Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic ‘deep’ volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug’s chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose–response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors. Hydroxychloroquine and chloroquine are antimalarial drugs commonly used for the treatment of rheumatic diseases. Multiple mechanisms might explain the efficacy and adverse effects of these drugs, but further investigation could lead to the development of more specific and potent drugs.

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.

https://zenodo.org/record/1259717/files/article.pdf

Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expression of defined embryonic factors. However, little is known of the molecular mechanisms underlying the reprogramming process. Here we explore somatic cell reprogramming by exploiting a secondary mouse embryonic fibroblast model that forms iPSCs with high efficiency upon inducible expression of Oct4, Klf4, c-Myc, and Sox2. Temporal analysis of gene expression revealed that reprogramming is a multistep process that is characterized by initiation, maturation, and stabilization phases. Functional analysis by systematic RNAi screening further uncovered a key role for BMP signaling and the induction of mesenchymal-to-epithelial transition (MET) during the initiation phase. We show that this is linked to BMP-dependent induction of miR-205 and the miR-200 family of microRNAs that are key regulators of MET. These studies thus define a multistep mechanism that incorporates a BMP-miRNA-MET axis during somatic cell reprogramming. PAPERCLIP:

Functional genomics reveals a bmp driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming (oral presentation)

This article reviews machine learning methods for bioinformatics. It presents modelling methods, such as supervised classification, clustering and probabilistic graphical models for knowledge discovery, as well as deterministic and stochastic heuristics for optimization. Applications in genomics, proteomics, systems biology, evolution and text mining are also shown.

/pdf/machine-learning-in-bioinformatics-5gfm1x1ssk.pdf

Machine learning in bioinformatics

Libraries of unimolecular, double-stranded oligonucleotides on a solid support. These libraries are useful in pharmaceutical discovery for the screening of numerous biological samples for specific interactions between the double-stranded oligonucleotides, and peptides, proteins, drugs and RNA. In a related aspect, the present invention provides libraries of conformationally restricted probes on a solid support. The probes are restricted in their movement and flexibility using double-stranded oligonucleotides as scaffolding. The probes are also useful in various screening procedures associated with drug discovery and diagnosis. The present invention further provides methods for the preparation and screening of the above libraries.

Surface-bound, unimolecular, double-stranded DNA

The invention provides a combinatorial library, a method for preparation of that combinatorial library, a method for sequence identification, a method for sequencing the elements of combinatorial libraries of oligonucleotides and/or oligonucleotide analogues, the use of a linker to generate combinatorial libraries and a sequence identification set. More precisely, the objective of the invention is the ability to "read" sequences of selected elements of combinatorial libraries of freely modified synthetic oligonucleotides. The solution may be used both for researching for leading compounds in the pharmaceutical industry, and as a tool for studying the properties of oligonucleotides in the aspect of their potential use in experimental antisense or antigen therapy. The invention develops an appropriate strategy for determining the structure of isolated library elements, as usefulness of the combinatorial library depends on the ability to recognize the structure of its elements. Thanks to the developed and presented method for sequencing combinatorial oligonucleotide libraries it is possible to indisputably identify the sequences of biologically active elements selected by the combinatorial synthesis method.

A combinatorial library, a method for preparation of that combinatorial library, a method for sequence identification, a method for sequencing the elements of combinatorial libraries of oligonucleotides and/or oligonucleotide analogues, the use of a linker to generate combinatorial libraries and a sequence identification set

Tetraisopropylsilane-1,2-Diyl: A New Bifunctional Protecting Group in Nucleoside Chemistry

The subject of the invention is the use of 4-furfurylcytosine and /or its derivatives in anti-aging compositions. As 4-furfurylcytosine and /or its derivatives possesses a series of biological properties it might be use as a composition having excellent anti-aging effect to prevent the sagging of skin and loss of luster and to improve sufficiently its aesthetic appearance without significantly change the growth rate and the total growth ability of the skin.

http://yadda.icm.edu.pl/yadda/element/bwmeta1.element.agro-8bcbcc22-2aec-40e7-b318-470644ad6136/c/4.pdf

Wojciech T. Markiewicz

Papers

Tetraisopropylsilane-1,2-Diyl: A New Bifunctional Protecting Group in Nucleoside Chemistry

Modified nucleic acids as an anti-aging agents