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Abstract Granulation of activated sludge is an increasingly important area within the field of wastewater treatment. Granulation is usually achieved by high hydraulic selection pressure, which results in the wash-out of slow settling particles. The effect of the harsh wash-out conditions on the granular sludge ecosystem is not yet fully understood, but different bacterial groups may be affected to varying degrees. In this study, we used high-throughput amplicon sequencing to follow the community composition in granular sludge reactors for 12 weeks, both in the granular phase and the suspended phase (effluent). The microbiome of the washed out biomass was similar but not identical to the microbiome of the granular biomass. Certain taxa (e.g. Flavobacterium spp. and Bdellovibrio spp.) had significantly (p

The granular sludge process is an effective, low-footprint alternative to conventional activated sludge wastewater treatment. The architecture of the microbial granules allows the co-existence of different functional groups, e.g., nitrifying and denitrifying communities, which permits compact reactor design. However, little is known about the factors influencing community assembly in granular sludge, such as the effects of reactor operation strategies and influent wastewater composition. Here, we analyze the development of the microbiomes in parallel laboratory-scale anoxic/aerobic granular sludge reactors operated at low (0.9 kg m-3d-1), moderate (1.9 kg m-3d-1) and high (3.7 kg m-3d-1) organic loading rates (OLRs) and the same ammonium loading rate (0.2 kg NH4-N m-3d-1) for 84 days. Complete removal of organic carbon and ammonium was achieved in all three reactors after start-up, while the nitrogen removal (denitrification) efficiency increased with the OLR: 0% at low, 38% at moderate, and 66% at high loading rate. The bacterial communities at different loading rates diverged rapidly after start-up and showed less than 50% similarity after 6 days, and below 40% similarity after 84 days. The three reactor microbiomes were dominated by different genera (mainly Meganema, Thauera, Paracoccus, and Zoogloea), but these genera have similar ecosystem functions of EPS production, denitrification and polyhydroxyalkanoate (PHA) storage. Many less abundant but persistent taxa were also detected within these functional groups. The bacterial communities were functionally redundant irrespective of the loading rate applied. At steady-state reactor operation, the identity of the core community members was rather stable, but their relative abundances changed considerably over time. Furthermore, nitrifying bacteria were low in relative abundance and diversity in all reactors, despite their large contribution to nitrogen turnover. The results suggest that the OLR has considerable impact on the composition of the granular sludge communities, but also that the granule communities can be dynamic even at steady-state reactor operation due to high functional redundancy of several key guilds. Knowledge about microbial diversity with specific functional guilds under different operating conditions can be important for engineers to predict the stability of reactor functions during the start-up and continued reactor operation.

The dental health of those individuals who require special dental care is way worse than the healthy population. In most cases, they need sedation or general anaesthesia during treatment and also require teamwork of a complex multidisciplinary team. These people with special needs are mostly young and have no tooth loss, so providing them with the necessary dental treatment at the right time is highly important. The patient is a 29 year old male with therapy-resistant epilepsy and mild mental retardation. First, his cooperative tendency was estimated by providing him with professional dental treatment and taking impressions. As his neurologist advised, teeth with hopeless prognoses were extracted in general anaesthesia, and also surgical coronal lengthening in the maxilla and mandible was carried out in the same way. After the conservative dental treatment process, metalceramic bridges were made using ceramic coverage only on the buccal surfaces. At the four-year control dental visit, even though he had epileptic seizures more often than before, his denture showed no signs of any damage. In the case of patients with special needs, estimating the cooperative tendency and creating the proper treatment individually is a must. In the following article, we present a complex full-mouth rehabilitation of a therapy-resistant epileptic, mentally retarded person who requires general anaesthesia for some of the treatments.

ObjectivesCell surface glycosylation can influence protein-protein interactions with particular relevance to changes in core fucosylation and terminal sialylation. Glycans are ligands for immune regulatory lectin families like galectins (Gals) or sialic acid immunoglobulin-like lectins (Siglecs). This study delves into the glycan alterations within immune subsets of systemic lupus erythematosus (SLE).MethodsEvaluation of binding affinities of Galectin-1, Galectin-3, Siglec-1, Aleuria aurantia lectin (AAL, recognizing core fucosylation), and Sambucus nigra agglutinin (SNA, specific for α-2,6-sialylation) was conducted on various immune subsets in peripheral blood mononuclear cells (PBMCs) from control and SLE subjects. Lectin binding was measured by multi-parameter flow cytometry in 18 manually gated subsets of T-cells, NK-cells, NKT-cells, B-cells, and monocytes in unstimulated resting state and also after 3-day activation. Stimulated pre-gated populations were subsequently clustered by FlowSOM algorithm based on lectin binding and activation markers, CD25 or HLA-DR.ResultsElevated AAL, SNA and CD25+/CD25- SNA binding ratio in certain stimulated SLE T-cell subsets correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores. The significantly increased frequencies of activated AALlow Siglec-1low NK metaclusters in SLE also correlated with SLEDAI-2K indices. In SLE, activated double negative NKTs displayed significantly lower core fucosylation and CD25+/CD25- Siglec-1 binding ratio, negatively correlating with disease activity. The significantly enhanced AAL binding in resting SLE plasmablasts positively correlated with SLEDAI-2K scores.ConclusionAlterations in the glycosylation of immune cells in SLE correlate with disease severity, which might represent potential implications in the pathogenesis of SLE.

BackgroundVaccination has proven the potential to control the COVID-19 pandemic worldwide. Although recent evidence suggests a poor humoral response against SARS-CoV-2 in vaccinated hematological disease (HD) patients, data on vaccination in these patients is limited with the comparison of mRNA-based, vector-based or inactivated virus-based vaccines.MethodsForty-nine HD patients and 46 healthy controls (HCs) were enrolled who received two-doses complete vaccination with BNT162b2, or AZD1222, or BBIBP-CorV, respectively. The antibodies reactive to the receptor binding domain of spike protein of SARS-CoV-2 were assayed by Siemens ADVIA Centaur assay. The reactive cellular immunity was assayed by flow cytometry. The PBMCs were reactivated with SARS-CoV-2 antigens and the production of activation-induced markers (TNF-α, IFN-γ, CD40L) was measured in CD4+ or CD8+ T-cells ex vivo.ResultsThe anti-RBD IgG level was the highest upon BNT162b2 vaccination in HDs (1264 BAU/mL) vs. HCs (1325 BAU/mL) among the studied groups. The BBIBP-CorV vaccination in HDs (339.8 BAU/mL ***p

IntroductionMacrophages significantly contribute to the regulation of vessel formation under physiological and pathological conditions. Although the angiogenesis-regulating role of alternatively polarized macrophages is quite controversial, a growing number of evidence shows that they can participate in the later phases of angiogenesis, including vessel sprouting and remodeling or regression. However, the epigenetic and transcriptional regulatory mechanisms controlling this angiogenesis-modulating program are not fully understood.ResultsHere we show that IL-4 can coordinately regulate the VEGFA-VEGFR1 (FLT1) axis via simultaneously inhibiting the proangiogenic Vegfa and inducing the antiangiogenic Flt1 expression in murine bone marrow-derived macrophages, which leads to the attenuated proangiogenic activity of alternatively polarized macrophages. The IL-4-activated STAT6 and IL-4-STAT6 signaling pathway-induced EGR2 transcription factors play a direct role in the transcriptional regulation of the Vegfa-Flt1 axis. We demonstrated that this phenomenon is not restricted to the murine bone marrow-derived macrophages, but can also be observed in different murine tissue-resident macrophages ex vivo and parasites-elicited macrophages in vivo with minor cell type-specific differences. Furthermore, IL-4 exposure can modulate the hypoxic response of genes in both murine and human macrophages leading to a blunted Vegfa/VEGFA and synergistically induced Flt1/FLT1 expression.DiscussionOur findings establish that the IL-4-activated epigenetic and transcriptional program can determine angiogenesis-regulating properties in alternatively polarized macrophages under normoxic and hypoxic conditions.

Abstract Background It has been demonstrated in non-oral tissues that the locally evoked vasoconstriction could elicit remote vasoconstriction. This study aimed to investigate the spreading vasoconstrictor effects of epinephrine in the gingiva. Methods Gingival blood flow (GBF) was measured by laser speckle contrast imager in 21 healthy volunteers. In group A, two wells were fabricated from orthodontic elastic ligature and placed 2 mm apically to the free gingival margin at the mid buccal line of 12 (test side) and 21 (control side) teeth. The GBF was measured in the wells and tightly apical, coronal, distal and mesial to the wells. In group B, the wells were made on the buccal surface of the same teeth, including the gingival sulcus. Four regions were selected for measurement from the gingival margin reaching the mucogingival line (coronal, midway1, midway2 and apical). After the baseline recording, 3 µg epinephrine was applied into the test, and physiological saline into the control well. The GBF was recorded for 14 min. The gingival thickness was measured with a PIROP Ultrasonic Biometer. Results In group A, the GBF did not increase or decrease after the application of epinephrine. In group B, the GBF significantly decreased in all regions of the test side and remained low for the observation period. The vasoconstriction appeared with delays in more apical regions (at min 1 in the coronal and the midway1, at min 2 in the midway2, at min 4 in the apical region). Similarly, the amount of the decrease at 14 min was the largest close to sulcus (− 53 ± 2.9%), followed by the midway1 (− 51 ± 2.8%) and midway2 (− 42 ± 4.2%) and was the lowest in the apical region (− 32 ± 5.8%). No correlation was found between GBF and gingival thickness. Conclusion Epinephrine could evoke intense vasoconstriction propagating to the mucogingival junction, indicating the presence of spreading vasoconstriction in the human gingiva. The attached gingiva is impermeable to epinephrine, unlike the gingival sulcus. This trial was registered in ClinicalTrials.gov titled as Evidence of Spreading Vasoconstriction in Human Gingiva with the reference number of NCT04131283 on 16 October 2019. https://clinicaltrials.gov/show/NCT04131283

In Mercier’s futuristic novel published in 1771, the author’s alter ego wakes up one day as a sevenhundred-year-old man and he rediscovers the city of Paris in the company of a citizen of the 25th century. Memory and forgetting can be interpreted in different ways in the novel: on the one hand, we can see how the elderly man remembers his own time, what memories he keeps from the 18th century, and also how the people of this new Paris are kept in the memory of future generations. On the other hand, we will examine the author’s point of view, especially the influence of the philosophers of his time. During Mercier’s meditations on the tombs and ruins, it is mainly the impact of Diderot’s thoughts that dominates, and these passages show that the notions of memory and forgetting are closely related to those of imagination and dream.

BackgroundVaccine-induced immunity is essential for controlling the COVID-19 pandemic. Data on humoral and cellular immunogenicity and safety of different SARS-CoV-2 vaccines in patients with autoimmune rheumatic and musculoskeletal diseases (RMDs) are limited.MethodsA single center observational study evaluated the immunogenicity and safety of the two-dose regimen of the BBIBP-CorV inactivated, Gam-COVID-Vac and AZD1222 adenovirus-based, and BNT162b2 and mRNA-1273 mRNA-based vaccines in patients with RMDs (n = 89) compared with healthy controls (n = 74). Neutralizing anti-RBD (receptor binding domain) specific antibodies and SARS-CoV-2 specific T-cell response were measured one and four months after the second vaccine dose in parallel with vaccination efficacy and safety.ResultsDisease-specific comparison showed that antibody response at four months was higher in spondylarthropathies compared to rheumatoid arthritis and autoimmune RMDs. Risk factors for reduced immunogenicity included longer disease duration, positive immunoserological profile and anti-CD20 therapy of patients. The rate of positive anti-RBD antibody response for healthy controls versus patients after 4 months post vaccination was 69% vs. 55% for the inactivated viral vaccine BBIBP-CorV, 97% vs. 53% for the pooled data of adenovirus vector-based vaccines Gam-COVID-Vac and AZD1222, or 100% vs. 81% for the pooled data of mRNA vaccines BNT162b2 and mRNA-1273, respectively. Patients who received the Gam-COVID-Vac or mRNA-1273 vaccines had a higher proportion of TNF-α producing CD4+ T-cells upon SARS-CoV-2 antigen stimulation compared to the inactivated viral vaccine.ConclusionAll five investigated vaccines were immunogenic in the majority of patients and healthy controls with variable antibody and T-cell response and an acceptable safety profile.

Malevolent creativity, which can be defined as creativity that is deliberately planned to damage others, is a concept that explains how the capacity to generate novel and effective outcomes (creativity) may, on occasion, be misapplied. The present study used 130 male inmates of the Oradea Maximum Security Penitentiary in Romania to explore the ability of a set of personality variables (the dark triad, self-efficacy, and self-esteem) to predict malevolent creative ideation. The findings indicate that Machiavellianism and self-efficacy were significant predictors of malevolent creative ideation in the form of lying, while only Machiavellianism was a significant predictor of malevolent creative ideation in the form of hurting people. In addition, the present study found significant differences among subgroups in the sample, with more experienced offenders showing higher levels of malevolent creative ideation.

PACAP was discovered 30 years ago in Dr. Akira Arimura's laboratory. In the past three decades since then, it has become evident that this peptide plays numerous crucial roles in mammalian organisms. The most important functions of PACAP are the following: 1. neurotransmitter, 2. neuromodulator, 3. hypophysiotropic hormone, 4. neuroprotector. This paper reviews the accumulated data regarding the distribution of PACAP and its receptors in the mammalian hypothalamus and pituitary gland, the role of PACAP in the gonadotropin hormone secretion of females and males. The review also summarizes the interaction between PACAP, GnRH, and sex steroids as well as hypothalamic peptides including kisspeptin. The possible role of PACAP in reproductive functions through the biological clock is also discussed. Finally, the significance of PACAP in the hypothalamo-hypophysial system is considered and the facts missing, that would help better understand the function of PACAP in this system, are also highlighted.

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/β-peptide tags with high affinity to the lipid raft-associated ganglioside GM1. These sequences induce effective internalization of the attached immunoglobulin cargo. The structural requirements of the GM1-peptide interaction are presented, and the importance of the membrane components are shown. The results contribute to the development of a receptor-based cell delivery platform.

Abstract There is a pressing need to develop ways to deliver therapeutic macromolecules to their intracellular targets. Certain viral and bacterial proteins are readily internalized in functional form through lipid raft‐mediated/caveolar endocytosis, but mimicking this process with protein cargoes at therapeutically relevant concentrations is a great challenge. Targeting ganglioside GM1 in the caveolar pits triggers endocytosis. A pentapeptide sequence WYKYW is presented, which specifically captures the glycan moiety of GM1 (KD = 24 nm). The WYKYW‐tag facilitates the GM1‐dependent endocytosis of proteins in which the cargo‐loaded caveosomes do not fuse with lysosomes. A structurally intact immunoglobulin G complex (580 kDa) is successfully delivered into live HeLa cells at extracellular concentrations ranging from 20 to 160 nm, and escape of the cargo proteins to the cytosol is observed. The short peptidic WYKYW‐tag is an advantageous endocytosis routing sequence for lipid raft‐mediated/caveolar cell delivery of therapeutic macromolecules, especially for cancer cells that overexpress GM1.

Abstract: The dog, seen today as the symbol of faith and alertness, has been present in pictorial arts, especially in Flemish and Dutch painting since the 15th century. Over time, this animal has lost its aggressive character in various forms of representation and has become a somewhat indispensable element of genre paintings. Our analysis aims to study the dogs which appear in the sketches and paintings of Jean-Baptiste Greuze. We wish to show the different roles that can be attributed to the dogs in the artist’s works, mainly through the analysis of his paintings in Diderot’s Salons, and also in works of less known art critics, such as Mathon de La Cour and abbé de la Porte.

Bone marrow derived mesenchymal stromal cells (MSCs) have recently been implicated as one source of the tumor-associated stroma, which plays essential role in regulating tumor progression. In spite of the intensive research, the individual factors in MSCs controlling tumor progression have not been adequately defined. In the present study we have examined the role of galectin-1 (Gal-1), a protein highly expressed in tumors with poor prognosis, in MSCs in the course of tumor development. Co-transplantation of wild type MSCs with 4T1 mouse breast carcinoma cells enhances the incidence of palpable tumors, growth, vascularization and metastasis. It also reduces survival compared to animals treated with tumor cells alone or in combination with Gal-1 knockout MSCs. In vitro studies show that the absence of Gal-1 in MSCs does not affect the number of migrating MSCs toward the tumor cells, which is supported by the in vivo migration of intravenously injected MSCs into the tumor. Moreover, differentiation of endothelial cells into blood vessel-like structures strongly depends on the expression of Gal-1 in MSCs. Vital role of Gal-1 in MSCs has been further verified in Gal-1 knockout mice. By administering B16F10 melanoma cells into Gal-1 deficient animals, tumor growth is highly reduced compared to wild type animals. Nevertheless, co-injection of wild type but not Gal-1 deficient MSCs results in dramatic tumor growth and development.These results confirm that galectin-1 is one of the critical factors in MSCs regulating tumor progression.