therapy. The aim of this study was to explore a novel mode of drug delivery for the intervention of bile duct cancer.

Methods

Oxaliplatin and photosensitizer HCE6 were loaded with mesoporous silica nanoparticles (MSNs) to synthesize Oxaliplatin/HCE6-MSNs (OH-MSNs); the structure of OH-MSNs was characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), the drug release rate was detected by high performance liquid chromatography; the cellular activity, apoptosis level, and the expression levels of intracellular apoptosis and autophagy-related factors of OH-MSNs on cholangiocarcinoma cells were observed by CCK-8, flow cytometry, colony formation assay, and Western blot; the effects of OH-MSNs on cholangioma growth were observed by mouse tumor formation, immunohistochemistry, and tissue Tunel staining.

Results

The release of OH-MSNs to Oxaliplatin was enhanced under acidic conditions; compared with Oxaliplatin or O-MSNs, OH-MSNs showed more potent killing effects against cholangiocarcinoma cells (P<0.05), and exerted notably inhibitory effects on the activity of cholangiocarcinoma cells (P<0.05), promoted their apoptosis (P<0.05), and greatly facilitated the expression of pro-apoptotic factors and autophagic factors in cholangiocarcinoma cells (P<0.05), and markedly inhibited the expression of anti-apoptotic factors and autophagic inhibitory factors (P<0.05); moreover, OH-MSNs could significantly suppress the growth of mouse cholangiocarcinoma (P<0.05) and induce apoptosis of tumor cells compared with Oxaliplatin or O-MSNs (P<0.05).

Conclusion

MSNs loading greatly increases the killing effect of Oxaliplatin on cholangiocarcinoma cells and upgrades the autophagic level of cholangiocarcinoma cells, while OH-MSNs synthesized by further loading HCE6 have a more apparent killing effect on cholangiocarcinoma cells.
Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy
Authors: Zheng Xiaobo , Yu Chune , Xu Mingqing
Published: June 2021

Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.
The Assessment of 3D Digital Models Using GOSLON Yardstick Index: Exploring Confounding Factors Responsible for Unfavourable Treatment Outcome in Multi-Population Children With UCLP
Authors: Haque Sanjida , Khamis Mohd Fadhli , Alam Mohammad Khursheed , Wan Ahmad Amir Wan Muhamad
Published: June 2021

To evaluate dental arch relationship (DAR) using GOSLON Yardstick and also to explore the association between multiple factors (age, gender, UCLP types, UCLP side, Family history of cleft, family history of Class III malocclusion, techniques of cheiloplasty, techniques of palatoplasty) and DAR in children unilateral cleft lip and palate (UCLP) in different populations. Two hundred fifty-five laser scanned 3D digital models (LS3DM) of UCLP children (5–12 years) from Malaysia, Bangladesh, and Pakistan were included. The intra- and inter-examiner agreements were evaluated by kappa statistics, to compare the GOSLON mean score between the populations and to explore the responsible factors that affect DAR, one way ANOVA, and crude logistic regression analysis was used, respectively. The mean GOSLON score was 2.97; 3.40 and 3.09 in Malaysia, Bangladesh, and Pakistan, respectively. Twenty seven, 40, and 30 subjects were in unfavourable (category rating 4 and 5) groups in Malaysia, Bangladesh, and Pakistan, respectively. A significant association was found between techniques of palatoplasty (p = 0.03; p = 0.04 and p = 0.04 in Malaysia, Bangladesh, and Pakistan, respectively) and unfavourable DAR. Different cheiloplasty techniques (p = 0.04) and gender (p = 0.03) also exhibited noteworthy associations with unfavourable DAR in the Bangladeshi population. Bardach techniques of palatoplasty were significantly associated with unfavourable DAR in all three populations. Moreover, male UCLP and modified Millard techniques of cheiloplasty were also associated with unfavourable DAR in the Bangladeshi population.
Long Term Experience in Patients With JIA-Associated Uveitis in a Large Referral Center
Authors: Marelli Luca , Romano Micol , Pontikaki Irene , Gattinara Maurizio Virgilio , Nucci Paolo , Cimaz Rolando , Miserocchi Elisabetta
Published: June 2021

Objectives: To describe demographic, clinical and therapeutic findings of a large cohort of patients with JIA-associated uveitis in a nationwide referral pediatric rheumatology and uveitis center in Northern Italy.

Methods: Retrospective study of 125 patients with JIA-associated uveitis followed from 2009 to 2019. Demographic and rheumatologic features including JIA ILAR classification, age at onset, and laboratory data were recorded. Ocular findings collected were: anatomic location of uveitis, laterality, type, recurrence rate, visual acuity, ocular complications, and local therapy. Systemic therapy with conventional and biologic immunosuppressants, occurrence of adverse events, and duration of treatments were recorded.

Results: One hundred and twenty-five patients with JIA-associated uveitis were followed for a meantime of 9.2 (±1.7) years. Oligoarticular JIA was present in 92.8% of patients and anterior uveitis in 96%. The most common ocular complications recorded in our sample were posterior synechiae (37.6%), cataract (20.8%), band keratopathy (19.2%), glaucoma (7.2%), and macular edema (5.6%). Conventional immunosuppressants were used in 75.2% of patients with a mean duration of 9.1 years (±5.4), while biologics were administered in 47.2% of them for a period of 5.4 years. Adverse events (AE) were seen in 23% of patients being treated with Methotrexate, in 10.4% of patients treated with Adalimumab, in 38.5% of patients in therapy with Infliximab, and in 14.3% of patients being treated with Tocilizumab. No AE were reported in patients treated with Golimumab, Certolizumab, Abatacept and Rituximab.

Conclusions: An aggressive treatment approach for patients with JIA-associated uveitis ensured a low number of ocular complications with a good safety profile.