Cellular binding partners of the human papillomavirus E6 protein

The high-risk strains of human papillomavirus (HR-HPV) are known to be causative agents of cervical cancer and have recently also been implicated in cancers of the oropharynx. E6 is a potent oncogene of HR-HPVs, and its role in the progression to malignancy has been and continues to be explored. E6 is known to interact with and subsequently inactivate numerous cellular proteins pivotal in the mediation of apoptosis, transcription of tumor suppressor genes, maintenance of epithelial organization, and control of cell proliferation. Binding of E6 to these proteins cumulatively contributes to the oncogenic potential of HPV. This paper provides an overview of these cellular protein partners of HR-E6, the motifs known to mediate oncoprotein binding, and the agents that have the potential to interfere with E6 expression and activity and thus prevent the subsequent progression to oncogenesis

A quantitative LumiFluo assay to test inhibitory compounds blocking p53 degradation induced by human papillomavirus oncoprotein E6 in living cells

High-risk human papillomaviruses (HR-HPVs) are the causative agents for the onset of several epithelial cancers in humans. The deregulated expression of the viral oncoproteins E6 and E7 is the driving force sustaining the progression of malignant transformation in pre-neoplastic lesions. Targeting the viral E6 oncoprotein through inhibitory compounds can counteract the survival of cancer cells due to the reactivation of p53-mediated pathways and represents an intriguing strategy to treat HPV-associated neoplasias. Here, we describe the development of a quantitative and easy-to-perform assay to monitor the E6-mediated degradation of p53 in living cells to be used for small-molecule testing. This assay allows to unbiasedly determine whether a compound can protect p53 from the E6-mediated degradation in cells, through a simple 3-step protocol. We validated the assay by testing two small molecules, SAHA and RITA, reported to impair the E6-mediated p53 degradation. Interestingly, we observed that only SAHA efficiently rescued p53, while RITA could not provide the same degree of protection. The possibility to specifically and quantitatively monitor the ability of a selected compound to rescue p53 in a cellular context through our LumiFluo assay could represent an important step towards the successful development of anti-HPV drugs

Continuously Adjustable, Molecular-Sieving "Gate" on 5A Zeolite for Distinguishing Small Organic Molecules by Size

Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving “gate” at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences were effectively distinguished via appropriate misalignment. This novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation

Space-like Penguin Effects in B→PPB \to PP Decays

The space-like penguin contributions to branching ratios and CP asymmetries in charmless decays of $B$ to two pseudoscalar mesons are studied using the next-to-leading order low energy effective Hamiltonian. Both the gluonic penguin and the electroweak penguin diagrams are considered. We find that the effects are significant.Comment: 18 pages, LaTex file, 2 figure

Acanthus montanus: An experimental evaluation of the antimicrobial, anti-inflammatory and immunological properties of a traditional remedy for furuncles

<p>Abstract</p> <p>Background</p> <p><it>Acanthus montanus </it>(Nees) T. Anderson (Acanthaceae) is a shrub widespread in Africa, the Balkans, Romania, Greece and Eastern Mediterranean. It is used in African traditional medicine for the treatment of urogenital infections, urethral pain, endometritis, urinary disease, cystitis, leucorrhoea, aches and pains. In southeastern Nigeria, the root is popular and acclaimed highly effective in the treatment of furuncles. This study was undertaken to experimentally evaluate the antimicrobial and anti-inflammatory properties of the root extract as well as its effect on phagocytosis and specific cell-mediated immune response which may underlie the usefulness of the roots in treatment of furuncles.</p> <p>Methods</p> <p>The aqueous root extract (obtained by hot water maceration of the root powder) was studied for effects on the growth of clinically isolated strains of <it>Pseudomonas aeruginosa </it>and <it>Staphylococcus aureus</it>. The anti-inflammatory activity was investigated using acute topical edema of the mouse ear induced by xylene, acute paw edema induced by agar in rats, formaldehyde arthritis in rats, vascular permeability induced by acetic acid in mice and heat- and hypotonicity-induced haemolysis of ox red blood cells (RBCs). Also evaluated were the effects on <it>in vivo </it>leukocyte migration induced by agar, phagocytic activity of macrophages on <it>Candida albicans </it>and specific cell-mediated immune responses (delayed type hypersensitivity reaction (DTHR) induced by sheep red blood cell (SRBC)). The acute toxicity and lethality (LD₅₀) in mice and phytochemical constituents of the extract were also determined.</p> <p>Results</p> <p>The extract moderately inhibited the growth of the test organisms and significantly (<it>P </it>< 0.05) inhibited (57%) topical acute edema in the mouse ear. It significantly (<it>P </it>< 0.05) suppressed the development of acute edema of the rat paw in a non-dose-related manner and was not effective in inhibiting the global edematous response to formaldehyde arthritis. It also inhibited vascular permeability induced by acetic acid in mice and the haemolysis of ox RBCs induced by heat- and hypotonicity. The extract increased total leukocyte and neutrophil counts and caused a significant (<it>P </it>< 0.05) dose-related increase in the total number of macrophages at the 800 mg/kg dose. On phagocytic activity, the extract evoked a significant (<it>P </it>< 0.05) increase in the number of macrophages with ingested <it>C. albicans </it>at 800 mg/kg dose, and significantly (<it>P </it>< 0.05) inhibited DTHR in a dose-related manner. Phytochemical tests on the extract revealed an abundant presence of alkaloids and carbohydrates while saponins, glycosides, and terpenoids occurred in trace amounts. Acute toxicity test established an oral and intraperitoneal LD₅₀greater than 5,000 mg/kg.</p> <p>Conclusion</p> <p>The effectiveness of the root of <it>A. montanus </it>in the treatment of furuncles may largely derive from mobilization of leukocytes to the site of the infection and activation of phagocytic activity as well as suppression of exacerbated immune responses by its constituents. Antimicrobial and anti-inflammatory activities are likely contributory mechanisms. Phytochemical constituents such as alkaloids and carbohydrates may be responsible for these pharmacological activities.</p

Evolutionary significance of inversions in legume chloroplast DNAs

Cloned genes from tobacco, spinach, and pea were used as hybridization probes to localize 36 protein genes on the chloroplast chromosomes of four legumes — mung bean, common bean, soybean, and pea. The first three chloroplast DNAs (cpDNAs), all of which retain a large inverted repeat, have an identical gene order with but one exception. A 78 kb segment encompassing nearly the entire large single copy region is inverted in mung bean and common bean relative to soybean and non-legumes. The simplest evolutionary explanation for this difference is a 78 kb inversion, with one endpoint between rps8 and inf A and the second between psb A and rpl2 . However, we can not rule out a two-step re-arrangement (consisting of successive expansion and contraction of the inverted repeat) leading to the relocation of a block of six ribosomal protein genes ( rps 19- rps 8) from one end of the large single copy region to the other. Analysis of gene locations in pea cpDNA, which lacks the large inverted repeat, combined with cross-hybridization studies using 59 clones covering the mung bean genome, leads to a refined picture of the position and nature of the numerous rearrangements previously described in the pea genome. A minimum of eight large inversions are postulated to account for these rearrangements. None of these inversions disrupt groups of genes that are transcriptionally linked in angiosperm cpDNA. Rather, the end-points of inversions are associated with relatively spacer-rich segments of the genome, many of which contain tRNA genes. All of the pea-specific inversions are shown to be positionally distinct from those recently described in a closely related legume, broad bean.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46965/1/294_2004_Article_BF00405856.pd

Future Trends in Digital Face Manipulation and Detection

Recently, digital face manipulation and its detection have sparked large interest in industry and academia around the world. Numerous approaches have been proposed in the literature to create realistic face manipulations, such as DeepFakes and face morphs. To the human eye manipulated images and videos can be almost indistinguishable from real content. Although impressive progress has been reported in the automatic detection of such face manipulations, this research field is often considered to be a cat and mouse game. This chapter briefly discusses the state of the art of digital face manipulation and detection. Issues and challenges that need to be tackled by the research community are summarized, along with future trends in the field

The unique genetic adaptation of the Himalayan wolf to high-altitudes and consequences for conservation

The Himalayan wolf seems uniquely adapted to life at high-altitudes of the Himalayas and the Tibetan Plateau. Through a non-invasive survey we confirm the presence of the Himalayan wolf across the Nepalese Himalayas and its phylogenetic distinctness based on mitochondrial and nuclear DNA. We use the data generated from 287 scat and hair samples combined with a reference dataset including canid samples from around the globe. The Himalayan wolf forms a genetically distinct lineage based on 1) 242bp of D-loop and 508bp of cytochrome b (mtDNA), 2) the ZF gene of both sex chromosomes, 3) a microsatellite panel of 17 nuclear loci, and 4) four non-synonymous SNPs in four hypoxia pathway related (functional) nuclear genes. The SNP analysis indicates a genetic adaptation to cope with the hypoxic stresses in the high altitude habitats which we did not find in the Holarctic grey wolf. Based on analysis of divergence time from full mitochondrial genomes we estimate that the Himalayan wolf diverged from the Holarctic grey wolf complex 691,000–740,000 years before the present day. We provide first insights into the population status of the Himalayan wolf in Nepal with nuclear genotyping revealing counts of 12, 16, and 2 wolf individuals in the three study areas Humla (384 km2), Dolpa (1,088 km2), and Kanchenjunga Conservation Area (368 km2) respectively. The methods presented here offer a complete toolkit for the non-invasive monitoring of this wolf lineage. Nepal holds a significant population of this unique wolf across its Himalayan landscapes and we recommend the country takes a leading role on its protection