Notes

Activity density with a ls scale: Precisely what hard disks invertebrate biomass relocating over the soil surface?
Regulation of bacterial stress responding σS is a sophisticated process and mediated by multiple interacting partners. Controlled proteolysis of σS is regulated by RssB which maintains minimal level of σS during exponential growth but then elevates σS level while facing stresses. Bacteria developed different strategies to regulate activity of RssB, including phosphorylation of itself and production of anti-adaptors. However, the function of phosphorylation is controversial and the mechanism of anti-adaptors preventing RssB-σS interaction remains elusive. Here, we demonstrated the impact of phosphorylation on the activity of RssB and built the RssB-σS complex model. Importantly, we showed that the phosphorylation site - D58 is at the interface of RssB-σS complex. Hence, mutation or phosphorylation of D58 would weaken the interaction of RssB with σS. We found that the anti-adaptor protein IraD has higher affinity than σS to RssB and its binding interface on RssB overlaps with that for σS. And IraD-RssB complex is preferred over RssB-σS in solution, regardless of the phosphorylation state of RssB. Our study suggests that RssB possesses a two-tier mechanism for regulating σS. First, phosphorylation of RssB provides a moderate and reversible tempering of its activity, followed by a specific and robust inhibition via the anti-adaptor interaction.Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.Musculoskeletal diseases often demand a drug treatment at the specific site of injury or defect site. In this context, the use of calcium phosphates is attractive as it allows both the bone substitution and the local delivery of a drug substance. In this work, we present a drug delivery device that combines calcium phosphate bioceramic granules and ibuprofen, a widely used anti-inflammatory drug. After verifying in vitro biocompatibility of the ibuprofen-loaded calcium phosphate granules on murine preosteoblastic cells (MC3T3), we evaluated in vitro efficiency of the drug substance released from the bioceramic using rheumatoid arthritis synoviocytes. Selleck AL3818 Our data document that ibuprofen-loaded calcium phosphate granules reduced inflammatory response and increased apoptosis of synoviocytes. In vivo study showed that both unloaded, and ibuprofen-loaded calcium phosphate granules induced a progressive osteogenesis, but in the case of ibuprofen-loaded implants, bone ingrowth was more limited in first weeks. However, as far as concerns inflammation, while unloaded granules showed inflammation up to 4 weeks, ibuprofen loaded granules did not show any significant inflammation. Ibuprofen concentration determination in blood samples showed that a very small amount of the drug reached the general circulation which render this drug delivery system suitable for both bone substitution and reduction of inflammation at the implantation site. Thus, this new drug carrier could be used to locally relieve inflammatory bone diseases symptoms including rheumatoid arthritis but, beyond this study, this kind of granules could be considered for the delivery of therapeutic agents such as antibiotic, analgesic or anticancer drugs.Pseudomonas aeruginosa is the predominant opportunistic bacterium that causes chronic respiratory infections in cystic fibrosis (CF) patients. This bacterium can form biofilms, which are structured communities of cells encased within a self-produced matrix. Such biofilms have a high level of resistance to multiple classes of antibiotics. A widely used treatment of P. aeruginosa lung infections in CF patients is tobramycin dry powder inhalation. The behaviour of particles in the lung has been well studied, and dry powder inhalers are optimised for optimal dispersion of the drug into different zones of the lung. However, one question that has not been addressed is whether the size of an antibiotic particle influences the antibiofilm activity against P. aeruginosa. We investigated this by fractionating tobramycin particles using a Next Generation Impactor (NGI). The fractions obtained were then tested in an in vitro model on P. aeruginosa biofilms. The results indicate that the antibiofilm activity of tobramycin dry powder inhaler can indeed be influenced by the particle size. Against P. aeruginosa biofilms of two clinical isolates, smaller tobramycin particles (aerodynamic diameter less then 2.82 µm) showed better efficacy by approximately 20% as compared to larger tobramycin particles (aerodynamic diameter less then 11.7 µm) However, this effect was only observed when biofilms were treated for 3 hours, whereas there was no difference after treatment for 24 hours. This suggests that in our model the rate of dissolution of larger particles limits the effectiveness of tobramycin over a 3-hour time period, which is relevant as this is equivalent to the time in which most tobramycin is cleared from the lung.
Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs).

We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models.
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