Synthesis and in vitro activity of novel 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinone antibacterial agents

The synthesis and antibacterial activity of 3-(4-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)phenyl)oxazolidin-2-ones is reported. Thiocarbonyl derivatives were found to be potent inhibitors of Gram-positive pathogens and compound 4l was two to fourfold more potent than Linezolid.     

Synthesis and anti-inflammatory activity of novel biscoumarin-chalcone hybrids

A series of synthesized novel biscoumarin-chalcone hybrids were evaluated for their anti-inflammatory and antioxidant activity. The tested compounds significantly inhibit the carrageenin induced paw oedema in albino rats and also exhibit important scavenging activities. These compounds thus constitute an interesting template for the design of new therapeutic tools against inflammation.     

Draft Genome Sequence of the Methyl Parathion (Pesticide) Degrading Bacterium Pseudomonas spp. MR3

Pseudomonas spp. MR3 was isolated from the surrounding soil of pesticide manufacturing industries of Ankleshwar, Gujarat. Under laboratory conditions these microbes were able to degrade up to 500 ppm of methyl parathion within 72 h. Genome sequencing of Pseudomonas spp. MR3 was carried out inIon Torrent (PGM), next generation sequencer. The data obtained revealed 1,268 contigs with genome size of 2.99 Mb and G + C content of 60.9 %. The draft genome sequence of strain MR3 will be helpful in studying the genetic pathways involved in the degradation of several pesticides.     

Identification of a novel ATPase activity in 14-3-3 proteins – Evidence from enzyme kinetics,structure guided modeling and mutagenesis studies

14-3-3 Proteins bind phosphorylated sequences in proteins and regulate multiple cellular functions. For the first time, we show that pure recombinant human 14-3-3 ζ, γ, ε and τ isofoms hydrolyze ATP with similar K_m and k_cat values. In sharp contrast the sigma isoform has no detectable activity. Docking studies identify two putative binding pockets in 14-3-3 zeta. Mutation of D124A in the amphipathic pocket enhances binding affinity and catalysis. Mutation of a critical Arg (R55A) at the dimer interface in zeta reduces binding and decreases catalysis. These experimental results coincide with a binding pose at the dimer interface. This newly identified function could be a moon lighting function in some of these isoforms.     

Tracking evolution of urban biogeochemical cycles: past,present, and future

This overview and synthesis paper focuses on the evolution of urban biogeochemical cycles across time. We synthesize empirical data and review existing literature, including papers in this special issue, and we propose the concept of “urban evolution.” The built environment often changes quickly in response to human activities, thus contributing to an urban evolution that affects structure, function, and ecosystem services of human settlements over time. Depending upon management, these changes can result in rapid losses of ecosystem functions/services or progress towards restoration. We explore urban evolution through empirical examples such as: (1) land development and nitrogen inputs within a metropolitan region over half a century; (2) watershed drainage by different forms of stormwater management over decades; (3) human-accelerated weathering in urbanized watersheds over decades; and (4) global salinization of freshwater across urbanizing landscapes over a century. We also synthesize concepts relevant to studying urban evolution of infrastructure and ecosystems including: (1) urban watersheds have challenged our whole notion of the “watershed approach” due to complex hydrologic boundaries and flow paths over time; (2) the urban hydrologic cycle evolves due to changing infrastructure and human water use over time; (3) the importance of extending research beyond individual sites using an urban watershed approach over space and time; (4) salinization as a universal tracer of watershed urbanization over time; (5) human-accelerated weathering of concrete and construction materials contributing to an “urban karst” over time; (6) human alteration of the carbon cycle in urban watersheds over time; and (7) detecting distinct biogeochemical signatures across cities globally over time. Our synthesis and this special issue suggest that urban biogeochemical cycles have exerted a major influence on the elemental composition of the Earth’s surface from local to global scales. A new global research agenda is needed to track the evolution of urban biogeochemical cycles as land development proceeds and infrastructure/management changes so we can better evaluate potential losses in ecosystem services, set realistic watershed and river restoration goals, and formulate effective environmental policy for Earth’s growing urban population.     

Intelligent Access to Sequence and Structure Databases (IASSD) ? an interface for accessing information from major web databases

AvailabilityThe Jar file is freely available through e-mail from the corresponding author.     

Unexpected Role for IL-17 in Protective Immunity against Hypervirulent Mycobacterium tuberculosis HN878 Infection

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world''s population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered “hypervirulent” as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.     

Calcium Binding to Beta-2-Microglobulin at Physiological Ph Drives the Occurrence of Conformational Changes Which Cause the Protein to Precipitate into Amorphous Forms That Subsequently Transform into Amyloid Aggregates

Using spectroscopic, calorimetric and microscopic methods, we demonstrate that calcium binds to beta-2-microglobulin (β2m) under physiological conditions of pH and ionic strength, in biological buffers, causing a conformational change associated with the binding of up to four calcium atoms per β2m molecule, with a marked transformation of some random coil structure into beta sheet structure, and culminating in the aggregation of the protein at physiological (serum) concentrations of calcium and β2m. We draw attention to the fact that the sequence of β2m contains several potential calcium-binding motifs of the DXD and DXDXD (or DXEXD) varieties. We establish (a) that the microscopic aggregation seen at physiological concentrations of β2m and calcium turns into actual turbidity and visible precipitation at higher concentrations of protein and β2m, (b) that this initial aggregation/precipitation leads to the formation of amorphous aggregates, (c) that the formation of the amorphous aggregates can be partially reversed through the addition of the divalent ion chelating agent, EDTA, and (d) that upon incubation for a few weeks, the amorphous aggregates appear to support the formation of amyloid aggregates that bind to the dye, thioflavin T (ThT), resulting in increase in the dye''s fluorescence. We speculate that β2m exists in the form of microscopic aggregates in vivo and that these don''t progress to form larger amyloid aggregates because protein concentrations remain low under normal conditions of kidney function and β2m degradation. However, when kidney function is compromised and especially when dialysis is performed, β2m concentrations probably transiently rise to yield large aggregates that deposit in bone joints and transform into amyloids during dialysis related amyloidosis.