Cutaneous human papillomavirus type 38 E7 regulates actin cytoskeleton structure for increasing cell proliferation through CK2 and the eukaryotic elongation factor 1A

We previously reported that the oncoproteins E6 and E7 from cutaneous human papillomavirus type 38 (HPV38) can immortalize primary human keratinocytes in vitro and sensitize transgenic mice to develop skin cancer in vivo. Immunofluorescence staining revealed that human keratinocytes immortalized by HPV38 E6 and E7 display fewer actin stress fibers than do control primary keratinocyte cells, raising the possibility of a role of the viral oncoproteins in the remodeling of the actin cytoskeleton. In this study, we show that HPV38 E7 induces actin stress fiber disruption and that this phenomenon correlates with its ability to downregulate Rho activity. The downregulation of Rho activity by HPV38 E7 is mediated through the activation of the CK2-MEK-extracellular signal-regulated kinase (ERK) pathway. In addition, HPV38 E7 is able to induce actin fiber disruption by binding directly to eukaryotic elongation factor 1A (eEF1A) and abolishing its effects on actin fiber formation. Finally, we found that the downregulation of Rho activity by HPV38 E7 through the CK2-MEK-ERK pathway facilitates cell growth proliferation. Taken together, our data support the conclusion that HPV38 E7 promotes keratinocyte proliferation in part by negatively regulating actin cytoskeleton fiber formation through the CK2-MEK-ERK-Rho pathway and by binding to eEF1A and inhibiting its effects on actin cytoskeleton remodeling.     

Preliminary evaluation of a 3H imidazoquinoline library as dual TLR7/TLR8 antagonists

Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. 2D-NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds.     

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.     

Centriole maturation requires regulated Plk1 activity during two consecutive cell cycles

Newly formed centrioles in cycling cells undergo a maturation process that is almost two cell cycles long before they become competent to function as microtubule-organizing centers and basal bodies. As a result, each cell contains three generations of centrioles, only one of which is able to form cilia. It is not known how this long and complex process is regulated. We show that controlled Plk1 activity is required for gradual biochemical and structural maturation of the centrioles and timely appendage assembly. Inhibition of Plk1 impeded accumulation of appendage proteins and appendage formation. Unscheduled Plk1 activity, either in cycling or interphase-arrested cells, accelerated centriole maturation and appendage and cilia formation on the nascent centrioles, erasing the age difference between centrioles in one cell. These findings provide a new understanding of how the centriole cycle is regulated and how proper cilia and centrosome numbers are maintained in the cells.     

Selection on GGU and CGU Codons in the High Expression Genes in Bacteria

The fourfold degenerate site (FDS) in coding sequences is important for studying the effect of any selection pressure on codon usage bias (CUB) because nucleotide substitution per se is not under any such pressure at the site due to the unaltered amino acid sequence in a protein. We estimated the frequency variation of nucleotides at the FDS across the eight family boxes (FBs) defined as Um(g), the unevenness measure of a gene g. The study was made in 545 species of bacteria. In many bacteria, the Um(g) correlated strongly with Nc′—a measure of the CUB. Analysis of the strongly correlated bacteria revealed that the U-ending codons (GGU, CGU) were preferred to the G-ending codons (GGG, CGG) in Gly and Arg FBs even in the genomes with G+C % higher than 65.0. Further evidence suggested that these codons can be used as a good indicator of selection pressure on CUB in genomes with higher G+C %.     

Vegetation Response and Landscape Dynamics of Indian Summer Monsoon Variations during Holocene: An Eco-Geomorphological Appraisal of Tropical Evergreen Forest Subfossil Logs

The high rainfall and low sea level during Early Holocene had a significant impact on the development and sustenance of dense forest and swamp-marsh cover along the southwest coast of India. This heavy rainfall flooded the coastal plains, forest flourishing in the abandoned river channels and other low-lying areas in midland.The coastline and other areas in lowland of southwestern India supply sufficient evidence of tree trunks of wet evergreen forests getting buried during the Holocene period under varying thickness of clay, silty-clay and even in sand sequences. This preserved subfossil log assemblage forms an excellent proxy for eco-geomorphological and palaeoclimate appraisal reported hitherto from Indian subcontinent, and complements the available palynological data. The bulk of the subfossil logs and partially carbonized wood remains have yielded age prior to the Holocene transgression of 6.5 k yrs BP, suggesting therein that flooding due to heavy rainfall drowned the forest cover, even extending to parts of the present shelf. These preserved logs represent a unique palaeoenvironmental database as they contain observable cellular structure. Some of them can even be compared to modern analogues. As these woods belong to the Late Pleistocene and Holocene, they form a valuable source of climate data that alleviates the lack of contemporaneous meteorological records. These palaeoforests along with pollen proxies depict the warmer environment in this region, which is consistent with a Mid Holocene Thermal Maximum often referred to as Holocene Climate Optimum. Thus, the subfossil logs of tropical evergreen forests constitute new indices of Asian palaeomonsoon, while their occurrence and preservation are attributed to eco-geomorphology and hydrological regimes associated with the intensified Asian Summer Monsoon, as recorded elsewhere.     

Role of Astrocytes in Major Neuropsychiatric Disorders

Neurochemical Research - Astrocytes are the primary homeostatic cells of the central nervous system, essential for normal neuronal development and function, metabolism and response to injury and...