3,693 research outputs found
Sensitive phases in the development of rodent social behavior
No full textSachser N, Zimmermann TD, Hennessy MB, Kaiser S. Sensitive phases in the development of rodent social behavior. Current Opinion in Behavioral Sciences. 2020;36:63-70
Expression of BRMS1 mutants within 293T and MDA-MB-231 cells.
No full textExpression of BRMS1WT, BRMS11-229, and phospho-mutants compared to parental and vector control 293T cells. (B) qPCR quantification of BRMS1230-246 expression in 293T cells. (C) Expression of BRMS1WT and phospho-mutants compared to vector control MDA-MB-231 cells. (D). Expression of BRMS11-229 within MDA-MB-231 cells. (E) qPCR quantification of BRMS1230-246 expression in MDA-MB-231 cells. (TIF)</p
Screening, identification, structure-activity, and mode of action studies with new antitrypanosomal leads of plant and fungal origin
No full textHuman African trypanosomiasis (HAT) is a neglected disease caused by the protozoan Trypanosoma brucei, which is transmitted during blood-feeding tsetse fly bites. The disease is endemic covering 36 sub-Saharan African countries and mainly impacts poor people living in remote areas, for which satisfactory treatment does not exist. As such, this protozoal disease would never be viewed as viable target market for the pharmaceutical industry. Therefore, it is referred to as a neglected disease. Chemotherapy remains the principal treatment for HAT and is based on four drugs: suramin, pentamidine, melarsoprol, eflornithine, and a recent approved eflornithine-nifurtimox combination. Reported severe side effects (e.g. melarsoprol), treatment failures of up to 25%, administration difficulties, and expensive medication urgently demand for safe, orally administered drugs, that are effective against both stages of HAT. Natural sources like plants and fungi provide a rich biological diversity with unique pharmacophores created by evolution and are therefore potential sources to discover such new drugs.
This thesis describes the search of new natural products (NPs) from nature. Over the last seven years we collected 724 plants and 64 fungi. The material was subsequently extracted and tested in vitro against T. b. rhodesiense, Plasmodium falciparum (the causative agent of malaria), Leishmania donovani (leishmaniasis), and T. cruzi (Chagas disease) to find potential hits. From the total 2151 extracts, 17.9% showed activity of more than 50% at 4.81 µg/mL test concentration against at least one parasite, and 3.4% showed potency of more than 50% at 0.81 µg/mL test concentration, respectively. Overall the plant extracts had six times higher "hit-rates" (15.3%) than the fungi extracts (2.6%), both resulting in high potencies against T. b. rhodesiense and P. falciparum. Yet, with up to 5 millions fungi, which outnumber higher plants by 16:1, the kingdom remains a relatively poorly studied source.
One of the antitrypanosomal hits was a dichloromethane (DCM) extract of the cornflower Centaurea salmantica with a growth inhibition of 61% tested at 4.81 µg/mL against T. b. rhodesiense. HPLC-based activity profiling led to the identification of the sesquiterpene lactone (STL) cynaropicrin (CYN), which was the first plant NP to show in vivo efficacy in T. b. rhodesiense infected mice, treated i.p. at 10 mg/kg/b.i.d. for four consecutive days. Despite of more than 10'000 known STLs is a better understanding of the structural features, which contribute to activity, expedient. The established structure-activity relationship (SAR) study included 18 natural STLs and demonstrated that antitrypanosomal and cytotoxic effect depended on their a,ß-unsaturated enone moieties. Many bioactivities of STLs have been attributed to a nucleophilic Michael-addition of these functional motifs to biological thiols. Considering that trypanosomes depend on their unique trypanothione-based redox system to deal with oxidative stress and to maintain a reducing intracellular milieu and that CYN contains reactive exocyclic a,ß-unsaturated methylenes, we anticipated that the mechanism of action depended on a direct interference with glutathione (GSH) and trypanothione (T(SH)2) in the cells. After 5 min. of CYN's exposure to trypanosomes, the intracellular thiol pool was completely depleted and a GS-CYN-monoadduct as well as a T(S-CYN)2-bisadduct were formed. This led to apoptosis of the trypanosomes over 40 min. linked to phenotype transformations from the typical slender to a stumpy-like form. Additionally, ornithine quantification studies by tandem mass spectroscopy (MS/MS) showed that ornithine decarboxylase (ODC) is a potential secondary target for CYN.
To improve CYN's pharmacokinetic (PK) profile the a,ß-unsaturated exocyclic double bond at the lactone was masked to create an amine prodrug with increased aqueous solubility and reduced unspecific binding to biological thiols. Through subsequent bioactivation the prodrug would be converted back to CYN and it would display a higher concentration on the target side. The lead optimization did not reward any better antitrypanosomal in vivo efficacy after oral application, but the prodrug had an improved in vivo cytotoxic profile. Further PK studies with other orally applied STL amino derivatives are needed to demonstrate if the use of amino STLs as prodrugs is a reasonable approach to improve STLs suitability as antitrypanosomal drug
Focus Fronting in a Language with In Situ Marking: The Case of Mǝ̀dʉ́mbà
No full textThis paper discusses the structural realisation of contrastive focus in the Grassfields Bantu language Bamileke Mǝ̀dʉ́mbà, yet another language with grammatically optional focus fronting. We show that the realisation of contrastive focus in Mǝ̀dʉ́mbà is by default marked in situ with the morphological focus marker á. We further show that á introduces an additional, not-at-issue exhaustivity inference as part of its lexical meaning. Taken together, this means that two often-discussed interpretive triggers of grammatically optional focus fronting, namely, contrastivity and exhaustivity, are not responsible for triggering Mǝ̀dʉ́mbà’s focus left-dislocation. Rather, the main semantic contribution of focus fronting consists in triggering an existence presupposition, a discourse-semantic effect well known from other focus–background bipartitions, possibly in combination with other, softer discourse-semantic effects, such as the special emphasis required in cases of discourse unexpectedness
Receiver Windowing Design for Narrowband Interference Mitigation in MB-OFDM UWB System
No full textIn 2005, the WiMedia Alliance working with the European Computer Manufacturers Association (ECMA) announced the establishment of the WiMedia MB-OFDM (Multiband Orthogonal Frequency Division Multiplexing) UWB radio platform as their global UWB standard. It was also chosen as the physical layer (PHY) of high data rate wireless specifications for high speed Wireless USB (W-USB), Bluetooth 3.0 and Wireless High-Definition Media Interface (HDMI). However, due to the low power and wide bandwidth nature of UWB systems, in-band narrowband interference (NBI) may hinder the receiver performance. This thesis presents an analysis of NBI impact on the MB-OFDM system for UWB communication. The intent of our analysis is to provide practical solutions for interference mitigation under different NBI models. In our work, a new receiver windowing for zero padding (ZP) OFDM system is proposed to reduce NBI spreading in the MB-OFDM UWB system. Simulations demonstrate the effectiveness of windowing under different NBI models.Microelectronics & Computer EngineeringElectrical Engineering, Mathematics and Computer Scienc
Methods to assess iron and iodine status
No full textFour methods are recommended for assessment of iodine nutrition: urinary iodine concentration, the goitre rate, and blood concentrations of thyroid stimulating hormone and thyroglobulin. These indicators are complementary, in that urinary iodine is a sensitive indicator of recent iodine intake (days) and thyroglobulin shows an intermediate response (weeks to months), whereas changes in the goitre rate reflect long-term iodine nutrition (months to years). Spot urinary iodine concentrations are highly variable from day-to-day and should not be used to classify iodine status of individuals. International reference criteria for thyroid volume in children have recently been published and can be used for identifying even small goitres using thyroid ultrasound. Recent development of a dried blood spot thyroglobulin assay makes sample collection practical even in remote areas. Thyroid stimulating hormone is a useful indicator of iodine nutrition in the newborn, but not in other age groups. For assessing iron status, haemoglobin measurement alone has low specificity and sensitivity. Serum ferritin remains the best indicator of iron stores in the absence of inflammation. Measures of iron-deficient erythropoiesis include transferrin iron saturation and erythrocyte zinc protoporphyrin, but these often do not distinguish anaemia due to iron deficiency from the anaemia of chronic disease. The serum transferrin receptor is useful in this setting, but the assay requires standardization. In the absence of inflammation, a sensitive method to assess iron status is to combine the use of serum ferritin as a measure of iron stores and the serum transferrin receptor as a measure of tissue iron deficiency
Altered immunolocalization of FGF23 in murine femora metastasized with human breast carcinoma MDA-MB-231 cells
No full textIntroduction After the onset of bone metastasis, tumor cells appear to modify surrounding microenvironments for their benefit, and particularly, the levels of circulating fibroblast growth factor (FGF) 23 in patients with tumors have been highlighted. Materials and methods We have attempted to verify if human breast carcinoma MDA-MB-231 cells metastasized in the long bone of nu/nu mice would synthesize FGF23. Serum concentrations of calcium, phosphate (Pi) and FGF23 were measured in control nu/nu mice, bone-metastasized mice, and mice with mammary gland injected with MDA-MB-231 cells mimicking primary mammary tumors. Results and conclusions MDA-MB-231 cells revealed intense FGF23 reactivity in metastasized lesions, whereas MDA-MB-231 cells cultured in vitro or when injected into the mammary glands (without bone metastasis) showed weak FGF23 immunoreactivity. Although the bone-metastasized MDA-MB-231 cells abundantly synthesized FGF23, osteocytes adjacent to the FGF23-immunopositive tumors, unlike intact osteocytes, showed no FGF23. Despite significantly elevated serum FGF23 levels in bone-metastasized mice, there was no significant decrease in the serum Pi concentration when compared with the intact mice and mice with a mass of MDA-MB-231 cells in mammary glands. The metastasized femora showed increased expression and FGFR1 immunoreactivity in fibroblastic stromal cells, whereas femora of control mice showed no obvious FGFR1 immunoreactivity. Taken together, it seems likely that MDA-MB-231 cells synthesize FGF23 when metastasized to a bone, and thus affect FGFR1-positive stromal cells in the metastasized tumor nest in a paracrine manner
ASIC FFT processor for MB-OFDM UWB system
No full textThe physical layer (PHY) standard of Multi-band Orthogonal Frequency Division Multiplexing (MB-OFDM) Ultra Wideband (UWB) system was defined by ECMA International. In this standard, the data sampling rate from the analog-to-digital converter to the physical layer is up to 528 Msample/s. Therefore, it is a challenge to realize the physical layer of the UWB system-especially the components with high computational complexity in Very Large Scale Integration (VLSI) implementation. Fast Fourier Transform (FFT) block is one of these components. FFT plays an important role in Multi-band OFDM UWB system, which is the demodulation block of OFDM signals. The purpose of this project is to design an Application Specific Integrated Circuit (ASIC) FFT solution for this system. The specification is defined from the system analysis and literature research. All the design choices and considerations are concluded and explained.Based on the algorithm and architecture analysis, a novel Radix22Parallel processor is proposed, which is a small-area and low-power-consumption solution for MB-OFDM UWB system. Both Field Programmable Gate Array (FPGA) and ASIC targeted synthesis results of this architecture are presented.Electrical Engineering, Mathematics and Computer Scienc
Iodine nutritional status and risk factors for goitre among schoolchildren in south Tajikistan
No full textIodine deficiency affects nearly 1.9 billion people worldwide, but it can be prevented by salt iodization. This cross-sectional survey assessed current iodine status, iodized salt coverage and risk factors for goitre among schoolchildren in South Tajikistan.; Ten primary schools in four districts in South Tajikistan were randomly selected. In schoolchildren aged 7 to 11 years, a spot urine sample was collected for measurement of urinary iodine, dried blood spots were collected for measurement of thyroglobulin, and goitre was assessed by palpation. Iodine content of salt samples and local selling points was determined by coloration using rapid test kits and titration method.; Of 623 schoolchildren enrolled, complete data was obtained from 589. The overall median urinary iodine concentration (UIC) was 51.2 mug/L indicating mild-to-moderate iodine deficiency. Among all children, 46.6% (95% Confidence Interval (CI) = 42.4%-50.6%) of children were found to be goitrous (grade 1 goitre: 30.6%, 95% CI = 26.9%-34.5%; grade 2 goitre: 16.0%, 95% CI = 13.1%-19.2%). The risk factor for goitre remaining significant in the multivariable logistic regression model was 'buying salt once a month' (OR = 2.89, 95% CI = 1.01-8.22) and 'buying salt once every six months' (OR = 2.26, 95% CI = 1.01-5.04) compared to 'buying salt every one or two weeks'. The overall median thyroglobulin concentration was elevated at 13.9 mug/L. Of the salt samples from households and selling points, one third were adequately iodised, one third insufficiently and one third were not iodised.; Iodine deficiency remains a serious health issue among children in southern Tajikistan. There is a persisting high prevalence of goitre, elevated thyroglobulin and low UIC despite interventions implemented by Tajikistan and international partners. Quality control of salt iodine content needs to be improved. Continued efforts to raise awareness of the health effects of iodine deficiency are needed to increase consum demand for iodised salt
Single-Photon Avalanche Photodiode Based Fiber Optic Receiver for Up to 200 Mb/s
No full textThe first fully integrated receiver based on singlephoton avalanche diodes (SPADs) for data rates of up to 200 Mb/s is reported. An array of four SPADs in combination with quenching circuits and a short dead time of 3.5 ns is fabricated in a 0.35 μm CMOS process. The responses of the SPADs are combined using an integrated digital latch-type processing circuit to create a single output data stream. In addition, the output of each quenching circuit is recorded and the bit error rates are extracted by postprocessing in MATLAB. Using a 635-nm single-mode laser source, the bit error rate at different optical ower is measured at 50, 100, 150, and 200 Mb/s. The integrated digital circuit achieved the best sensitivity at -46.3 dBm (BER = 2·10⁻³) for 100 Mb/s. Using the MATLAB postprocessing, a sensitivity of -43.8 dBm at 200 Mb/s (BER = 6.5·10⁻³) is reached
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