Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins.

Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pneumoniae, the main cause for bacterial pneumonia. Liberation of PLY during infection leads to compromised immune system and cytolytic cell death. Here, we report discovery, development, and validation of targeted small molecule inhibitors of PLY (pore-blockers, PB).

Enabling ultra-high dose rate electron beams at a clinical linear accelerator for isocentric treatments.

Background And Purpose: Radiotherapy delivery with ultra-high dose rates (UHDR) has consistently produced normal tissue sparing while maintaining efficacy for tumour control in preclinical studies, known as the FLASH effect. Modified clinical electron linacs have been used for pre-clinical studies at reduced source-surface distance (SSD) and novel intra-operative devices are becoming available. In this context, we modified a clinical linac to deliver 16 MeV UHDR electron beams with an isocentric setup.

Nanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antivirals.

Viral proteases have been established as drug targets in several viral diseases including human immunodeficiency virus and hepatitis C virus infections due to the essential role of these enzymes in virus replication. In contrast, no antiviral therapy is available to date against flaviviral infections including those by Zika virus (ZIKV), West Nile virus (WNV), or dengue virus (DENV). Numerous potent inhibitors of flaviviral proteases have been reported; however, a huge gap remains between the in vitro and intracellular activities, possibly due to low cellular uptake of the charged compounds.

Dosimetric and geometric end-to-end accuracy of a magnetic resonance guided linear accelerator.

The introduction of real-time imaging by magnetic resonance guided linear accelerators (MR-Linacs) enabled adaptive treatments and gating on the tumor position. Different end-to-end tests monitored the accuracy of our MR-Linac during the first year of clinical operation. We report on the stability of these tests covering a static, adaptive and gating workflow.

Biological Characterization, Mechanistic Investigation and Structure-Activity Relationships of Chemically Stable TLR2 Antagonists.

Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1-9) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks.

Identification and validation of a novel dual small-molecule TLR2/8 antagonist.

Toll-like receptor 2 (TLR2) and TLR8 are involved in the recognition of bacterial and viral components and are linked not only to protective antimicrobial immunity but also to inflammatory diseases. Recently, increasing attention has been paid to the receptor crosstalk between TLR2 and TLR8 to fine-tune innate immune responses. In this study, we report a novel dual TLR2/TLR8 antagonist, compound 24 that was developed by a modeling-guided synthesis approach.

Adsorption and desorption behavior of NO on H-ZSM-5, Na-ZSM-5, and Na-A as studied by EPR.

Nitric monoxide probe molecules are used to characterize the Lewis acid properties of sodium cations and aluminum defect centers in various zeolite materials. The adsorption-desorption behavior of NO probe molecules is studied at different temperatures for Na-A, Na-ZSM-5, H-ZSM-5, and silicalite. Adsorbed NO molecules form paramagnetic adsorption complexes with Lewis acid sites which can be examined by EPR transitions ((Delta)m(S)+/-1) at g approximately 2.