A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Co-receptor choice by Vα14i NKT cells is driven by Th-POK expression rather than avoidance of CD8-mediated negative selection

Mouse natural killer T (NKT) cells with an invariant Vα14-Jα18 rearrangement (Vα14 invariant [Vα14i] NKT cells) are either CD4+CD8− or CD4−CD8−. Because transgenic mice with forced CD8 expression in all T cells exhibited a profound NKT cell deficit, the absence of CD8 has been attributed to negative selection. We now present evidence that CD8 does not serve as a coreceptor for CD1d recognition and that the defect in development in CD8 transgene homozygous mice is the result of a reduction in secondary T cell receptor α rearrangements. Thymocytes from mice hemizygous for the CD8 transgene have a less severe rearrangement defect and have functional CD8+ Vα14i NKT cells. Furthermore, we demonstrate that the transcription factor Th, Poxviruses and Zinc finger, and Krüppel family (Th-POK) is expressed by Vα14i NKT cells throughout their differentiation and is necessary both to silence CD8 expression and for the functional maturity of Vα14i NKT cells. We therefore suggest that Th-POK expression is required for the normal development of Vα14i NKT cells and that the absence of CD8 expression by these cells is a by-product of such expression, as opposed to the result of negative selection of CD8-expressing Vα14i NKT cells

Antiinflammatory Medicinal Plants from the Ugandan Greater Mpigi Region Act as Potent Inhibitors in the COX-2/PGH2 Pathway

Our study investigates 16 medicinal plants via assessment of inhibition of proinflammatory enzymes such as cyclooxygenases (COX). The plants are used by traditional healers in the Greater Mpigi region in Uganda to treat inflammation and related disorders. We present results of diverse in vitro experiments performed with 76 different plant extracts, namely, (1) selective COX-2 and COX-1 inhibitor screening; (2) 15-LOX inhibition screening; (3) antibacterial resazurin assay against multidrug-resistant Staphylococcus aureus, Listeria innocua, Listeria monocytogenes, and Escherichia coli K12; (4) DPPH assay for antioxidant activity; and (5) determination of the total phenolic content (TPC). Results showed a high correlation between traditional use and pharmacological activity, e.g., extracts of 15 out of the 16 plant species displayed significant selective COX-2 inhibition activity in the PGH2 pathway. The most active COX-2 inhibitors (IC50 < 20 µg/mL) were nine extracts from Leucas calostachys, Solanum aculeastrum, Sesamum calycinum subsp. angustifolium, Plectranthus hadiensis, Morella kandtiana, Zanthoxylum chalybeum, and Warburgia ugandensis. There was no counteractivity between COX-2 and 15-LOX inhibition in these nine extracts. The ethyl acetate extract of Leucas calostachys showed the lowest IC50 value with 0.66 µg/mL (COX-2), as well as the most promising selectivity ratio with 0.1 (COX-2/COX-1). The TPCs and the EC50 values for DPPH radical scavenging activity showed no correlation with COX-2 inhibitory activity. This led to the assumption that the mechanisms of action are most likely not based on scavenging of reactive oxygen species and antioxidant activities. The diethyl ether extract of Harungana madagascariensis stem bark displayed the highest growth inhibition activity against S. aureus (MIC value: 13 µg/mL), L. innocua (MIC value: 40 µg/mL), and L. monocytogenes (MIC value: 150 µg/mL). This study provides further evidence for the therapeutic use of the previously identified plants used medicinally in the Greater Mpigi region.BMBF, 13FH066PX5, FHprofUnt 2015: Modifikation von Proteinen bei der technischen Prozessierung von Melasse und Vinasse: Einfluss auf die Produktion von Bioethanol und BiogasDFG, 414051096, Open Access Publizieren 2020 - 2021 / Hochschule NeubrandenburgBMBF, 13FH026IX5, IngenieurNachwuchs 2015: Schutz der Gesundheit durch Einsatz biologischer Fungizide in der Landwirtschaft - Anwendung von Trihydroxy-octadecensäuren (TriOH) als natürliche Pflanzenschutzmittel zur Sicherung einer gesunden Ernährung (OxiLiFungi

Thermal storage by thermoreversible chemical reaction systems

Recent research work on the development of smart pumpable materials for thermal storage at temperatures below 200 °C will be presented. Currently two different systems being analyzed: additive enhanced CO2-hydrates for climate and cooling purposes and neutralization reactions of organic acids with nitrogen bases for waste heat utilization. CO2-hydrate formation and growth are studied while using hydrogel additives of different morphological structure. In particular hydrogels with a low content of cross- linker significantly promotes the hydrate formation. Several combinations of organic acids and bases are tested in mixing experiments and show that high energy densities can be obtained by these neutralization reactions in liquid systems. Special emphasis is put on the option of long-term-storage of heat. This possibility is demonstrated by distilling off the acid component for the reference reaction system trioctylamine and acetic acid

A unique squalenoylated and non pegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity

We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol’s biosynthesis, led to the formation of squalenoyl doxorubicin (SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original “loop-train” structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy, compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a fivefold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions, such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug’s therapeutic index