Acceptability with general orderings

We present a new approach to termination analysis of logic programs. The essence of the approach is that we make use of general orderings (instead of level mappings), like it is done in transformational approaches to logic program termination analysis, but we apply these orderings directly to the logic program and not to the term-rewrite system obtained through some transformation. We define some variants of acceptability, based on general orderings, and show how they are equivalent to LD-termination. We develop a demand driven, constraint-based approach to verify these acceptability-variants. The advantage of the approach over standard acceptability is that in some cases, where complex level mappings are needed, fairly simple orderings may be easily generated. The advantage over transformational approaches is that it avoids the transformation step all together. {\bf Keywords:} termination analysis, acceptability, orderings.Comment: To appear in "Computational Logic: From Logic Programming into the Future

Repetitive Immunization Enhances the Susceptibility of Mice to Peripherally Administered Prions

The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease

The Comprehensive Native Interactome of a Fully Functional Tagged Prion Protein

The enumeration of the interaction partners of the cellular prion protein, PrPC, may help clarifying its elusive molecular function. Here we added a carboxy proximal myc epitope tag to PrPC. When expressed in transgenic mice, PrPmyc carried a GPI anchor, was targeted to lipid rafts, and was glycosylated similarly to PrPC. PrPmyc antagonized the toxicity of truncated PrP, restored prion infectibility of PrPC-deficient mice, and was physically incorporated into PrPSc aggregates, indicating that it possessed all functional characteristics of genuine PrPC. We then immunopurified myc epitope-containing protein complexes from PrPmyc transgenic mouse brains. Gentle differential elution with epitope-mimetic decapeptides, or a scrambled version thereof, yielded 96 specifically released proteins. Quantitative mass spectrometry with isotope-coded tags identified seven proteins which co-eluted equimolarly with PrPC and may represent component of a multiprotein complex. Selected PrPC interactors were validated using independent methods. Several of these proteins appear to exert functions in axomyelinic maintenance

Cannabidiol and oxygen-ozone combination induce cytotoxicity in human pancreatic ductal adenocarcinoma cell lines

Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations in BRCA1/2, ATM, MLH1, TP53, or CDKN2A. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors. Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. O2/O3 therapy has been found to ameliorate mechanisms promoting chronic pain and inflammation, including hypoxia, inflammatory mediators, and infection. The advantages of using cannabinoids have been evaluated in vitro and in vivo models of several human cancers. Regarding PDAC, activation of cannabinoid receptors was found to induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells. In a murine model of PDAC, a combination of cannabidiol (CBD) and gemcitabine increased survival length by nearly three times. Herein, we evaluate the anticancer effect of CBD and O2/O3, alone or in combination, on two human PDAC cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel. Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced

NORIT project: The incidence of Norway lobster (Nephrops norvegicus L.) emergence activity rhythms on its population assessment

Sardà, Francisco ... et. al.-- Marine Technology Workshop (Martech05), 17-18 November 2005, Vilanova i la Geltrú, Barcelona.-- 1 pageThe Norway lobster, Nephrops norvegicus (L.) is a decapod crustacean inhabiting complex burrow systems in muddy continental shelves and slopes on the European waters of the Atlantic Ocean and Mediterranean Sea. This species is object of an important multispecific fishery in the Mediterranean, showing signs of overexploitation. Animals of this species show marked behavioural rhythms of emergence in the field. Emergence is performed under an optimum light intensity whose timing varies at different depths depending upon light penetration into the water column and hence upon the sun position. Present data indicate that not all the individuals emerge from their burrows at a circadian basis. [...]Peer Reviewe

Changes in high-intensity precipitation on the northern Apennines (Italy) as revealed by multidisciplinary data over the last 9000 years

Several record-breaking precipitation events have struck the mountainous area of the Emilia-Romagna region (northern Apennines, Italy) over the last 10 years. As a consequence, severe geomorphological processes such as debris avalanches and debris flows, shallow landslides, and overbank flooding have affected the territory, causing severe damage to human-made structures. The unusual intensity of these phenomena prompted an investigation into their frequency in the past, beyond instrumental time. In the quest for an understanding of whether these phenomena are unprecedented in the region, peat bog and lake deposits were analyzed to infer the frequency of extreme precipitation events that may have occurred in the past. We present the results of a dedicated field campaign performed in summer 2017 at Lake Moo in the northern Apennines, a 0.15 km2peat bog located at an altitude of 1130ma.s.l. During the extreme precipitation event of 13-14 September 2015, several debris flows generated by small streams affected the Lake Moo plain. In such a small drainage basin (<2 km2), high-density floods can be triggered only by high-intensity precipitation events. The sedimentary succession (ca. 13m thick) was studied through the drilling of two cores and one trench. The sequence, characterized by clusters of coarse-grained alluvial deposits interbedded with organic-rich silty clays and peat layers, was analyzed by combining sedimentological, pollen, microanthracological and pedological data with radiocarbon dating (AMS 14C) in an innovative multidisciplinary approach for this area. Original data acquired during the field campaign were also correlated with other specific paleoclimatic proxies available in the literature for the northern Apennines area. We discover that the increase in extreme paleoflooding, associated with coarse-grained deposits similar to the ones observed recently, correlates well with the warm phases of the Holocene Thermal Maximum and with the ongoing warming trend observed that started at the beginning of the last century

Integrity of H1 helix in prion protein revealed by molecular dynamic simulations to be especially vulnerable to changes in the relative orientation of H1 and its S1 flank

In the template-assistance model, normal prion protein (PrPC), the pathogenic cause of prion diseases such as Creutzfeldt-Jakob (CJD) in human, Bovine Spongiform Encephalopathy (BSE) in cow, and scrapie in sheep, converts to infectious prion (PrPSc) through an autocatalytic process triggered by a transient interaction between PrPC and PrPSc. Conventional studies suggest the S1-H1-S2 region in PrPC to be the template of S1-S2 $\beta$-sheet in PrPSc, and the conformational conversion of PrPC into PrPSc may involve an unfolding of H1 in PrPC and its refolding into the $\beta$-sheet in PrPSc. Here we conduct a series of simulation experiments to test the idea of transient interaction of the template-assistance model. We find that the integrity of H1 in PrPC is vulnerable to a transient interaction that alters the native dihedral angles at residue Asn$^{143}$, which connects the S1 flank to H1, but not to interactions that alter the internal structure of the S1 flank, nor to those that alter the relative orientation between H1 and the S2 flank.Comment: A major revision on statistical analysis method has been made. The paper now has 23 pages, 11 figures. This work was presented at 2006 APS March meeting session K29.0004 at Baltimore, MD, USA 3/13-17, 2006. This paper has been accepted for pubcliation in European Biophysical Journal on Feb 2, 200

Novel regulators of PrPC biosynthesis revealed by genome-wide RNA interference

The cellular prion protein PrPC is necessary for prion replication, and its reduction greatly increases life expectancy in animal models of prion infection. Hence the factors controlling the levels of PrPC may represent therapeutic targets against human prion diseases. Here we performed an arrayed whole-transcriptome RNA interference screen to identify modulators of PrPC expression. We cultured human U251-MG glioblastoma cells in the presence of 64'752 unique siRNAs targeting 21'584 annotated human genes, and measured PrPC using a one-pot fluorescence-resonance energy transfer immunoassay in 51'128 individual microplate wells. This screen yielded 743 candidate regulators of PrPC. When downregulated, 563 of these candidates reduced and 180 enhanced PrPC expression. Recursive candidate attrition through multiple secondary screens yielded 54 novel regulators of PrPC, 9 of which were confirmed by CRISPR interference as robust regulators of PrPC biosynthesis and degradation. The phenotypes of 6 of the 9 candidates were inverted in response to transcriptional activation using CRISPRa. The RNA-binding post-transcriptional repressor Pumilio-1 was identified as a potent limiter of PrPC expression through the degradation of PRNP mRNA. Because of its hypothesis-free design, this comprehensive genetic-perturbation screen delivers an unbiased landscape of the genes regulating PrPC levels in cells, most of which were unanticipated, and some of which may be amenable to pharmacological targeting in the context of antiprion therapies