Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity

The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy

Spinal pain: Current understanding, trends, and the future of care

© 2015 Trainor et al. This commissioned review paper offers a summary of our current understanding of nonmalignant spinal pain, particularly persistent pain. Spinal pain can be a complex problem, requiring management that addresses both the physical and psychosocial components of the pain experience. We propose a model of care that includes the necessary components of care services that would address the multidimensional nature of spinal pain. Emerging care services that tailor care to the individual person with pain seems to achieve better outcomes and greater consumer satisfaction with care, while most likely containing costs. However, we recommend that any model of care and care framework should be developed on the basis of a multidisciplinary approach to care, with the scaffold being the principles of evidence-based practice. Importantly, we propose that any care services recommended in new models or frameworks be matched with available resources and services-this matching we promote as the fourth principle of evidence-based practice. Ongoing research will be necessary to offer insight into clinical outcomes of complex interventions, while practice-based research would uncover consumer needs and workforce capacity. This kind of research data is essential to inform health care policy and practice

Label-free profiling of white adipose tissue of rats exhibiting high or low levels of intrinsic exercise capacity

Divergent selection has created rat phenotypes of high- and low-capacity runners (HCR and LCR, respectively) that have differences in aerobic capacity and correlated traits such as adiposity. We analyzed visceral adipose tissue of HCR and LCR using label-free high-definition MS (elevated energy) profiling. The running capacity of HCR was ninefold greater than LCR. Proteome profiling encompassed 448 proteins and detected 30 significant (p <0.05; false discovery rate <10%, calculated using q-values) differences. Approximately half of the proteins analyzed were of mitochondrial origin, but there were no significant differences in the abundance of proteins involved in aerobic metabolism. Instead, adipose tissue of LCR rats exhibited greater abundances of proteins associated with adipogenesis (e.g. cathepsin D), ER stress (e.g. 78 kDa glucose response protein), and inflammation (e.g. Ig gamma-2B chain C region). Whereas the abundance antioxidant enzymes such as superoxide dismutase [Cu-Zn] was greater in HCR tissue. Putative adipokines were also detected, in particular protein S100-B, was 431% more abundant in LCR adipose tissue. These findings reveal low running capacity is associated with a pathological profile in visceral adipose tissue proteome despite no detectable differences in mitochondrial protein abundance

Controlled synthesis of SPION@SiO₂ nanoparticles using design of experiments

The synthesis of single-core superparamagnetic iron oxide nanoparticles (SPIONs) coated with a silica shell of controlled thickness remains a challenge, due to the dependence on a multitude of experimental variables. Herein, we utilise design of experiment (DoE) to study the formation of SPION@SiO2 nanoparticles (NPs) via reverse microemulsion. Using a 33 full factorial design, the influence of reactant concentration of tetraethyl orthosilicate (TEOS) and ammonium hydroxide (NH4OH), as well as the number of fractionated additions of TEOS on the silica shell was investigated with the aim of minimising polydispersity and increasing the population of SPION@SiO2 NPs formed. This investigation facilitated a reproducible and controlled approach for the high yield synthesis of SPION@SiO2 NPs with uniform silica shell thickness. Application of a multiple linear regression analysis established a relationship between the applied experimental variables and the resulting silica shell thickness. These experimental variables were similarly found to dictate the monodispersity of the SPION@SiO2 NPs formed. The overall population of single-core@shell particles was dependent on the interaction between the number of moles of TEOS and NH4OH, with no influence from the number of fractionated additions of TEOS. This work demonstrates the complexity of the preparative method and produces an accessible and flexible synthetic model to achieve monodisperse SPION@SiO2 NPs with controllable shell thickness

The Effect of Insecticide Synergists on the Response of Scabies Mites to Pyrethroid Acaricides

Synergists are commonly used in combination with pesticides to suppress metabolism-based resistance and increase the efficacy of the agents. They are also useful as tools for laboratory investigation of specific resistance mechanisms based on their ability to inhibit specific metabolic pathways. To determine the role of metabolic degradation as a mechanism for acaricide resistance in human scabies, PBO (piperonyl butoxide), DEF (S,S,S-tributyl phosphorotrithioate) and DEM (diethyl maleate) were used with permethrin as synergists in a bioassay of mite killing. A statistically significant difference in survival time of permethrin-resistant Sarcoptes scabiei variety canis was noted when any of the three synergists were used in combination with permethrin compared to survival time of mites exposed to permethrin alone (p<0.0001). These results indicate the potential utility of synergists in reversing tolerance to pyrethroid-based acaricides (i.e. the addition of synergists to permethrin-containing topical acaricide cream commonly used to treat scabies). To further verify specific metabolic pathways being inhibited by these synergists, enzyme assays were developed to measure esterase, glutathione S-transferase (GST) and cytochrome P450 monooxygenase activity in scabies mites. Results of in vitro enzyme inhibition experiments showed lower levels of esterase activity with DEF; lower levels of GST activity with DEM and lower levels of cytochrome monooxygenase activity with PBO. These findings indicate a metabolic mechanism as mediating pyrethroid resistance in scabies mites

The AGNIFS survey: spatially resolved observations of hot molecular and ionized outflows in nearby active galaxies

\ua9 2023 The Author(s). We present the hot molecular and warm ionized gas kinematics for 33 nearby (0.001 ≲ z ≲ 0.056) X-ray selected active galaxies using the H2 2.1218 μm and Br γ emission lines observed in the K band with the Gemini near-infrared integral field spectrograph. The observations cover the inner 0.04–2 kpc of each active galactic nucleus at spatial resolutions of 4–250 pc with a velocity resolution of σinst ≈ 20 km s-1. We find that 31 objects (94 per cent) present a kinematically disturbed region (KDR) seen in ionized gas, while such regions are observed in hot molecular gas for 25 galaxies (76 per cent). We interpret the KDR as being due to outflows with masses of 102–107 and 100–104 M☉ for the ionized and hot molecular gas, respectively. The ranges of mass-outflow rates (M\ub7out) and kinetic power (ĖK) of the outflows are 10-3–101 M☉ yr-1 and ∼1037–1043 erg s-1 for the ionized gas outflows, and 10-5–10-2 M☉ yr-1 and 1035–1039 erg s-1 for the hot molecular gas outflows. The median coupling efficiency in our sample is ĖK/Lbol ≈ 1.8 7 10-3 and the estimated momentum fluxes of the outflows suggest they are produced by radiation-pressure in low-density environment, with possible contribution from shocks

Geo-mapping of caries risk in children and adolescents - a novel approach for allocation of preventive care

<p>Abstract</p> <p>Background</p> <p>Dental caries in children is unevenly distributed within populations with a higher burden in low socio-economy groups. Thus, tools are needed to allocate resources and establish evidence-based programs that meet the needs of those at risk. The aim of the study was to apply a novel concept for presenting epidemiological data based on caries risk in the region of Halland in southwest Sweden, using geo-maps.</p> <p>Methods</p> <p>The study population consisted of 46,536 individuals between 3-19 years of age (75% of the eligible population) from whom caries data were reported in 2010. Reported dmfs/DMFS>0 for an individual was considered as the primary caries outcome. Each study individual was geo-coded with respect to his/her residence parish. A parish-specific relative risk (RR) was calculated as the observed-to-expected ratio, where the expected number of individuals with dmfs/DMFS>0 was obtained from the age- and sex-specific caries (dmfs/DMFS>0) rates for the total study population. Smoothed caries risk geo-maps, along with corresponding statistical certainty geo-maps, were produced by using the free software Rapid Inquiry Facility and the ESRI^®ArcGIS system.</p> <p>Results</p> <p>The geo-maps of preschool children (3-6 years), schoolchildren (7-11 years) and adolescents (12-19 years) displayed obvious geographical variations in caries risk, albeit most marked among the preschoolers. Among the preschool children the smoothed relative risk (SmRR) varied from 0.33 to 2.37 in different parishes. With increasing age, the contrasts seemed to diminish although the gross geographical risk pattern persisted also among the adolescents (SmRR range 0.75-1.20).</p> <p>Conclusion</p> <p>Geo-maps based on caries risk may provide a novel option to allocate resources and tailor supportive and preventive measures within regions with sections of the population with relatively high caries rates.</p

The Galactic Center Black Hole Laboratory

The super-massive 4 million solar mass black hole Sagittarius~A* (SgrA*) shows flare emission from the millimeter to the X-ray domain. A detailed analysis of the infrared light curves allows us to address the accretion phenomenon in a statistical way. The analysis shows that the near-infrared flare amplitudes are dominated by a single state power law, with the low states in SgrA* limited by confusion through the unresolved stellar background. There are several dusty objects in the immediate vicinity of SgrA*. The source G2/DSO is one of them. Its nature is unclear. It may be comparable to similar stellar dusty sources in the region or may consist predominantly of gas and dust. In this case a particularly enhanced accretion activity onto SgrA* may be expected in the near future. Here the interpretation of recent data and ongoing observations are discussed.Comment: 30 pages - 7 figures - accepted for publication by Springer's "Fundamental Theories of Physics" series; summarizing GC contributions of 2 conferences: 'Equations of Motion in Relativistic Gravity' at the Physikzentrum Bad Honnef, Bad Honnef, Germany, (Feb. 17-23, 2013) and the COST MP0905 'The Galactic Center Black Hole Laboratory' Granada, Spain (Nov. 19 - 22, 2013