Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

BACKGROUND: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. METHODS: For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. RESULTS: The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. CONCLUSIONS: In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases

Iron, silicate, and light co-limitation of three Southern Ocean diatom species

The effect of combined iron, silicate, and light co-limitation was investigated in the three diatom species Actinocyclus sp. Ehrenberg, Chaetoceros dichaeta Ehrenberg, and Chaetoceros debilis Cleve, isolated from the Southern Ocean (SO). Growth of all species was co-limited by iron and silicate, reflected in a significant increase in the number of cell divisions compared to the control. Lowest relative Si uptake and drastic frustule malformation was found under iron and silicate co-limitation in C. dichaeta, while Si limitation in general caused cell elongation in both Chaetoceros species. Higher light intensities similar to SO surface conditions showed a negative impact on growth of C. dichaeta and Actinocyclus sp. and no effect on C. debilis. This is in contrast to the assumed light limitation of SO diatoms due to deep wind driven mixing. Our results suggest that growth and species composition of Southern Ocean diatoms is influenced by a sensitive interaction of the abiotic factors, iron, silicate, and light

Mangarara Formation: exhumed remnants of a middle Miocene, temperate carbonate, submarine channel-fan system on the eastern margin of Taranaki Basin, New Zealand

The middle Miocene Mangarara Formation is a thin (1–60 m), laterally discontinuous unit of moderately to highly calcareous (40–90%) facies of sandy to pure limestone, bioclastic sandstone, and conglomerate that crops out in a few valleys in North Taranaki across the transition from King Country Basin into offshore Taranaki Basin. The unit occurs within hemipelagic (slope) mudstone of Manganui Formation, is stratigraphically associated with redeposited sandstone of Moki Formation, and is overlain by redeposited volcaniclastic sandstone of Mohakatino Formation. The calcareous facies of the Mangarara Formation are interpreted to be mainly mass-emplaced deposits having channelised and sheet-like geometries, sedimentary structures supportive of redeposition, mixed environment fossil associations, and stratigraphic enclosure within bathyal mudrocks and flysch. The carbonate component of the deposits consists mainly of bivalves, larger benthic foraminifers (especially Amphistegina), coralline red algae including rhodoliths (Lithothamnion and Mesophyllum), and bryozoans, a warm-temperate, shallow marine skeletal association. While sediment derivation was partly from an eastern contemporary shelf, the bulk of the skeletal carbonate is inferred to have been sourced from shoal carbonate factories around and upon isolated basement highs (Patea-Tongaporutu High) to the south. The Mangarara sediments were redeposited within slope gullies and broad open submarine channels and lobes in the vicinity of the channel-lobe transition zone of a submarine fan system. Different phases of sediment transport and deposition (lateral-accretion and aggradation stages) are identified in the channel infilling. Dual fan systems likely co-existed, one dominating and predominantly siliciclastic in nature (Moki Formation), and the other infrequent and involving the temperate calcareous deposits of Mangarara Formation. The Mangarara Formation is an outcrop analogue for middle Miocene-age carbonate slope-fan deposits elsewhere in subsurface Taranaki Basin, New Zealand

How Strong Do Global Commodity Prices Influence Domestic Food Prices in Developing Countries? A Global Price Transmission and Vulnerability Mapping Analysis

This paper analyzes the transmission from global commodity to domestic food prices for a large set of countries. First, a theoretical model is developed to explain price transmission for different trade regimes. Drawing from the competitive storage model under rational expectations, it is shown that domestic prices can respond instantaneously to global prices even if no trade takes place but future trade is expected. Using a global database on food prices, we construct national and international grain price indices. With an autoregressive distributed lag model, we empirically detect countries in which food prices are influenced by global commodity prices, including futures prices. Mapping transmission elasticities with the size of the population below the poverty line which spends typically a large share of its income on food, we are able to estimate the size of vulnerable population. Our empirical analysis reveals that 90 percent of the global poor (income below 1.25$/day) live in countries where domestic food prices respond to international prices - but the extent of transmission varies substantially. For 360 million poor people, international prices transmit to their country at rates of 30 percent or higher within three months

Investigating Adsorption of Cellulose Nanocrystals at Air–Liquid and Substrate–Liquid Interfaces after pH Manipulation

Coatings of anisotropic nanoparticles such as cellulose nanocrystals (CNCs) can provide tuneable physicochemical surface properties to a substrate such as modifying wettability. These coatings are often formed using dip coating, with CNCs enriched at the air–water interface transferred to a substrate as a monolayer. This process is commonly facilitated by surfactants, which can remain present in the final product, affecting coating properties. In this work, an “additive free” method for creating CNC coatings by exploiting electrostatic interactions within the pH window between pH 2–4 is demonstrated. Within this pH window, the air–water interface is positively charged and CNCs are negatively charged, with surface pressure tensiometry, X-ray reflectivity, and Brewster angle microscopy indicating that CNCs are driven to the air–water interface. The optimal condition for monolayer coverage was pH 3; at pH 2 charge screening causes localized flocculation at the air–water interface, and at pH 4 interparticle repulsion leads to incomplete, patchy coverage. These findings successfully translate to dip coated CNC monolayers as characterized by atomic force microscopy, showing that the manipulation of pH can facilitate the surfactant-free dip coating of CNCs, with advantages over the surfactants that are more typically used

A new approach to bad news effects on volatilit y: the multiple-sign-volume sensitive regime EGARCH model (MSV-EGARCH)

In this paper, using daily data for six major international stock market indexes and a modified EGARCH specification, the links between stock market returns, volatility and trading volume are investigated in a new nonlinear conditional variance framework with multiple regimes and volume eff ects. Volatility forecast comparisons, using the Harvey-Newbold test for multiple forecasts encompassing, seem to demonstrate that the MSV- EGARCH complex threshold structure is able to correctly fit GARCH- type dynamics of the series under study and dominates competing standard asymmetric models in several of the considered stock indexes.info:eu-repo/semantics/publishedVersio

Epidemiological Interactions between Urogenital and Intestinal Human Schistosomiasis in the Context of Praziquantel Treatment across Three West African Countries

© 2015 Knowles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

Cytogenetic analysis of five Hypostomus species (Siluriformes, Loricariidae)

In this work, we analyzed the karyotypes of five Hypostomus species. Hypostomus cf. heraldoi, from the Mogi-Guaçu River, had 2n = 72 chromosomes, with a nucleolar organizer region (NOR) in one chromosomal pair. Hypostomus regani, from the Mogi-Guaçu River had 2n = 72 chromosomes with NORs in two chromosomal pairs. Hypostomus sp., from the Mogi-Guaçu River basin, had 2n = 68 chromosomes, with NORs in two chromosomal pairs. Hypostomus aff. agna, from Cavalo Stream, had 2n = 74 chromosomes with NORs in two chromosomal pairs. Hypostomus cf. topavae, from Carrapato Stream, had 2n = 80 chromosomes, with NORs in two chromosomal pairs. Hypostomus species showed marked diversity in the karyotypic formula, which suggested the occurrence of several Robertsonian rearrangements and pericentric inversions during the evolutionary history of this genus. This hypothesis was supported by the occurrence of a large number of uniarmed chromosomes and multiple NORs in a terminal position in most species and may be a derived condition in the Loricariidae

Molecular Evolution and Functional Divergence of the Cytochrome P450 3 (CYP3) Family in Actinopterygii (Ray-Finned Fish)

The cytochrome P450 (CYP) superfamily is a multifunctional hemethiolate enzyme that is widely distributed from Bacteria to Eukarya. The CYP3 family contains mainly the four subfamilies CYP3A, CYP3B, CYP3C and CYP3D in vertebrates; however, only the Actinopterygii (ray-finned fish) have all four subfamilies and detailed understanding of the evolutionary relationship of Actinopterygii CYP3 family members would be valuable.Phylogenetic relationships were constructed to trace the evolutionary history of the Actinopterygii CYP3 family genes. Selection analysis, relative rate tests and functional divergence analysis were combined to interpret the relationship of the site-specific evolution and functional divergence in the Actinopterygii CYP3 family. The results showed that the four CYP3 subfamilies in Actinopterygii might be formed by gene duplication. The first gene duplication event was responsible for divergence of the CYP3B/C clusters from ancient CYP3 before the origin of the Actinopterygii, which corresponded to the fish-specific whole genome duplication (WGD). Tandem repeat duplication in each of the homologue clusters produced stable CYP3B, CYP3C, CYP3A and CYP3D subfamilies. Acceleration of asymmetric evolutionary rates and purifying selection together were the main force for the production of new subfamilies and functional divergence in the new subset after gene duplication, whereas positive selection was detected only in the retained CYP3A subfamily. Furthermore, nearly half of the functional divergence sites appear to be related to substrate recognition, which suggests that site-specific evolution is closely related with functional divergence in the Actinopterygii CYP3 family.The split of fish-specific CYP3 subfamilies was related to the fish-specific WGD, and site-specific acceleration of asymmetric evolutionary rates and purifying selection was the main force for the origin of the new subfamilies and functional divergence in the new subset after gene duplication. Site-specific evolution in substrate recognition was related to functional divergence in the Actinopterygii CYP3 family