Nelsonmaclean4529

Drug information centers (DICs) are institutions dedicated to provide objective, independent, and up-to-date information on drugs and their rational use. To overcome the lack of recent DIC reports from central Europe, we analyzed all queries (n = 594) submitted to the DIC run by the Institute for Clinical Pharmacology of Hannover Medical School between October 2018 and April 2022. Approximately one in three queries (31.1%; 185/594) was submitted by internists. 82.8% (492/594) of the queries were patient-specific, while the remaining 17.2% (102/594) were general queries. Adverse drug reactions (ADRs), indications/contraindications, and pharmacodynamic interactions (PDIs) represented the three most frequently addressed query categories, being involved in 44.8% (266/594), 43.3% (257/594), and 34.3% (204/594) of all queries, respectively (assignment of more than one category per query was possible). As compared to general queries, patient-specific queries were statistically significantly more often related to ADRs, PDIs, and pharmacokinetic interactions (PKIs) (ADRs 35.3% vs. 46.7%, P = 0.034; PDIs 14.7% vs. 38.4%, P  less then  0.001; PKIs 20.6% vs. 31.5%, P = 0.028). To demonstrate the complexity of queries submitted to the clinical-pharmacological DIC, we present and comment on an illustrative selection of queries.Mechanosensitive channels of small conductance, found in many living organisms, open under elevated membrane tension and thus play crucial roles in biological response to mechanical stress. Amongst these channels, MscK is unique in that its activation also requires external potassium ions. To better understand this dual gating mechanism by force and ligand, we elucidate distinct structures of MscK along the gating cycle using cryo-electron microscopy. The heptameric channel comprises three layers a cytoplasmic domain, a periplasmic gating ring, and a markedly curved transmembrane domain that flattens and expands upon channel opening, which is accompanied by dilation of the periplasmic ring. Furthermore, our results support a potentially unifying mechanotransduction mechanism in ion channels depicted as flattening and expansion of the transmembrane domain.Coronaviruses of the genera Gammacoronavirus and Deltacoronavirus are globally widespread and circulate primarily in wild and domestic birds. Prior studies have established frequently occurring crossover events from avian to mammalian reservoirs. However, there is limited understanding of the diversity and geographical distribution of coronaviruses among birds. In this study, the surveillance of coronaviruses in birds in Russia during 2020 revealed the presence of coronaviruses in 12% of samples from birds. Targeted NGS approach was used for the evaluation of genetic diversity based on RdRp gene. While gammacoronviruses were found in both wild birds and poultry, deltacoronaviruses were found in wild birds only and represent the first detections for Russia. A number of cases with the simultaneous detection of gamma- and deltacoronaviruses in one bird was reported. The results of this study highlight the importance of further research concerning the spread and diversity of coronaviruses among birds within and migrating throughout the territory of Russia across the globe.Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.This study revealed how Bacteria and Archaea communities and their metabolic functions differed between two groups of black deposits identified in gorge and cave environments. Scanning electron microscopy coupled with energy dispersive spectroscopy was used to analyse the presence of microbial biosignatures and the elemental composition of samples. Metabarcoding of the V3-V4 regions of 16S rRNA was used to investigate Bacteria and Archaea communities. Based on 16S rRNA sequencing results, PICRUSt software was used to predict metagenome functions. Micrographs showed that samples presented microbial biosignatures and microanalyses highlighted Mn concretions and layers on Al-Si surfaces. The 16S rRNA metabarcoding alpha-diversity metrics showed similar Simpson's and Shannon indices and different values of the Chao-1 index. The amplicon sequence variants (ASVs) analysis at the different taxonomic levels showed a diverse genera composition. However, the communities of all samples shared the presence of uncultured ASVs belonging to the Gemmatales family (Phylogenesis Gemmataceae; Planctomycetes; Planctomycetota; Bacteria). The predicted metagenome functions analysis revealed diverse metabolic profiles of the Cave and Gorge groups. Genes coding for essential Mn metabolism were present in all samples. Overall, the findings on structure, microbiota, and predicted metagenome functions showed a similar microbial contribution to epigean and hypogean black deposits Mn metabolism.Three-dimensional (3D) organotypic models that capture native-like physiological features of tissues are being pursued as clinically predictive assays for therapeutics development. find more A range of these models are being developed to mimic brain morphology, physiology, and pathology of neurological diseases. Biofabrication of 3D gel-based cellular systems is emerging as a versatile technology to produce spatially and cell-type tailored, physiologically complex and native-like tissue models. Here we produce 3D fibrin gel-based functional neural co-culture models with human-iPSC differentiated dopaminergic or glutamatergic neurons and astrocytes. We further introduce genetically encoded fluorescence biosensors and optogenetics activation for real time functional measurements of intracellular calcium and levels of dopamine and glutamate neurotransmitters, in a high-throughput compatible plate format. We use pharmacological perturbations to demonstrate that the drug responses of 3D gel-based neural models are like those expected from in-vivo data, and in some cases, in contrast to those observed in the equivalent 2D neural models.Cell-cell communication and physical interactions play a vital role in cancer initiation, homeostasis, progression, and immune response. Here, we report a system that combines live capture of different cell types, co-incubation, time-lapse imaging, and gene expression profiling of doublets using a microfluidic integrated fluidic circuit that enables measurement of physical distances between cells and the associated transcriptional profiles due to cell-cell interactions. We track the temporal variations in natural killer-triple-negative breast cancer cell distances and compare them with terminal cellular transcriptome profiles. The results show the time-bound activities of regulatory modules and allude to the existence of transcriptional memory. Our experimental and bioinformatic approaches serve as a proof of concept for interrogating live-cell interactions at doublet resolution. Together, our findings highlight the use of our approach across different cancers and cell types.Long-term air pollution (AP) exposure, including diesel exhaust exposure, is increasingly being recognized as a major contributor to the development of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. How AP increases the risk of neurodegeneration is not well understood but might include direct neurotoxicity and CNS inflammation. We investigated the impact of diesel exhaust particulate extract (DEPe) exposure on the brain and the mechanisms by which microglia and astroglia might mediate neuronal changes. Zebrafish (ZF) were utilized to determine neuronal toxicity of and microglial response to DEPe and single cell RNA sequencing was employed to study cell type-specific transcriptomic responses within the ZF brain. DEPe exposure induced neuronal injury and microglial activation in vivo. However, preventing the development of microglia did not attenuate DEPe-induced neuron loss, leading us to investigate microglial, astroglial, and neuronal response to DEPe exposure at single-cell resolution. Differentially expressed genes and disease-relevant pathways were identified within glial and neuronal clusters after DEPe exposure. Microglia and astroglia existed in multiple states, some of which appear toxic and others protective to neurons. Neuronal transcriptomic analysis revealed that DEPe exposure reduced expression of autophagy-related genes consistent with direct neurotoxicity. In summary, DEPe exposure was neurotoxic in developing ZF larvae and induced neuroinflammation. The microglial inflammatory response did not contribute to neurotoxicity of DEPe and in fact, some glial clusters upregulated transcriptional pathways that are likely protective. Furthermore, DEPe exposure led to reduced expression of autophagy-related genes in neurons that likely contribute to its toxicity.Static contact angle measurements are one of the most popular methods to analyze the wetting behavior of materials of any kind. Although this method is readily applicable without the need of sophisticated machinery, the results obtained for the very same material may vary strongly. The sensitivity of the measurement against environmental conditions, sample preparation and measurement conduction is a main factor for inconsistent results. Since often no detailed measurement protocols exist alongside published data, contact angle values as well as elaborated wetting studies do not allow for any comparison. This paper therefore aims to discuss possible influences on static contact angle measurements and to experimentally demonstrate the extent of these effects. Sample storage conditions, cleaning procedures, droplet volume, water grade and droplet application as well as the influence of evaporation on the static contact angle are investigated in detail. Especially sample storage led to differences in the contact angle up to 60%. Depending on the wetting state, evaporation can reduce the contact angle by 30-50% within 10 min in dry atmospheres. Therefore, this paper reviews an existing approach for a climate chamber and introduces a new measuring setup based on these results. It allows for the observation of the wetting behavior for several minutes by successfully suppressing evaporation without negatively affecting the surface prior to measurement by exposure to high humidity environments.