Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of mutations.

Mutations in splicing factor 3B subunit 1 () frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDSs). These mutations have different effects on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge on mutation effects on RNA splicing and its contribution to patient survival and treatment options.

FUBP1 is a general splicing factor facilitating 3' splice site recognition and splicing of long introns.

Splicing of pre-mRNAs critically contributes to gene regulation and proteome expansion in eukaryotes, but our understanding of the recognition and pairing of splice sites during spliceosome assembly lacks detail. Here, we identify the multidomain RNA-binding protein FUBP1 as a key splicing factor that binds to a hitherto unknown cis-regulatory motif. By collecting NMR, structural, and in vivo interaction data, we demonstrate that FUBP1 stabilizes U2AF2 and SF1, key components at the 3' splice site, through multivalent binding interfaces located within its disordered regions.

Innovative Partnerships for the Elimination of Human African Trypanosomiasis and the Development of Fexinidazole.

Human African Trypanosomiasis (HAT or sleeping sickness) is a life-threatening neglected tropical disease that is endemic in 36 sub-Saharan African countries. Until recently, treatment options were limited and hampered by unsatisfactory efficacy, toxicity, and long and cumbersome administration regimens, compounded by infrastructure inadequacies in the remote rural regions worst affected by the disease. Increased funding and awareness of HAT over the past two decades has led to a steady decline in reported cases (<1000 in 2018).

Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation.

Makorins are evolutionary conserved proteins that contain C3H-type zinc finger modules and a RING E3 ubiquitin ligase domain. In Drosophila, maternal Makorin 1 (Mkrn1) has been linked to embryonic patterning but the mechanism remained unsolved. Here, we show that Mkrn1 is essential for axis specification and pole plasm assembly by translational activation of oskar (osk).

The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.

Background: Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via ribosome-associated quality control.

Improved library preparation with the new iCLIP2 protocol.

Individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) is a state-of-the-art technology to map the RNA interaction sites of an RNA-binding protein (RBP) across the transcriptome. Here, we present the new iCLIP2 protocol that allows to obtain high-quality iCLIP libraries in a fast and efficient manner. The new protocol comprises separate adapter ligations, two cDNA amplification steps and bead-based size selection.

Intergenic Alu exonisation facilitates the evolution of tissue-specific transcript ends.

The 3' untranslated regions (3' UTRs) of transcripts serve as important hubs for posttranscriptional gene expression regulation. Here, we find that the exonisation of intergenic Alu elements introduced new terminal exons and polyadenylation sites during human genome evolution. While Alu exonisation from introns has been described previously, we shed light on a novel mechanism to create alternative 3' UTRs, thereby opening opportunities for differential posttranscriptional regulation.

Comparison of the dose accuracy of prefilled insulin pens.

Background: Prefilled insulin pens have become a convenient and accurate way for diabetes patients to inject insulin. Their ease of use has helped to reduce the resistance of patients with type 1 diabetes and type 2 diabetes in the United States and Europe toward initiation of insulin therapy. This study compared the dosing accuracy of two prefilled insulin pens (the SoloStar((R)) from Sanofi Aventis, Berlin, Germany, and the Next Generation [NG] FlexPen((R)) from Novo Nordisk, Mainz, Germany).

Determination of nitrotyrosine concentrations in plasma samples of diabetes mellitus patients by four different immunoassays leads to contradictive results and disqualifies the majority of the tests.

Background: In the course of type 2 diabetes mellitus, insulin resistance has a severe impact on endothelial function leading to decreased synthesis of nitric oxide (NO). Postprandial hyperglycemia leads to the generation of reactive oxygen species, which counteracts the beneficial NO effects. NO and superoxide combine very fast in solution to form peroxynitrite, which is a potent protein-oxidizing agent.

Differences in the dose accuracy of insulin pens.

Background: Modern insulin injection pens provide a convenient and accurate way for diabetes patients to inject insulin. They have widespread use among children and adults with type 1 and type 2 diabetes in the U.S.

Epidemiology, clinical manifestations and diagnosis of zoonotic cestode infections: an update.

This paper reviews the literature on zoonotic cestode infections with specific reference to the years 1999-2003. The sources and prevalence of various zoonotic tapeworm infections caused by adult and larval stages of the genera Taenia, Echinococcus, Diphyllobothrium, Hymenolepis and Dipylidium continue to be an important cause of morbidity and mortality, not only in most underdeveloped countries but also in industrialized countries, particularly in rural areas or among immigrant groups from endemic areas. The review gives a detailed report on recent molecular epidemiological studies on the taxonomy and phylogenetic variations in Echinococcus granulosus, immunological tests and imaging techniques used in epidemiological surveys and clinical investigations of important adult and larval tapeworm infections of animals and humans.

Nitroheterocyclic drugs with broad spectrum activity.

The group of biologically active nitroheterocyclic compounds includes various 5- and 2-nitroimidazoles and 5-nitrofurans, which can be used as therapeutic agents against a variety of protozoan and bacterial (anaerobic) infections of humans and animals. The current status in the the treatment of giardiasis, trichomoniasis, balantidiasis, histomoniasis, and amebiasis (including infections due to opportunistic amebas) is presented. The most relevant drugs (benznidazole, furazolidone, metronidazole, misonidazole, nifurtimox, nimorazole, nitazoxanide, ornidazole, secnidazole, and tinidazole) are characterized with regard to their chemical, chemotherapeutic, toxicological, pharmacokinetic, and pharmacological properties, including the mechanism of action and resistance in certain parasitic protozoa.

Detection of a flow induced magnetic field eigenmode in the riga dynamo facility.

In a closed volume of molten sodium an intense single-vortex-like helical flow has been produced by an outside powered propeller. At a flow rate of 0.67 m(3)/s a slowly growing magnetic field eigenmode was detected.

New systematically active antimycotics from the beta-blocker category.

Candida albicans secretes phospholipases, which are considered to be one of the mediators of cell penetration. It is known that other phospholipases from mammalian cells can be inhibited by lipophilic beta-blocking structures. As the result of a synthesis programme of several years' duration, structures deriving from beta-hydroxyethylamines were introduced.

Modification of cisplatin-induced renal p-aminohippurate uptake alteration and lipid peroxidation by thiols, Ginkgo biloba extract, deferoxamine and torbafylline.

To determine whether inhibition of lipid peroxidation modifies cisplatin-induced changes of renal p-aminohippurate (PAH) uptake, we examined the effects of various radical scavengers and torbafylline on cisplatin-induced lipid peroxidation and PAH accumulation changes in rat renal cortical slices. Renal cortical slices were incubated with different cisplatin concentrations (0.3, 0.

Effects of rilopirox on rabbit blastocysts in a protein-free in vitro culture under different culture conditions.

The effect of rilopirox (Hoe 351, CAS 104153-37-9) on rabbit blastocysts in vitro was studied. Blastocysts of day 6 post coitum were cultured in Ham's F 10 medium supplemented with polyvinylpyrrolidone using different concentrations of rilopirox with and without serum proteins. In culture conditions without serum proteins there were no differences in the growth rates of the blastocysts after 24 h of culture in the presence of 1 microgram/ml of rilopirox.

Ultrastructural investigations of Candida albicans after in vitro treatment with the new fungicidal agent rilopirox.

Candida albicans was maintained in various culture media and incubated with different concentrations of the antifungal agent rilopirox. After fixation, dehydration and embedding in Spurr's medium, the cells were analysed at the ultrastructural level to investigate morphological aspects of the antifungal mode of action of this new hydroxpyridone compound. All untreated or sham-treated control cells exhibited a normal ultrastructural appearance.

A modified method for experimental candidosis in mice avoiding lethality.

A model is presented which selected one out of 150 Candida albicans strains for the evaluation of antifungal agents. The mice were inoculated with 6 x 10(5) CFU of strain 352 into the tail vein. The strain has a moderate phospholipase B (PLB) activity in vitro and was originally isolated from a stool sample from a patient in an intensive care unit.

Pretreatment with pancuronium before suxamethonium administration in patients heterozygous for the usual and the atypical plasma cholinesterase gene.

The object of this study was to investigate whether pretreatment with pancuronium before i.v. injection of suxamethonium could cause prolonged neuromuscular blockade in patients heterozygous for the usual and the atypical plasma cholinesterase gene (E1uE1a).

Ciclopiroxolamine cream 1%: in vitro and in vivo penetration into the stratum corneum.

Studies were conducted to assess the penetration of 1% ciclopiroxolamine cream, establishing the concentrations of the antimycotic compound in different layers of the stratum corneum with two skin models. Results of in vitro studies using skin from domestic pigs indicate that ciclopiroxolamine has the ability to penetrate fast into the epidermis, by inhibiting and killing inoculated Trichophyton mentagrophytes. In vivo investigation of the stratum corneum has been performed in healthy human volunteers by 20 strippings collected in four layers.

[Therapy of seborrheic eczema with an antifungal agent with an antiphlogistic effect].

Numerous AIDS patients show the typical seborrheic eczema in a very prominent way. For this is an inflammatory disease, combination preparations were taken frequently which contain antimycotics and corticosteroids. We investigated 7 antimycotic compounds in 3 inflammatory models: amorolfin, ciclopiroxolamine (cic), fluconazole, ketoconazole, miconazole, naftifine, and rilopirox.

Ciclopirox nail lacquer 8%: in vivo penetration into and through nails and in vitro effect on pig skin.

This report presents original methods to assess the bioavailability of an antifungal drug from a varnish preparation in finger nails. For the studies with human volunteers a ciclopirox 8% nail lacquer was used to determine its efficacy in the treatment of onychomycoses. In vivo studies were performed on the fingernails of healthy volunteers by determining the total amount of ciclopirox penetrated per milligram of nail and the partition of the drug in the plate of the nails (technically divided into four layers).

Quantification of keratinolytic activity from Dermatophilus congolensis.

The bacterium Dermatophilus congolensis is the causative agent of pitted keratolysis, a skin disease. Infection occurs mainly in keratinized tissues and it is necessary for the organism to produce and excrete exoenzymes which are able to degrade keratin. We investigated the amount of keratinase liberated using Keratinazure as substrate and the fungal protease XI as standard.

Studies for the elucidation of the mode of action of the antimycotic hydroxypyridone compound, rilopirox.

Rilopirox is a synthetic, fungicidal antimycotic agent with hydrophobic characteristics. Its chemical name is 6-[4-(4-chlorophenoxy)-phenoxy-methyl]-1-hydroxy-4-methyl-2-pyridone and it has a molecular weight of 357.79.