Etiology and pathogenesis of spondyloarthritides

Seronegative spondyloarthritides are inflammatory rheumatic diseases which are classified together because of numerous common and similar clinical, epidemiologic and genetic characteristics. Pathogenesis of seronegative spondyloarthritides is usually described as development of clinical characteristics of the disease in genetically susceptible person in the presence of favorable environmental factors. Development of seronegative spondyloarthritides, notably ankylosing spondylitis, is strongly connected with presence of the HLA-B27 gene. There are clear evidence that HLA-B27 positive individuals have significantly higher risk for disease development. The role of infection in occurence of seronegative spondyloarthritides is not completely understood--its role is better clarified in the case of reactive arthritis than in ankylosing spondylitis. The relation between HLA-B27 gene and infection is not clarified. Molecular mimicry theory is based on similarities between HLA-B27 molecule and microbial particle.     

Interactions of Aminopropyl–Azithromycin Derivatives,Precursors in the Synthesis of Bioactive Macrozones,with E. coli Ribosome: NMR and Docking Studies

The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. ¹³C and ¹⁵N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.     

The Emergence of SARS-CoV-2 within the Dog Population in Croatia: Host Factors and Clinical Outcome

Over a year into the COVID-19 pandemic, there is growing evidence that SARS-CoV-2 infections among dogs are more common than previously thought. In this study, the prevalence of SARS-CoV-2 antibodies was investigated in two dog populations. The first group was comprised of 1069 dogs admitted to the Veterinary Teaching Hospital for any given reason. The second group included dogs that shared households with confirmed COVID-19 cases in humans. This study group numbered 78 dogs. In COVID-19 infected households, 43.9% tested ELISA positive, and neutralising antibodies were detected in 25.64% of dogs. Those data are comparable with the secondary attack rate in the human population. With 14.69% of dogs in the general population testing ELISA positive, there was a surge of SARS-CoV-2 infections within the dog population amid the second wave of the pandemic. Noticeably seroprevalence of SARS-CoV-2 in the dog and the human population did not differ at the end of the study period. Male sex, breed and age were identified as significant risk factors. This study gives strong evidence that while acute dog infections are mostly asymptomatic, they can pose a significant risk to dog health. Due to the retrospective nature of this study, samples for viral isolation and PCR were unavailable. Still, seropositive dogs had a 1.97 times greater risk for developing central nervous symptoms.     

Geometric cues for directing the differentiation of mesenchymal stem cells

Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature—and with each occupying the same area—display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates.     

Effect of temephos on cholinesterase activity in the earthworm Eisenia fetida (Oligochaeta, Lumbricidae)

In this study, adult Eisenia fetida earthworms were exposed to the sub-lethal concentrations of temephos using the contact filter paper test procedure. Since temephos is an organophosphate pesticide, its effects on earthworms were determined by measuring ChE inhibition--a known biomarker of exposure. The ChE activity was measured after a short time of exposure--1 and 2 h. As expected, the lowest ChE activity (72.70% and 38.03% inhibition) was measured at the highest concentration of temephos (120 ng cm(-2)) applied. More interestingly, at the 0.12 ng cm(-2) concentration the ChE activity increased up to 36.28% of activity in the control in all three conducted experiments. Dose-response curves showed an inverted U-shape characteristic for hormesis. This hormetic-like effect could be important for health status of an earthworm.     

Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non‐MDR paclitaxel resistant ovarian cancer lines ES‐2/TP, MES‐OV/TP and OVCAR‐3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti‐human CCL2 antibody CNTO 888 and the anti‐mouse MCP‐1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.