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Background: The genus Burkholderia consists of species that occupy remarkably diverse ecological niches. Its best known members are important pathogens, B. mallei and B. pseudomallei, which cause glanders and melioidosis, respectively. Burkholderia genomes are unusual due to their multichromosomal organization, generally comprised of 2-3 chromosomes. Results: We performed integrated genomic analysis of 127 Burkholderia strains. The pan-genome is open with the saturation to be reached between 86,000 and 88,000 genes. The reconstructed rearrangements indicate a strong avoidance of intra-replichore inversions that is likely caused by selection against the transfer of large groups of genes between the leading and the lagging strands. Translocated genes also tend to retain their position in the leading or the lagging strand, and this selection is stronger for large syntenies. Integrated reconstruction of chromosome rearrangements in the context of strains phylogeny reveals parallel rearrangements that may indicate inversion-based phase variation and integration of new genomic islands. In particular, we detected parallel inversions in the second chromosomes of B. pseudomallei with breakpoints formed by genes encoding membrane components of multidrug resistance complex, that may be linked to a phase variation mechanism. Two genomic islands, spreading horizontally between chromosomes, were detected in the B. cepacia group. Conclusions: This study demonstrates the power of integrated analysis of pan-genomes, chromosome rearrangements, and selection regimes. Non-random inversion patterns indicate selective pressure, inversions are particularly frequent in a recent pathogen B. mallei, and, together with periods of positive selection at other branches, may indicate adaptation to new niches. One such adaptation could be a possible phase variation mechanism in B. pseudomallei. [ABSTRACT FROM AUTHOR]

Since the first attempt to administer insulin orally in humans more than 90 years ago, the oral delivery of macromolecular drugs (> 1000 g/mol) has been rather disappointing. Although several clinical pilot studies have demonstrated that the oral absorption of macromolecules is possible, the bioavailability remains generally low and variable. This article reviews the formulations and biopharmaceutical aspects of orally administered biomacromolecules on the market and in clinical development for local and systemic delivery. The most successful approaches for systemic delivery often involve a combination of enteric coating, protease inhibitors and permeation enhancers in relatively high amounts. However, some of these excipients have induced local or systemic adverse reactions in preclinical and clinical studies, and long-term studies are often missing. Therefore, strategies aimed at increasing the oral absorption of macromolecular drugs should carefully take into account the benefit–risk ratio. In the absence of specific uptake pathways, small and potent peptides that are resistant to degradation and that present a large therapeutic window certainly represent the best candidates for systemic absorption. While we acknowledge the need for systemically delivering biomacromolecules, it is our opinion that the oral delivery to local gastrointestinal targets is currently more promising because of their accessibility and the lacking requirement for intestinal permeability enhancement. [ABSTRACT FROM AUTHOR]

The use of stimuli-responsive bioactive molecules is an attractive strategy to circumvent selectivity issues in vivo. Here, we report an activatable cell penetrating peptide (CPP) strategy ultimately aimed at delivering nucleic acid drugs to the colon mucosa using bacterial azoreductase as the local reconversion trigger. Through screening of a panel of CPPs, we identified a sequence (M918) capable of carrying a nucleic acid analogue payload. A modified M918 peptide conjugated to a peptide nucleic acid (PNA) was shown to silence luciferase in colon adenocarcinoma cells (HT-29-luc), Reversible functionalization of the conjugate’s lysine residues via an azobenzene self-immolative linkage abolished transfection activity, and the free CPP-PNA was recovered after reduction of the azobenzene bond. This activatable CPP conjugate platform could find applications in the selective delivery of nucleic acid drugs to the colon mucosa, opening therapeutic avenues in colon diseases. [ABSTRACT FROM AUTHOR]

The number of published findings in biomedicine increases continually. At the same time, specifics of the domain's terminology complicates the task of relevant publications retrieval. In the current research, we investigate influence of terms' variability and ambiguity on a paper's likelihood of being retrieved. We obtained statistics that demonstrate significance of the issue and its challenges, followed by presenting the sci.AI platform, which allows precise terms labeling as a resolution. [ABSTRACT FROM AUTHOR]

A simplified model of conducting ferromagnetic sheet, which describes magnetization of isotropic electrical steels is proposed. The model improvement is achieved by determining eddy current component of the magnetic field at the sheet surface in the framework of the method by Wolman and Kaden, which describes the dynamic magnetization of the material with rectangular hysteresis loop. An algorithm of model fitting is proposed and a comparison of calculated and experimental results has been carried out. [ABSTRACT FROM AUTHOR]