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Recent proposals suggest that timing in acquisition, i.e., the age at which a phenomenon is mastered by monolingual children, influences acquisition of the L2, interacting with age of onset of bilingualism and amount of L2 input. Here, we examine whether timing affects acquisition of the bilingual child’s heritage language, possibly modulating the effects of environmental and child-internal factors. The performance of 6- to 12-year-old Greek heritage children residing in Germany (age of onset of German: 0–4 years) was assessed across a range of nine syntactic structures via the Greek LITMUS (Language Impairment Testing in Multilingual Settings) Sentence Repetition Task. Based on previous studies on monolingual Greek, the structures were classified as “early” (main clauses (SVO), coordination, clitics, complement clauses, sentential negation, non-referential wh-questions) or as “late” (referential wh-questions, relatives, adverbial clauses). Current family use of Greek and formal instruction in Greek (environmental), chronological age, and age of onset of German (child-internal) were assessed via the Questionnaire for Parents of Bilingual Children (PABIQ); short-term memory (child-internal) was measured via forward digit recall. Children’s scores were generally higher for early than for late acquired structures. Performance on the three early structures with the highest scores was predicted by the amount of current family use of Greek. Performance on the three late structures was additionally predicted by forward digit recall, indicating that higher short-term memory capacity is beneficial for correctly reconstructing structurally complex sentences. We suggest that the understanding of heritage language development and the role of child-internal and environmental factors will benefit from a consideration of timing in the acquisition of the different structures.
This paper intends to provide some speculative remarks on how consistency and continuity in language use practices within and across contexts inform heritage language acquisition outcomes. We intend “consistency” as maintenance of similar patterns of home language use over the years. “Continuity” refers to the possibility for heritage language speakers to be exposed to formal education in the heritage language. By means of a questionnaire study, we analyze to what extent Italian heritage families in Germany are consistent in their use of the heritage language with their children. Furthermore, by analyzing the educational offer related to Italian as a heritage language across different areas in Germany, we reflect on children’s opportunities to experience continuity between home and school language practices. Finally, we interpret the results of previous studies on Italian heritage language acquisition through the lens of consistency and continuity of language experience. In particular, we show that under the appropriate language experience conditions (involving consistency and continuity), heritage speakers may be successful even in the acquisition of linguistic phenomena that have been shown to be acquired late in first language acquisition.
Based on recent perturbative and non-perturbative lattice calculations with almost quark flavors and the thermal contributions from photons, neutrinos, leptons, electroweak particles, and scalar Higgs bosons, various thermodynamic quantities, at vanishing net-baryon densities, such as pressure, energy density, bulk viscosity, relaxation time, and temperature have been calculated up to the TeV-scale, i.e., covering hadron, QGP, and electroweak (EW) phases in the early Universe. This remarkable progress motivated the present study to determine the possible influence of the bulk viscosity in the early Universe and to understand how this would vary from epoch to epoch. We have taken into consideration first- (Eckart) and second-order (Israel–Stewart) theories for the relativistic cosmic fluid and integrated viscous equations of state in Friedmann equations. Nonlinear nonhomogeneous differential equations are obtained as analytical solutions. For Israel–Stewart, the differential equations are very sophisticated to be solved. They are outlined here as road-maps for future studies. For Eckart theory, the only possible solution is the functionality, H(a(t)), where H(t) is the Hubble parameter and a(t) is the scale factor, but none of them so far could to be directly expressed in terms of either proper or cosmic time t. For Eckart-type viscous background, especially at finite cosmological constant, non-singular H(t) and a(t) are obtained, where H(t) diverges for QCD/EW and asymptotic EoS. For non-viscous background, the dependence of H(a(t)) is monotonic. The same conclusion can be drawn for an ideal EoS. We also conclude that the rate of decreasing H(a(t)) with increasing a(t) varies from epoch to epoch, at vanishing and finite cosmological constant. These results obviously help in improving our understanding of the nucleosynthesis and the cosmological large-scale structure.
The incidence of invasive mold disease (IMD) has significantly increased over the last decades, and IMD of the central nervous system (CNS) is a particularly severe form of this infection. Solid data on the incidence of CNS IMD in the pediatric setting are lacking, in which Aspergillus spp. is the most prevalent pathogen, followed by mucorales. CNS IMD is difficult to diagnose, and although imaging tools such as magnetic resonance imaging have considerably improved, these techniques are still unspecific. As microscopy and culture have a low sensitivity, non-culture-based assays such as the detection of fungal antigens (e.g., galactomannan or beta-D-glucan) or the detection of fungal nucleic acids by molecular assays need to be validated in children with suspected CNS IMD. New and potent antifungal compounds helped to improve outcome of CNS IMD, but not all agents are approved for children and a pediatric dosage has not been established. Therefore, studies have to rapidly evaluate dosage, safety and efficacy of antifungal compounds in the pediatric setting. This review will summarize the current knowledge on diagnostic tools and on the management of CNS IMD with a focus on pediatric patients.
Osteoarthritis (OA) is a slow-progressing joint disease, leading to the degradation and remodeling of the cartilage extracellular matrix (ECM). The usually quiescent chondrocytes become reactivated and accumulate in cell clusters, become hypertrophic, and intensively produce not only degrading enzymes, but also ECM proteins, like the cartilage oligomeric matrix protein (COMP) and thrombospondin-4 (TSP-4). To date, the functional roles of these newly synthesized proteins in articular cartilage are still elusive. Therefore, we analyzed the involvement of both proteins in OA specific processes in in vitro studies, using porcine chondrocytes, isolated from femoral condyles. The effect of COMP and TSP-4 on chondrocyte migration was investigated in transwell assays and their potential to modulate the chondrocyte phenotype, protein synthesis and matrix formation by immunofluorescence staining and immunoblot. Our results demonstrate that COMP could attract chondrocytes and may contribute to a repopulation of damaged cartilage areas, while TSP-4 did not affect this process. In contrast, both proteins similarly promoted the synthesis and matrix formation of collagen II, IX, XII and proteoglycans, but inhibited that of collagen I and X, resulting in a stabilized chondrocyte phenotype. These data suggest that COMP and TSP-4 activate mechanisms to protect and repair the ECM in articular cartilage.
Nematophilic bacteria as a source of novel macrocyclised antimicrobial non-ribosomal peptides
(2020)
A solution to ineffective clinical antimicrobials is the discovery of new ones from under-explored sources such as macrocyclic non-ribosomal peptides (NRP) from nematophilic bacteria. In this dissertation an antimicrobial discovery process –from soil sample to inhibitory peptide– is demonstrated through investigations on six nematophilic bacteria: Xenorhabdus griffiniae XN45, X. griffiniae VH1, Xenorhabdus sp. nov. BG5, Xenorhabdus sp. nov. BMMCB, X. ishibashii and Photorhabdus temperata. To demonstrate the first step of bacterium isolation and species delineation, endosymbionts were isolated from Steinernema sp. strains BG5 and VH1 that were isolated directly from soil samples in Western Kenya. After genome sequencing and assembly of novel Xenorhabdus isolates VH1 and BG5, species delineation was done via three overall genome relatedness indices. VH1 was identified as X. griffiniae VH1, BG5 as Xenorhabdus sp. nov. BG5 and X. griffiniae BMMCB was emended to Xenorhabdus sp. nov. BMMCB. The nematode host of X. griffiniae XN45, Steinernema sp. scarpo was highlighted as a putative novel species. To demonstrate the second step of genome mining and macrocyclic non-ribosomal peptide structure elucidation, chemosynthesis and biosynthesis, the non-ribosomal peptide whose production is encoded by the ishA-B genes in X. ishibashii was investigated. Through a combination of refactoring the ishA-B operon by a promoter exchange mechanism, isotope labelling experiments, high resolution tandem mass spectrometry analysis, bioinformatic protein domain analysis and chemoinformatic comparisons of actual to hypothetical mass spectrometry spectra, the structures of Ishipeptides were elucidated and confirmed by chemical synthesis. Ishipeptide A was a branch cyclic depsidodecapeptide macrocyclised via an ester bond between serine and the terminal glutamate. It chemosynthesis route was via a late stage macrolactamation and linearised Ishipeptide B was synthesised via solid phase iterative synthesis. Ishipeptides were not N-terminally acylated despite being biosynthesised from the IshA protein that had a C-starter domain. It was highlighted that more than restoration of the histidine active site of this domain is required to restore N-terminal acylation activity.
To demonstrate the final step of determination of antimicrobial activity, minimum inhibitory concentrations of Ishipeptides and Photoditritide from Photorhabdus temperata against fungi and bacteria were determined. None were antifungal while only the macrocyclic compounds were inhibitory, with Ishipeptide A inhibitory to Gram-positive bacteria at 37 µM. The cationic Photoditritide, a cyclic hexapeptide macrocyclised via a lactam bond between homoarginine and tryptophan, was 12 times more inhibitory (3.0 µM), even more effective than a current clinical compound, Ampicillin (4.2 µM). For both, macrocyclisation was hypothesised to contribute to antimicrobial activity. Ultimately, this dissertation demonstrated not only nematophilic bacteria as a source of novel macrocyclic antimicrobial non-ribosomal peptides but also a process of antimicrobial discovery–from soil sample to inhibitory peptide– from these useful bacteria genera. This is significant for the fight against antimicrobial resistance.
Bacterial and fungal toll-like receptor activation elicits type I IFN responses in mast cells
(2021)
Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.
The paper examines the importance of international labour standards for ESG reporting. International labour standards exist today for almost all working conditions. There are many reasons why ESG criteria should be based on these standards. This is already happening to some extent. However, the references to international labor standards should be expanded and the existing references deepened.
According to the standard account, IPRs allocate objects to owners, just like ownership allocates real property. In this paper, I explain that this simplistic paradigm operates on the basis of three fictions: The first – truly Polanyian – fiction concerns IP subject matter that was originally not produced for sale but created for other purposes, e.g. private pleasure. The second fiction is that IP is treated as a marketable good whereas much IP, in particular works and signs, are embedded in communication. Finally, IP is a fictitious concept in that we speak of works, inventions, and other IP objects as of tangible commodities, where in fact IP objects only exist insofar and because we speak and regulate as if they exist as abstract “goods” of value.
Three types of post-translation modifications (PTMs) containing N-glycosylation, phosphorylation, ubiquitylation were characterized in diffuse large B-cell lymphoma (DLBCL) on a global scale using quantitative mass spectrometry based proteomics technology in this study.
DLBCL is the most common type of malignant lymphomas and has a heterogeneous gene expression profiling, phenotype and clinical response to chemotherapy. DLBCL is a good model for the correct classification of cancers into molecularly different subtypes, which benefits for the selection of rational therapeutic strategies. It resulted in two histologically indistinguishable subtypes-activated B-cell-like (ABC) subgroup and germinal center B-cell-like (GCB) subgroup according to gene expression profiling. Signals originating from the B-cell receptor (BCR), the key protein on the surface of B cells, promote growth and survival of DLBCL. Antigen-dependent/independent BCR signaling is found in DLBCL subtypes.
Recent researches reveal that glycosylation plays role in human cells via site-specific regulation. Aberrant N-glycosylation in BCR-related effectors, such as, CD79a, immunoglobulin M or G (IgM or IgG), has been found to be associated with lymphoid malignancies. However, accurate quantification of intact glycopeptides and their individual glycan moieties in a cell-wide manner is still challenging. Here we established a site-specific quantitative N-glycoproteomics platform termed SugarQuant. It included a fast sample preparation workflow using Protein Aggregation Capture (PAC), an optimized multi-notch MS3 acquisition workflow (Glyco-SPS-MS3), a self-developed R-based tool (GlycoBinder). The robustness and accuracy of quantitation in SugarQuant were proved in a study using the different amounts of TMT-labelled IgM N-glycopeptides spiked into a background of TMT-labelled yeast peptides. Next, we used SugarQuant to identify and quantify more than 5000 unique glycoforms in Burkitt’s lymphoma cells treated with a series of doses of 2-deoxy-2-fluoro-L-fucose (2FF) and determine the more accurate site-specific glycosylation changes that occurred upon inhibition of fucosylation compared to using MS2 analysis. It revealed that 2FF-sensitive N-glycosylation on key players in BCR-mediated signaling in DG75. Furthermore, 2FF treatment also affects phosphorylation of the key players involving in B cell receptor signaling.
Then we investigated the site-specific quantitative N-glycoproteome in the cell lines of DLBCL subtypes using SugarQuant. More than 7000 unique intact glycopeptides (glycoforms) were quantified in five ABC DLBCL and four GCB DLBCL cell lines. The glycoproteome mapping (intact glycopeptide expressions) in each cell line allows to segregate DLBCL subtypes. The majority of these glycoforms were from the key cell-surface BCR effectors, such as IgM, CD79 and PTPRC. Lastly, we investigated the change of fucosylated glycopeptides in TMD8 cell line upon knockout of the fucosyltransferase FUT8, which is responsible for core-fucose synthesis, and by the treatment with 2FF. The results revealed that FUT8 might also regulate the synthesis of sub/terminal fucose on glycan chain and the inhibition of fucosylation increased the sialyated glycopeptide expression.
Phosphorylation is involved in regulating multiple processes as an important mediator in BCR signaling. Likewise, ubiquitylation plays vital roles in the activation of the nuclear factor-kappaB (NF-κB) pathway in BCR signaling. There are two vital upstream BCR-proximal tyrosine kinases, Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK), which regulate the auto-phosphorylation and phosphorylation of other proteins in BCR signaling pathway. Here we investigated the dynamics of downstream phosphorylation and ubiquitylation signaling in ABC DLBCL and GCB DLBCL cell lines upon the inhibitions of BTK and SYK using quantitative proteomics strategy. In the phosphoproteome analysis, a large dataset of quantified phosphorylation sites was obtained in the three ABC and four GCB DLBCL cell lines. BCR signaling in the subtypes of DLBCL cell lines was found to be highly individual in distinct cell lines. These significantly regulated phosphorylation events in each cell line with individual treatment were involved in multiple Reactome pathways, such as, M phase, signaling by Rho GTPases and diseases of signal transduction. Moreover, the gene regulation-related biological processes including chromosome organization and medication, DNA metabolic process, nuclear export, were involved in the DLBCL cell lines. In the ubiquitinome analysis, we identified more than 15,000 ubiquitylation sites in two ABC and one GCB cell lines upon the inhibition of BTK and SYK. The different ubiquitylation events observed in ABC and GCB subtypes revealed distinct BCR signaling pathways in two subtypes. The similar signaling perturbations across each cell line upon BTK and SYK inhibition, which were obtained from the significantly regulated ubiquitylated peptides expression, revealed the cell-type-specific concordance in ubiquitylation regulation upon BTK and SYK inhibition. These ubiquitylation modified proteins who bore the significantly regulated ubi-peptides in the samples were also found to be highly involved in gene regulatory processes.
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