Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-alpha and IL-6 inhibitors

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl-D-glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-alpha and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60-65% inhibition at 10 microM concentration. Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC(50)'s of 0.2, 0.3 and 0.16 microM, respectively. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 microM.     

Repeated,Long-Term Cycling of Putative Stem Cells between Niches in a Basal Chordate

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Highlights? Identification of a niche for germline and somatic stem cells in a basal chordate ? Stem cells repeatedly migrate between aged or damaged niches into developing niches     

Bacterial and eukaryote microbiomes of mosquito habitats in dengue-endemic southern Taiwan

Mosquitoes interact with the microbiome of the waters where they oviposit in several ways. Past work suggests adult mosquitoes can detect certain microbes that stimulate oviposition. The presence or absence of certain microbes in water containers thus can attract or repel mosquito species to different containers. I hypothesized that these relationships could be detected via metagenomics. I focused on two container breeders that coexist in Southern Taiwan: the dengue vector Aedes aegypti and the less competent vector Ae. albopictus. In addition to culturing, I performed 16S and 18S rDNA metagenomics assays, the latter of which had never been applied to mosquito waters before, to identify the microbial diversity of artificial containers with and without mosquito larvae. I found no correlation between mosquito presence to any features of the containers or to their microbiomes, which instead correlated strongly with location. Microbial diversity across containers was highly variable, even within the same location, with multiple taxa only found in single containers. This variability is reasonable, because mosquito gut microbiomes are also extremely variable. The possibility remains that microbes in natural containers differ significantly from those in artificial containers, and that these differences drive Aedes preferences for human-associated containers. Broad, single-microbe experimental work is recommended to identify possible attractant or repellent microbial taxa.     

Tyrosine phosphorylation of WW proteins

A number of key regulatory proteins contain one or two copies of the WW domain known to mediate protein–protein interaction via proline-rich motifs, such as PPxY. The Hippo pathway components take advantage of this module to transduce tumor suppressor signaling. It is becoming evident that tyrosine phosphorylation is a critical regulator of the WW proteins. Here, we review the current knowledge on the involved tyrosine kinases and their roles in regulating the WW proteins.     

On the limited recognition of inorganic surfaces by short peptides compared with antibodies

The vast potential applications of biomolecules that bind inorganic surfaces led mostly to the isolation of short peptides that target selectively specific materials. The demonstrated differential affinity toward certain surfaces created the impression that the recognition capacity of short peptides may match that of rigid biomolecules. In the following, we challenge this view by comparing the capacity of antibody molecules to discriminate between the (100) and (111A) facets of a gallium arsenide semiconductor crystal with the capacity of short peptides to do the same. Applying selection from several peptide and single chain phage display libraries, we find a number of antibody molecules that bind preferentially a given crystal facet but fail to isolate, in dozens of attempts, a single peptide capable of such recognition. The experiments underscore the importance of rigidity to the recognition of inorganic flat targets and therefore set limitations on potential applications of short peptides in biomimetics. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Vital staining of the stick insect digestive system identifies appendices of the midgut as novel system of excretion

The stick insects or phasmids (Phamsatodea) have a series of pyriform ampulles with long, thin filaments on the posterior end of their midgut referred to as the “appendices of the midgut.” Found only in phasmids, their function had never been determined until now. Their similarity to the Malpighian tubules, which are ubiquitous insect organs of excretion, suggested a similar function. To differentiate between the appendices and the Malpighian tubules and compare functional differences between the two tissue types, vital staining (the injection of histological stains into living organisms) was done in conjunction with light and scanning electron microscopy in multiple phasmid species. The results showed that the appendices originated in the basal phasmids (Timematidae) and grew more numerous in derived species. The appendices stain selectively, notably failing to pick up the indicators of the two known systems of invertebrate excretory function, indigo carmine and ammonium carmine. Appendices sequester stains in the ampule portion before eliminating the compounds into the midgut. We conclude by confirming that the appendices do have an excretory function, but one unlike any other known in invertebrates. Their function is likely cation excretion, playing a role in calcium regulation and/or organic alkaloid sequestration. The appendices must thus be considered distinct organs from the Malpighian tubules. J. Morphol. 275:623–633, 2014. © 2013 Wiley Periodicals, Inc.     

Characterization of sponge-associated Verrucomicrobia: microcompartment-based sugar utilization and enhanced toxin–antitoxin modules as features of host-associated Opitutales

Bacteria of the phylum Verrucomicrobia are ubiquitous in marine environments and can be found as free-living organisms or as symbionts of eukaryotic hosts. Little is known about host-associated Verrucomicrobia in the marine environment. Here we reconstructed two genomes of symbiotic Verrucomicrobia from bacterial metagenomes derived from the Atlanto-Mediterranean sponge Petrosia ficiformis and three genomes from strains that we isolated from offshore seawater of the Eastern Mediterranean Sea. Phylogenomic analysis of these five strains indicated that they are all members of Verrucomicrobia subdivision 4, order Opitutales. We compared these novel sponge-associated and seawater-isolated genomes to closely related Verrucomicrobia. Genomic analysis revealed that Planctomycetes-Verrucomicrobia microcompartment gene clusters are enriched in the genomes of symbiotic Opitutales including sponge symbionts but not in free-living ones. We hypothesize that in sponge symbionts these microcompartments are used for degradation of l -fucose and l -rhamnose, which are components of algal and bacterial cell walls and therefore may be found at high concentrations in the sponge tissue. Furthermore, we observed an enrichment of toxin–antitoxin modules in symbiotic Opitutales. We suggest that, in sponges, verrucomicrobial symbionts utilize these modules as a defence mechanism against antimicrobial activity deriving from the abundant microbial community co-inhabiting the host.