Quantitative Structure-Activity Relationship (QSAR) Analysis of Antileishmanial Natural Products

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Transitionen, Selektionsentscheidungen und Bildungschancen

Herkunftsbedingte Disparitäten und ungleiche Bildungschancen von Schüler*innen aus Familien mit Migrationsgeschichte charakterisieren insbesondere die Gelenkstellen des Bildungssystems, wie den Schuleintritt und den Übertritt von der Grundschule auf eine weiterführende Schule. Diese Transitionen werden in der vorliegenden Studie aus der Perspektive von Eltern mit Migrationsgeschichte betrachtet. Diese skizzieren, im Sinne eines Participatory Research Approachs, mittels der Critical Incident Technique bedeutsame Ereignisse, die sie in diesen Übergangsphasen ihrer Kinder erlebt haben. Eltern schildern die Transitionen geprägt von leistungs- und verhaltensbezogenen Zuschreibungen gegenüber ihren Kindern wie auch ihren eigenen Erziehungspraktiken. Die besondere Tragweite liegt darin, dass diese Zuschreibungen die Bildungsbiografie ihrer Kinder von Beginn an begleiten, beginnend in der Einschulungsphase vor dem Schuleintritt über die ersten Tage und Wochen nach Schulbeginn bis zum Übertritt in eine weiterführende Schule. Ein Teil der Eltern berichtet, dass der angestrebte Bildungsweg letztendlich verwirklicht werden konnte. Zuschreibungen haben allerdings selbst bei formal gelungenen Transitionen weitreichende Folgen. Eltern und Kinder leiden langanhaltend unter Gefühlen von Demütigung sowie unter Verunsicherung, Ängsten und emotionaler Erschöpfung. Diese Ergebnisse gehen über den Diskurs zu sekundären Herkunftseffekten hinaus. Bildungserfolg bzw. das Gelingen von Transitionen darf nicht nur an der Übertritts- oder Rückstellungsquote gemessen werden – daran, ob der Übergang formal gelingt oder nicht. Es bedarf, auch bei formal gelungenen Übergängen, Indikatoren wie Wohlbefinden von Kindern und Eltern, soziale Integration und Fähigkeiten, Freundschaften zu schließen etc. Solche Indikatoren sind nicht nur direkt im Übergang, sondern mit Blick auf die leistungsbezogene und soziale Entwicklung der Kinder längerfristig zu verfolgen.Inequalities within the educational career of students from families with a migrant history characterise especially the transitional points in the educational system, such as the transitions to primary school and to secondary education. In the present study, these transitions were considered from the perspective of parents with a migrant history. Using the critical incident technique within a participatory research approach, parents outlined significant situations which they have experienced during their children’s transitions. From the parents’ view, transitions were characterised by attributions related to their children’s performance and behaviours as well to their own parenting. These attributions were part of the children’s educational biography from the beginning: they were present during the transition from kindergarten to primary school, in the first days and weeks after starting school and during transition to secondary education. The intended educational career was often achieved; nevertheless, even if transitions formally succeeded attributions had far-reaching consequences. Parents and children suffered long-lasting feelings of humiliation, helplessness, anxieties and emotional exhaustion. These findings go beyond the discourse on inequalities within the educational system and their outcome. Educational success or the success of transitions must not only be measured by the fact if the transition succeeded or not. Indicators such as well-being of parents and children, children’s social integration and abilities to make friends are to be considered even if the transition was successful. Additionally, such indicators need to be pursued for the longer term with regard to the children’s performance-related and social development

Metabolic fate, mass spectral fragmentation, detectability, and differentiation in urine of the benzofuran designer drugs 6-APB and 6-MAPB in comparison to their 5-isomers using GC-MS and LC-(HR)-MSn techniques

The number of so-called new psychoactive substances (NPS) is still increasing by modification of the chemical structure of known (scheduled) drugs. As analogues of amphetamines, 2-aminopropyl-benzofurans were sold. They were consumed because of their euphoric and empathogenic effects. After the 5-(2-aminopropyl)benzofurans, the 6-(2-aminopropyl)benzofuran isomers appeared. Thus, the question arose whether the metabolic fate, the mass spectral fragmentation, and the detectability in urine are comparable or different and how an intake can be differentiated. In the present study, 6-(2-aminopropyl)benzofuran (6-APB) and its N-methyl derivative 6-MAPB (N-methyl-6-(2-aminopropyl)benzofuran) were investigated to answer these questions. The metabolites of both drugs were identified in rat urine and human liver preparations using GC-MS and/or liquid chromatography-high resolution-mass spectrometry (LC-HR-MSn). Besides the parent drug, the main metabolite of 6-APB was 4-carboxymethyl-3-hydroxy amphetamine and the main metabolites of 6-MAPB were 6-APB (N-demethyl metabolite) and 4-carboxymethyl-3-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 6-MAPB N-demethylation were CYP1A2, CYP2D6, and CYP3A4. An intake of a common users’ dose of 6-APB or 6-MAPB could be confirmed in rat urine using the authors’ GC-MS and the LC-MSn standard urine screening approaches with the corresponding parent drugs as major target allowing their differentiation. Furthermore, a differentiation of 6-APB and 6-MAPB in urine from their positional isomers 5-APB and 5-MAPB was successfully performed after solid phase extraction and heptafluorobutyrylation by GC-MS via their retention times

In vitro development of resistance against antipseudomonal agents: comparison of novel beta-lactam/beta-lactamase inhibitor combinations and other beta-lactam agents

We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane- tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other β-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and merope nem. These alterations, along with ones in mexR and amrR, provided resistance to most β-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in β-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer β-lactam/β-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other β-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents

T1000: a reduced gene set prioritized for toxicogenomic studies

There is growing interest within regulatory agencies and toxicological research communities to develop, test, and apply new approaches, such as toxicogenomics, to more efficiently evaluate chemical hazards. Given the complexity of analyzing thousands of genes simultaneously, there is a need to identify reduced gene sets. Though several gene sets have been defined for toxicological applications, few of these were purposefully derived using toxicogenomics data. Here, we developed and applied a systematic approach to identify 1,000 genes (called Toxicogenomics-1000 or T1000) highly responsive to chemical exposures. First, a co-expression network of 11,210 genes was built by leveraging microarray data from the Open TG-GATEs program. This network was then re-weighted based on prior knowledge of their biological (KEGG, MSigDB) and toxicological (CTD) relevance. Finally, weighted correlation network analysis was applied to identify 258 gene clusters. T1000 was defined by selecting genes from each cluster that were most associated with outcome measures. For model evaluation, we compared the performance of T1000 to that of other gene sets (L1000, S1500, Genes selected by Limma, and random set) using two external datasets based on the rat model. Additionally, a smaller (T384) and a larger version (T1500) of T1000 were used for dose-response modeling to test the effect of gene set size. Our findings demonstrated that the T1000 gene set is predictive of apical outcomes across a range of conditions (e.g., in vitro and in vivo, dose-response, multiple species, tissues, and chemicals), and generally performs as well, or better than other gene sets available

Phenotypic Expansion of Knobloch Syndrome Type 2 in an Individual With a De Novo PAK2 Variant.

P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelic PAK2 variants cause Knobloch syndrome type 2 (KNO2)-a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novel de novo heterozygous missense variant in PAK2, NM_002577.4:c.1273G\u3eA, p.(D425N), by genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes observed in this individual were global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging by in silico analysis. Previous clinical genetic testing did not report this variant due to unknown relevance of PAK2 variants at the time of testing, highlighting the importance of reanalysis. Our findings substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical phenotypic spectrum

Scaled mass index derived from aerial photogrammetry associated with predicted metabolic pathway disruptions in free-ranging St. Lawrence Estuary belugas

The St. Lawrence Estuary (SLE) belugas (Quebec, Canada) are an endangered population whose numbers remain low despite ongoing conservation efforts. Multiple anthropogenic factors and changing environmental conditions are thought to have contributed to the recent 20-year decline in blubber fatty acid concentrations reported in stranded SLE belugas. Despite this evidence that energy reserves within the population are declining, there is currently no method for estimating the body condition of free-ranging animals. The potential metabolic consequences of declining fat reserves have also yet to be explored. The objectives of this study were to use unmanned aerial vehicle (UAV)-based photogrammetry to estimate the scaled mass index (SMI) of free-ranging SLE belugas, and to compare this proxy of body condition to the lipidome of outer-layer blubber samples collected from the same individuals via remote biopsy darting. Morphometric analysis of aerial images (n = 44 SLE belugas), combined with data collected from animals under professional human care, produced SMI estimates (females: 807 ± 98 kg, males: 743 ± 39 kg) similar in range to those previously calculated for SLE beluga carcasses of known weight. A non-targeted lipidomic analysis followed by pathway enrichment analysis, identified metabolic pathways predicted to show altered activity in association with SMI in the blubber of free-ranging male SLE belugas (n = 27). Mapping of enriched pathways compared to the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways maps, revealed that enriched pathways pertained to the metabolism of multiple lipid classes including fatty acyls and glycerophospholipids. Vitamin A, Vitamin E, and tyrosine metabolism pathways were also enriched in correlation with SMI. This study provides the basis for the development of a non-invasive technique for estimating the body condition of free-ranging SLE belugas and identifies metabolic pathways that merit further exploration to improve our understanding of the potential metabolic impacts of energy loss in cetaceans

Anti-bacterial activity of inorganic nanomaterials and their antimicrobial peptide conjugates against resistant and non-resistant pathogens

This review details the antimicrobial applications of inorganic nanomaterials of mostly metallic form, and the augmentation of activity by surface conjugation of peptide ligands. The review is subdivided into three main sections, of which the first describes the antimicrobial activity of inorganic nanomaterials against gram-positive, gram-negative and multidrug-resistant bacterial strains. The second section highlights the range of antimicrobial peptides and the drug resistance strategies employed by bacterial species to counter lethality. The final part discusses the role of antimicrobial peptide-decorated inorganic nanomaterials in the fight against bacterial strains that show resistance. General strategies for the preparation of antimicrobial peptides and their conjugation to nanomaterials are discussed, emphasizing the use of elemental and metallic oxide nanomaterials. Importantly, the permeation of antimicrobial peptides through the bacterial membrane is shown to aid the delivery of nanomaterials into bacterial cells. By judicious use of targeting ligands, the nanomaterial becomes able to differentiate between bacterial and mammalian cells and, thus, reduce side effects. Moreover, peptide conjugation to the surface of a nanomaterial will alter surface chemistry in ways that lead to reduction in toxicity and improvements in biocompatibility

MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene

INTRODUCTION: The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for microRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged. METHODS: microRNA profiling was conducted on stromal and epithelial cellular subsets microdissected from the pubertal mouse mammary gland. miR-184 was reactivated by transient or stable overexpression in breast cancer cell lines and examined using a series of in vitro (proliferation, tumour-sphere and protein synthesis) assays. Orthotopic xenografts of breast cancer cells were used to assess the effect of miR-184 on tumourigenesis as well as distant metastasis. Interactions between miR-184 and its putative targets were assessed by quantitative PCR, microarray, bioinformatics and 3' untranslated region Luciferase reporter assay. The methylation status of primary patient samples was determined by MBD-Cap sequencing. Lastly, the clinical prognostic significance of miR-184 putative targets was assessed using publicly available datasets. RESULTS: A large number of microRNA were restricted in their expression to specific tissue subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of triple negative breast cancer (TNBC) cell lines in vitro and delayed primary tumour formation and reduced metastatic burden in vivo. Gene expression studies uncovered multi-factorial regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients. CONCLUSIONS: These studies elucidate a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour progression and identify miR-184 as a putative breast tumour suppressor