Overweight children : can parent education put a halt on this epidemic?

Scholarly project (M.S.)

Ein selbstassoziierender difunktioneller Rezeptor

Durch Komplexierung eines Na+ ‐Ions „einschalten”︁ läßt sich die Fähigkeit des Kationenrezeptors 1, eines Calixarens, Wasserstoffbrückenbindungen zwischen der Diamidopyridingruppe und einer komplementären Gruppe wie Thymin zu bilden. Ist diese ihrerseits an einen Anionenrezeptor (z.B. ein metalliertes Porphyrin) gebunden, erhält man einen nichtkovalent zusammengesetzten, difunktionellen Rezeptor, in dem Kation und Anion eines anorganischen Salzes wie NaSCN gleichzeitig komplexiert vorliegen

Effect of a high surface-to-volume ratio on fluorescence-based assays

In the work discussed in this paper, the effect of a high surface-to-volume ratio of a microfluidic detection cell on fluorescence quenching was studied. It was found that modification of the geometry of a microchannel can provide a wider linear range. This is a phenomenon which should be taken into consideration when microfluidic systems with fluorescence detection are developed. The dependence of the linear range for fluorescein on the surface-to-volume ratio was determined. Both fluorescence inner-filter effects and concentration self-quenching were taken into consideration. It was found that inner-filter effects have little effect on the extent of the linear range on the microscale. [Figure: see text

Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer

Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERalpha expression, suggesting that CDK8 could be functionally associated with ER. We have found that CDK8 inhibition by CDK8/19-selective small-molecule kinase inhibitors, by shRNA knockdown or by CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells; this effect was exerted downstream of ER. Estrogen addition stimulated the binding of CDK8 to the ER-responsive GREB1 gene promoter and CDK8/19 inhibition reduced estrogen-stimulated association of an elongation-competent phosphorylated form of RNA Polymerase II with GREB1. CDK8/19 inhibitors abrogated the mitogenic effect of estrogen on ER-positive cells and potentiated the growth-inhibitory effects of ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive breast cancer cells with CDK8/19 inhibitors strongly impeded the development of estrogen independence. In vivo treatment with a CDK8/19 inhibitor Senexin B suppressed tumor growth and augmented the effects of fulvestrant in ER-positive breast cancer xenografts. These results identify CDK8 as a novel downstream mediator of ER and suggest the utility of CDK8 inhibitors for ER-positive breast cancer therapy

The rabies virus phosphoprotein P: a key regulator of innate immune responses

Interferons are the key cytokines of innate immunity and represent the first line of defense against invading viruses. By activating immediate antiviral mechanisms and stimulating the adaptive immune response, interferon signaling is decisive for the outcome of disease and virus clearance. The work presented in this thesis reveals a central role of the phosphoprotein P of rabies virus (Rhabdoviridae family), known as a polymerase cofactor, as an inhibitor of the host interferon system. Counter-mechanism to escape form recognition by the immune system were previously unknown for the neurotropic rabies virus, which is characterized by the highest case-fatality ratio. In my work I have shown that rabies virus (strain SAD L16) is able to prevent both the production IFN-alpha/beta and the effector functions of IFN-alpha/beta and IFN-gamma. The factor responsible is the viral phosphoprotein P. P interferes with transcriptional activation of IFN-alpha/beta by preventing phosphorylation of the essential transcription factors IRF3 and IRF7 by their kinases TBK1 and IKKepsilon. Unphosphorylated IRFs are unable to dimerize and fail to enter the nucleus. In addition, rabies virus P prevents IFN-mediated JAK/STAT signaling and the expression of IFN-stimulated genes which include a broad spectrum of antiviral and immune regulatory genes. The inhibition of JAK/STAT signaling by P involves a unique mechanism, namely, specific binding of the tyrosine-phosphorylated STAT1 and STAT2 isoforms and their retention in the cytoplasm. The inhibitory activities of RV P on IFN induction and signaling are independent functions, as shown by site-directed mutagenesis of P and identification of different short amino acid stretches required for either function. Importantly, the inhibitory activities of P were demonstrated in the context of recombinant viruses. Using reverse genetics, a rabies virus was constructed, in which P expression was “knocked down” by moving the P gene to a promoter-distal position of the genome (SAD deltaPLP). This virus caused efficient IFN-alpha/beta production in infected cells and upregulation of interferon stimulated genes. The IFN sensitivity of SAD deltaPLP was confirmed in cell culture and is now being studied in animal experiments including IFN receptor knock of mice, to verify the relevance of P functions in vivo. The described work contributes to the understanding of host responses to virus infections in general and of rabies virus pathogenicity in particular. In addition, viruses with modified IFN antagonists provide interesting opportunities for development of attenuated vaccines and vectors

Liquid levothyroxine improves thyroid control in patients with different hypothyroidism aetiology and variable adherence — case series and review

It is estimated that hypothyroidism treatment may be either suboptimal or excessive in about 32–45% patients treated with L-thyroxine (LT4). There are multiple possible causes of poor control of hypothyroidism, including narrow LT4 therapeutic index, food and drug interactions, comorbidities, and patient non-adherence. Some of these obstacles could possibly be overcome with the novel liquid LT4 formulation. Liquid LT4 reaches maximum blood concentration about 30 minutes faster than the tablet form. Faster pharmacokinetics might lead to more efficient LT4 absorption, as suggested by a recent real-world study in patients with primary and central hypothyroidism. Liquid LT4 treatment led to increased free thyroxine (FT4) and sex hormone binding globulin (SHBG) with decreased low-density lipoprotein (LDL) cholesterol concentration and substantially improved quality of life for the patients. Herein we present a series of 31 patients with hypothyroidism of different aetiologies treated with the novel liquid LT4 formulation in standard clinical care in light of the latest scientific publications on liquid LT4 formula. We observed normalization of thyroid function tests shortly after introduction of liquid LT4, irrespective of concurrent diseases or concomitant medications that could diminish LT4 absorption. In more detail, the treatment with liquid LT4 managed to normalize thyroid-stimulating hormone (TSH) concentrations in patients without any known causes of LT4 absorption disturbances, as well as in those with malabsorption: with gastric bypass, partial small and large intestine resection, scleroderma, gluten intolerance, celiac disease, atrophic gastritis, and polytherapy. In conclusion, considering many factors disturbingLT4 absorption, hypothyroidism therapy with liquid LT4 seems to be a particularly effective option.