Biology subjects

Szabo, A.

Publications and source records attributed to Szabo, A..

30 records · Page 2Linked to original sources

bioRxiv2023

Contrasting Response of Microeukaryotic and Bacterial Communities to the Interplay of Seasonality and Stochastic Events in Shallow Soda Lakes

Seasonal environmental variation is a leading driver of microbial planktonic community assembly and interactions. Yet, unexpected departures from general seasonal successional trends are often reported. To understand the role of local stochastic events in modifying seasonal succession, we sampled fortnightly throughout three seasons (spring, summer, and autumn) five nearby shallow soda lakes exposed to the same seasonal meteorological changes. We characterised their microeukaryotic and bacterial communities by 18S and 16S rRNA gene sequencing, respectively. Biological interactions were inferred by the analyses of synchronous and time-shifted interaction networks, and the keystone taxa were topologically identified. The pans showed similar succession patterns during the study period with spring being characterised by high relevance of trophic interactions and certain level of community stability followed by a more dynamic and variable summer-autumn period both in respect of community composition and microbial interactions. Adaptation to general seasonal changes happened through the abundant shared core microbiome of the pans. However, stochastic events such as desiccation and cyanobacterial blooms disrupted common network attributes and introduced shifts from the prevalent seasonal trajectory. These were more pronounced for microeukaryotes than for bacteria which was reflected in increased turnover and contribution of non-core microeukaryotes. Our results demonstrated that despite being extreme and highly variable habitats, shallow soda lakes exhibit certain similarities in the seasonality of their planktonic communities, yet random stochastic events such as droughts can instigate substantial deviations from prevalent trends for the microeukaryotic but not bacterial communities.

microbiology↗

bioRxiv2022

A TYPE 2 INNATE LYMPHOID CELL-INTERLEUKIN 9 CIRCUIT INDUCES PANETH CELL METAPLASIA AND SMALL INTESTINAL REMODELING

Paneth cell metaplasia (PCM) typically arises in the setting of pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract has not been delineated. Herein, we describe the development of PCM in a murine model of inducible bcr/abl oncogene-driven chronic myelogenous leukemia (CML) in which metaplasia is causally and temporally linked to the development of leukemia. Mechanistically, CML induced a proinflammatory state within the GI tract that resulted in the production of epithelial-derived IL-33. Binding of IL-33 to ST2 led to the production of IL-9 by type 2 innate lymphoid cells (ILC2s) which was directly responsible for the induction of PCM in the colon and Paneth cell hyperplasia in the ileum. In addition, IL-9 directed remodeling of the small intestines characterized by goblet and tuft cell hyperplasia along with the expansion of mucosal mast cells. Thus, we identify that an extra intestinal disease can trigger an ILC2/IL-9 immune circuit which induces PCM and regulates epithelial cell fate decisions in the GI tract.

immunology↗

bioRxiv2022

Zymosan-induced leukocyte and cytokine changes in pigs: a new model for streamlined drug testing against severe COVID-19

Injection of 0.1 mg/kg zymosan in pigs i.v. elicited transient hemodynamic disturbance within minutes, without major blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This change was followed by a transient granulopenia with a trough at 1 h, and then, up to about 6 h, a major granulocytosis, resulting in a 3-4-fold increase of neutrophil-to-lymphocyte ratio (NLR). In parallel with the changes in WBC differential, qRT-PCR and ELISA analyses showed increased transcription and/or release of inflammatory cytokines and chemokines into blood, including IL-6, TNF-, CCL-2, CXCL-10, and IL-1RA. The expression of IL-6 peaked at already 1.5-2.5 h, and we observed significant correlation between lymphopenia and IL-6 gene expression. While these changes are consistent with zymosans known stimulatory effect on both the humoral and cellular arms of the innate immune system, what gives novel clinical relevance to the co-manifestation of above hemodynamic, hematological, and immune changes is that they represent independent bad prognostic indicators in terminal COVID-19 and other diseases involving cytokine storm. Thus, within a 6 h experiment, the model enables consecutive reproduction of a symptom triad that is characteristic of late-stage COVID-19. Given the limitations of modeling cytokine storm in animals and effectively treating severe COVID-19, the presented relatively simple large animal model may advance the R&D of drugs against these conditions. One of these disease markers (NLR), obtained from a routine laboratory endpoint (WBC differential), may also enable streamlining the model for high throughput drug screening against innate immune overstimulation.

immunology↗

bioRxiv2021

Microbial stowaways - waterbirds as dispersal vectors of aquatic pro- and microeukaryotic communities

AimWaterbirds are important dispersal vectors of multicellular organisms such as macrophytes, aquatic macroinvertebrates, and zooplankton. However, no study to date has focused on their potential role in dispersing aquatic microbial communities (i.a., bacteria, algae, protozoa). Here, we explicitly studied passive transport (endozoochory) of prokaryotes and unicellular microeukaryotes by waterbirds based on DNA metabarcoding approaches. By directly comparing the dispersed set of organisms to the source pool of a natural metacommunity, we aimed for a realistic estimate of the overall importance of waterbird zoochory for natural microbial communities. LocationShallow saline temporary ponds (soda pans) in the cross-border region of Austria and Hungary. TaxonProkaryotes and unicellular microeukaryotes. MethodsIn 2017 and 2018, water samples from 25 natural aquatic habitats along with fresh droppings of the dominant greylag goose (Anser anser) and four other waterbird species were collected in a habitat network of temporary ponds. Their prokaryotic and microeukaryotic communities were identified via 16S and 18S rRNA gene amplicon sequencing. Sequence reads were analysed using mothur. After quality filtering of the reads, pro- and microeukaryotic amplicon sequencing variant (ASV) compositions were compared between the aquatic and dropping samples, across years and waterbird species. ResultsWe found that 28% of the dominant aquatic prokaryotic and 19% of the microeukaryotic ASVs were transported by A. anser. ASV richness in A. anser droppings was lower, but compositional variation was higher compared to the aquatic communities, probably resulting from stochastic pick-up of microbes from multiple aquatic habitats. We furthermore found that the composition of prokaryotic ASVs in bird droppings were different among the two years and reflected the actual aquatic communities. The dispersed set of microbes were largely similar among the different waterbird species except for the planktivore filter-feeder northern shoveler (Spatula clypeata) which was outstanding by dispersing a more species-rich subset of microeukaryotes than shorebirds or geese. Main conclusionsBy using a combined amplicon-sequencing approach to characterize microorganisms in waterbird droppings and in the associated environment, our study provides strong evidence for endozoochory of natural aquatic microorganism communities. These results imply that waterbirds may be crucial in maintaining ecological connectivity between discrete aquatic habitats at the level of microbial communities.

ecology↗

bioRxiv2020

A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In this study we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA-sequencing. The model generated astrocyte-specific patterns of gene expression during differentiation, and demonstrated that these patterns correspond well to astroglia-specific expression signatures of in vivo cortical fetal development. Applying this model, we were able to identify SCZ-specific expression dynamics in human astrocytes, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results provide strong support for the validity of our astrocyte model, and implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.

neuroscience↗

bioRxiv2020

Grazing pressure-induced shift in planktonic bacterial communities with the dominance of acIII-A1 actinobacterial lineage in soda pans

Astatic soda pans of the Pannonian Steppe are unique environments with respect to their multiple extreme physical and chemical characteristics (high daily water temperature fluctuation, high turbidity, alkaline pH, salinity, polyhumic organic carbon concentration, hypertrophic state and special ionic composition). However, little is known about the seasonal dynamics of the bacterial communities inhabiting these lakes and the role of environmental factors that have the main impact on their structure. Therefore, two soda pans were sampled monthly between April 2013 and July 2014 to reveal changes in the planktonic community. By late spring in both years, a sudden shift in the community structure was observed, the previous algae-associated bacterial communities had collapsed, resulting the highest ratio of actinobacteria within the bacterioplankton (89%, with the dominance of acIII-A1 lineage) ever reported in the literature. Before these peaks, an extremely high abundance (>10,000 individuum l-1) of microcrustaceans (Moina and Arctodiaptomus) was observed. OTU-based statistical approaches showed that in addition to algal blooms and water-level fluctuations, zooplankton densities had the strongest effect on the composition of bacterial communities. In these extreme environments, this implies a surprisingly strong, community-shaping top-down role of microcrustacean grazers.

microbiology↗

bioRxiv2020

Autocrine inhibition of cell motility can drive epithelial branching morphogenesis in absence of growth

Epithelial branching morphogenesis drives the development of organs such as the lung, salivary gland, kidney and the mammary gland. It involves cell proliferation, cell differentiation and cell migration. An elaborate network of chemical and mechanical signals between the epithelium and the surrounding mesenchymal tissues regulates the formation and growth of branching organs. Surprisingly, when cultured in isolation from mesenchymal tissues, many epithelial tissues retain the ability to exhibit branching morphogenesis even in absence of proliferation. In this work, we propose a simple, experimentally-plausible mechanism that can drive branching morphogenesis in absence of proliferation and cross-talk with the surrounding mesenchymal tissue. The assumptions of our mathematical model derive from in vitro observations of the behavior of mammary epithelial cells. These data show that autocrine secretion of the growth factor TGF{beta}1 inhibits the formation of cell protrusions, leading to curvature dependent inhibition of sprouting. Our hybrid cellular Potts and partial-differential equation model correctly reproduces the experimentally observed tissue-geometry dependent determination of the sites of branching, and it suffices for the formation of self-avoiding branching structures in absence and also in presence of cell proliferation.

biophysics↗

bioRxiv2020

In response to Li et al.: Linker histones function in Drosophila embryogenesis

In an earlier paper (Perez-Montero et al., 2013), we reported that the embryonic linker histone of Drosophila dBigH1 was essential for early Drosophila embryogenesis since embryos homozygous for the bigH1100 mutation showed strong defects and did not survive beyond zygotic genome activation (ZGA) at cellularization. Recent results challenge these observations since null bigH1 mutations generated by CRISPR/Cas9 methodology turn out to be homozygous viable, as reported in Li et al. (2019) and here. In this regard, Li et al. described a novel mechanism by which lack of dBigH1 is compensated by the early expression of maternal dH1. Here, we confirm this observation and show that such compensatory mechanism is not activated in bigH1100 embryos.

molecular biology↗

bioRxiv2019

Cannabis use is associated with increased levels of soluble gp130 in schizophrenia but not in bipolar disorder

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered cannabis use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ, n=401) and bipolar disorder patients (BD, n=242). A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ and BD patients after subdividing each group into cannabis user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among cannabis users in the SCZ group (p=0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p=0.0059), YKL40 (p=0.0069), CatS (p=0.013), sTNFR1 (p=0.031), and BDNF (p=0.020), where these factors exhibited higher plasma levels in cannabis user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. In sum, our results show that cannabis self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential neuroimmune, anti-inflammatory, and biobehavioral-cognitive effects of cannabis use in SCZ.

pharmacology and toxicology↗

bioRxiv2019

Cell types of the human retina and its organoids at single-cell resolution: developmental convergence, transcriptomic identity, and disease map

How closely human organoids recapitulate cell-type diversity and cell-type maturation of their target organs is not well understood. We developed human retinal organoids with multiple nuclear and synaptic layers. We sequenced the RNA of 158,844 single cells from these organoids at six developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable developed state at a rate similar to human retina development in vivo and the transcriptomes of organoid cell types converged towards the transcriptomes of adult peripheral retinal cell types. The expression of disease-associated genes was significantly cell-type specific in adult retina and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in adult human retinas.

neuroscience↗

bioRxiv2019

Low Replication Capacity Virus Is Preferentially Transmitted In Mother-To-Child-Transmission But Not In Adult-To-Adult-Transmission Of HIV-1

Previous studies of the transmitted/founder virus compared to viral quasispecies in the donor have yielded conflicting results. In heterosexual adult-to-adult transmission (ATAT), the viral replicative capacity (VRC) of transmitted virus is reportedly either similar to, or somewhat higher than, that of donor virus, whilst transmitted virus in mother-to-child transmission (MTCT) has a significantly lower VRC than that of maternal virus. These discrepancies may be explained by the different methodologies used in these studies, or they may reflect true differences in the transmission bottleneck. To resolve this question, we here use the same methodology to compare transmitted versus donor virus in MTCT and ATAT. We show that, in a South African mother-child cohort, infant virus samples obtained at 1-2 days after birth had VRC significantly lower than in the mothers (p=0.0003). By contrast, in Zambian ATAT transmission pairs, VRC of transmitted virus was similar to or somewhat higher than donor virus (p=ns). The VRC of virus transmitted to the recipient, compared to that in the donor, was significantly lower in MTCT versus heterosexual ATAT (p=0.01). These studies demonstrate that fundamental differences exist between the viruses transmitted via the MTCT and ATAT bottlenecks that are not explained by methodological factors. This result is of importance since transmission of low replicative capacity virus results in low immune activation and a small viral reservoir, and therefore the preferential transmission of low fitness viruses in MTCT might be expected to increase cure potential in in utero infected infants and children.\n\nIMPORTANCEUnderstanding the factors determining which viruses are preferentially transmitted in HIV infection is critical to the development of new, effective strategies to prevent transmission. Despite this, much remains unknown in this respect, both with regard to adult-to-adult transmission (ATAT) but especially with respect to mother-to-child transmission (MTCT). The finding here that fundamental differences exist in the genetic bottleneck of HIV transmission between heterosexual ATAT and MTCT is an important initial step to help define the viral mechanisms contributing to transmission in each case. In addition, we show that viruses of low viral replicative capacity are preferentially transmitted in MTCT. This suggests the possibility that a window of opportunity exists following in utero infection in which early anti-viral intervention not only reduces the size and diversity of the viral reservoir, but additionally maintains a reservoir comprising low viral replicative capacity HIV. Low replicative capacity of transmitted virus has previously been shown to result in low immune activation and low proviral DNA load in central memory cells, factors likely to be directly relevant to increasing cure potential in HIV-infected infants and children.

immunology↗

bioRxiv2018

Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans

Targeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retina in vivo, and in the human retina in vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.

neuroscience↗