Himmele

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BACKGROUND: Birds chronically infected with avian malaria parasites often show relapses of parasitaemia after latent stages marked by absence of parasites in the peripheral circulation. These relapses are assumed to result from the activation of dormant exo-erythrocytic stages produced during secondary (post-erythrocytic) merogony of avian Plasmodium spp. Yet, there is no morphological proof of persistent or dormant tissue stages in the avian host during latent infections. This study investigated persistence of Plasmodium relictum pSGS1 in birds with latent infections during winter, with the goal to detect presumed persisting tissue stages using a highly sensitive RNAscope® in situ hybridization technology...

BACKGROUND: Ensuring vaccination coverage reaches established herd immunity thresholds (HIT) is the cornerstone of any vaccination programme. Diverse migrant populations in European countries have been associated with cases of vaccine-preventable diseases (VPD) and outbreaks, yet it is not clear to what extent they are an under-immunised group. METHODS: We did a systematic review and meta-analysis to synthesise peer-reviewed published primary research reporting data on the immune status of migrants in EU/EEA countries, the UK and Switzerland, calculating their pooled immunity coverage for measles, mumps, rubella, and diphtheria using random-effects models...

The opportunistic fungal pathogen Candida albicans damages host cells via its peptide toxin, candidalysin. Before secretion, candidalysin is embedded in a precursor protein, Ece1, which consists of a signal peptide, the precursor of candidalysin and seven non-candidalysin Ece1 peptides (NCEPs), and is found to be conserved in clinical isolates. Here we show that the Ece1 polyprotein does not resemble the usual precursor structure of peptide toxins. C. albicans cells are not susceptible to their own toxin, and single NCEPs adjacent to candidalysin are sufficient to prevent host cell toxicity...

BACKGROUND: It is estimated that 9.9% of children have developmental language disorders (DLD), 7.6% in the form of circumscribed DLD without any serious accompanying impairment and 2.3% with comorbidities that have a bearing on language, such as hearing disorders. Developmental language disorders are among the more commonly treated childhood disorders; if they persist, they often adversely affect educational attainment and social standing later in life. Developmental language delay during the third year of life is an important risk factor for developmental language disorders...

Protein engineering and screening of processive fungal cellobiohydrolases (CBHs) remain challenging due to limited expression hosts, synergy-dependency, and recalcitrant substrates. In particular, GH7 CBHs are a family critically important for the bioeconomy as well as a methodology for improving these and other difficult to engineer enzymes. Here, we target the discovery of highly active natural GH7 CBHs and engineering of variants with improved activity. Using experimentally assayed activities of genome mined CBHs, we applied sequence and structural alignments to top performers to identify key point mutations linked to improved activity...

Neglected avian blood parasites of the genus Haemoproteus (Haemoproteidae) have recently attracted attention due to the application of molecular diagnostic tools, which unravelled remarkable diversity of their exo-erythrocytic (or tissue) stages both regarding morphology and organ tropism levels. The development of haemoproteids might result in pathologies of internal organs, however the exo-erythrocytic development (EED) of most Haemoproteus species remains unknown. Seven individual birds - Curruca communis (1) and Phylloscopus trochilus (6) - with high gametocytaemia (between 1% and 24%) of Haemoproteus angustus n...

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839 , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity...

Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.5 sodium, hCav1.2 calcium, and human ether-à-go-go-related gene (hERG) potassium channels was investigated in vitro...

BACKGROUND: Diagnostic laboratory tests are an integral part of managing hospitalized patients. In particular, patients in the intensive care units (ICUs) can experience a concerning amount of blood loss due to diagnostic testing, which can increase the risk developing iatrogenic anemia. Several interventions exist to curtail avoidable blood loss, for example computerized decision support, smaller phlebotomy tubes, and other blood conservation devices. Nevertheless, use of these interventions is not standardized...

Transition metal complexes featuring redox-active ligands often exhibit multiple redox states, influenced by the interplay between the metal center and the ligand. This study delves into the electronic structures of two mononuclear complexes of copper with two similar redox-active urea azine ligands. The ligands differ by the replacement of an NCH3 moiety by an S atom in the ligand backbone. Experimental analysis yields pronounced electronic structural disparities between these complexes, observable in both the solution and solid phases...

Four zebra finches in a closed research colony presented with variable clinical signs, including masses, skin lesions, shivering, and/or ruffled feathers. These birds were not responsive to treatment efforts; 3 died and one was euthanized. All 4 were submitted for necropsy to determine the cause of the clinical signs. Gross necropsy and histopathologic findings from all birds resulted in a diagnosis of round cell neoplasia in multiple organs, including the skin, liver, kidney, and reproductive tract, with intranuclear inclusion bodies in the neoplastic cells...

BACKGROUND AND OBJECTIVE: Benzodiazepines and Z-drugs are prescribed to a considerable extent as private prescription also for persons insured by a statutory health insurance (SHI), with formerly large differences between East and West Germany. The aim of the present study was to investigate whether these differences still exist today. METHOD: This secondary data analysis used anonymized prescription data from general practitioners (GPs), community neurologists, and psychiatrists...

The selective formation of homonuclear bonds is of key importance in synthetic chemistry. Especially, dehydrocoupling reactions are attractive as ecologically and economically friendly alternatives to established reductive bond forming reactions, since they do not require the use of stoichiometric amounts of a reducing reagent and produce only valuable dihydrogen as by-product. Here, we report on a metal-free B-B dehydrocoupling reaction that starts directly from a simple, easily accessible BH3 adduct, providing convenient access to a new nucleophilic dihydrodiborane in excellent yield...

Many proteins exist in the so-called "twilight zone" of sequence alignment, where low pairwise sequence identity makes it difficult to determine homology and phylogeny.1 , 2 As protein tertiary structure is often more conserved,3 recent advances in ab initio protein folding have made structure-based identification of putative homologs feasible.4 , 5 , 6 We present a pipeline for the identification and characterization of distant homologs and apply it to 7-transmembrane-domain ion channels (7TMICs), a protein group founded by insect odorant and gustatory receptors...

In this work, matrix isolation spectroscopy and quantum-chemical calculations are used together to analyse the structure and properties of weakly bound dimers of the two isomers benzo[a]acridine and benzo[c]acridine. Our measured experimental electronic absorbance spectra agree with simulated spectra calculated for the equilibrium structures of the dimers in gas-phase, but in contrast, disagree with the simulated spectra calculated for the structures obtained by optimising the experimental solid-state structures...

Novel redox-active hexaguanidine molecules with multiple redox states were synthesized by connecting three o-diguanidinobenzene units. In 2,3,6,7,14,15-hexaguanidino-triptycenes, the three redox-active o-diguanidinobenzene units are connected through C-C bonds to the sp3-hybridized bridgehead C atoms, and in 2,3,6,7,10,11-hexaguanidino-triphenylenes they are directly connected. The connectivity difference leads to different electronic coupling between the three redox-active o-diguanidinobenzene units, with homoconjugation being present in the triptycene, but not in the triphenylene compounds...

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Research on the role of extracellular vesicles (sEV) in physiology has demonstrated their undoubted importance in processes such as the transportation of molecules with significance for cell metabolism, cell communication, and the regulation of mechanisms such as cell differentiation, inflammation, and immunity. Although the role of EVs in the immune response is actively investigated, there is little literature revising, in a comprehensive manner, the role of small EVs produced by immune cells. Here, we present a review of studies reporting the release of sEV by different types of leukocytes and the implications of such observations on cellular homeostasis...

The ditriflato-diborane B2(μ-hpp)2(OTf)2 (hpp = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidinate) acts as a stable surrogate of the elusive dication [B2(hpp)2]2+, being both electrophilic (vacant boron p orbitals) and nucleophilic (filled B-B bond orbital). This combination of seemingly contrasting behaviors could be used to develop a metallomimetic diborane chemistry, with Lewis σ-basic and π-acidic substrates being bound and reduced at the diborane. Here, we report on a novel reaction type within this general theme, in which double electron transfer from the diboron unit to the boron-bound organic substrate is coupled with halide transfer in the other direction...