Stochastic optimization methods for ship resistance and operational efficiency via CFD

Hull-form stochastic optimization methods are presented and evaluated for resistance reduction and operational efficiency (operability), addressing stochastic sea state and operations. The cost/benefit analysis of the optimization procedure is presented by comparison of four hierarchical problems, from stochastic most general to deterministic least general. The parent hull is a high-speed catamaran, with geometrical constraints for maximum variation of length, beam, draft, and displacement. Problem 1 is used as a benchmark for the evaluation of the other problem formulations and is defined as a multi-objective stochastic optimization for resistance and operability, considering stochastic sea state and speed, but limited to head waves. Problem 2 is a multi-objective stochastic optimization for resistance and motions at fixed sea state and speed. Problem 3 is a multi-objective deterministic optimization for resistance and motions using a single regular wave at fixed speed. Problem 4 is a single-objective deterministic optimization for calm-water resistance at fixed speed. The design optimization is based on hull-form modifications by the Karhunen-Loève expansion of a free-form deformation, URANS-based CFD simulations, regular wave approximations for irregular waves, metamodels and multi-objective particle swarm. The design optimization achieves an 8.7, 23, 53, and 10% average improvements for problems 1, 2, 3, and 4, respectively. Comparing to problem 1, problem 2, 3, 4 optimized designs have average performances 1, 2.1 and 1.7% worse, respectively. The most efficient problem, from the computational cost/benefit viewpoint, is problem 3. Nevertheless, problem 1 is needed to evaluate and compare the stochastic performance of the designs and finally assess the optimization cost/benefit.     

Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Under the unmet need of efficient tumor‐targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22‐mRTA‐H6) is engineered to self‐assemble as protein‐only, CXCR4‐targeted nanoparticles. The soluble version of the construct self‐organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4⁺ cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor‐dependent mechanism of cytotoxicity. The insoluble version of T22‐mRTA‐H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22‐mRTA‐H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22‐mRTA‐H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self‐mediated intracellular drug delivery.     

Clinical pharmacokinetic assessment of an anti-MAdCAM monoclonal antibody therapeutic by LC-MS/MS

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been shown to be a viable tool for preclinical pharmacokinetic (PK) analysis of monoclonal antibody (mAb) therapeutics. This work describes free and total PK assays for the mAb PF-00547,659 in serum of ulcerative colitis patients in a First-In-Human study [Vermeire, S. et al. Gut2011, 60 (8), 1068-1075]. The assay to measure free PF-00547,659 used immuno-enrichment with a biotinylated anti-idiotypic antibody and streptavidin magnetic beads. The total assay used enrichment by protein G magnetic beads. Following elution of PF-00547,659 from the beads, addition of an extended sequence stable isotope labeled peptide and trypsin digestion, a proteotypic peptide derived from the CDR region of the light chain of PF-00547,659 was quantified by LC-MS/MS. The free assay had a calibration range from 7.03 ng/mL to 450 ng/mL. The assay was precise and accurate with interbatch imprecision <16.5%, and interbatch inaccuracy <13.7% at all concentrations investigated during assay qualification. Results from LC-MS/MS methodologies are compared with historical immunoassay data originally acquired during the course of the clinical study. PK parameter estimates were highly correlated between the two analytical approaches. This work provides precedence that immunoaffinity LC-MS/MS can effectively be used to measure the serum concentrations of mAb therapeutics in clinical studies.     

Screening Anti-Inflammatory Effects of Flavanones Solutions

There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years. Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. In this paper, natural flavanone 1 (extracted from Eysenhardtia platycarpa) as lead compound and flavanones 1a–1d as its structural analogues were screened for anti-inflammatory activity using Molinspiration^® and PASS Online in a computational study. The hydro alcoholic solutions (FS) of flavanones 1, 1a–1d (FS1, FS1a–FS1d) were also assayed to investigate their in vivo anti-inflammatory cutaneous effect using two experimental models, a rat ear edema induced by arachidonic acid (AA) and a mouse ear edema induced by 12-O-tetradecanoylphorbol acetate (TPA). Histological studies and analysis of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were also assessed in AA-inflamed rat ear tissue. The results showed that the flavanone hydro alcoholic solutions (FS) caused edema inhibition in both evaluated models. This study suggests that the evaluated flavanones will be effective when used in the future in skin pathologies with inflammation, with the results showing 1b and 1d to be the best.     

Influence of Layer-Thickness Ratio on Magnetic Properties in F-La2/3Ca1/3MnO3/AF-La1/3Ca2/3MnO3 Bilayers

Magnetic properties were investigated in ferromagnetic/antiferromagnetic bilayers based on a Ca-doped lanthanum manganite system via hysteretic loops, La_1?x Ca _x MnO₃ grown in?situ on (001) oriented SrTiO₃ crystalline substrates by using a dc sputtering technique at high-pressure (3.5?mbar) pure oxygen as sputter gas and at a substrate temperature of 850?^°C. We grew the antiferromagnetic layer La_1/3Ca_2/3MnO₃ (AF-LCMO) with a given thickness, t _AF, and the ferromagnetic layer La_2/3Ca_1/3MnO₃ (F-LCMO) with a given thickness, t _F. We produced two series of samples: the first one with thickness ratio, t _F/t _AF, of 1/6 and 6/1, maintaining constant the total thickness of the bilayer to 70?nm, and the second one with t _F/t _AF of 3/25, 9/25, 15/25, maintaining constant the antiferromagnetic thickness to 25?nm. Magnetization versus applied field loop was strongly dependent on the t _F/t _AF ratio, which was influenced by both the strains presented in very thin films originated during the growth of the bilayer and the magnetic moment interaction at the ferromagnetic/antiferromagnetic interface due to changes of the electronic structure in this strongly correlated system.     

A macroscopic model for high intensity radiofrequency signal detection in swarm robotics systems

In recent years, there has been a growing interest in resource location in unknown environments for robotic systems, which are composed of multiple simple robots rather than one highly capable robot [M. Sempere, F. Aznar, M. Pujol, and R. Rizo, On cooperative swarm foraging for simple, non explicitly connected, agents, 2010]. This tradeoff reduces the design and hardware complexity of the robots and removes single point failures, but adds complexity in algorithm design. The challenge is to programme a swarm of simple robots, with minimal intercommunication and individual capability, to perform a useful task as a group. This paper is focused on finding the highest intensity area of a radiofrequency (RF) signal in urban environments. These signals are usually more intense near the city centre and its proximity, since in these zones the risk of signal saturation is high. RF radiation (RFR) is boosted or blocked mainly depending on orography or building structures. RF providers need to supply enough coverage, setting up different antennas to be able to provide a minimum quality of service. We will define a micro/macroscopic mathematical model to efficiently study a swarm robotic system, predict their long-term behaviour and gain insight into the system design. The macroscopic model will be obtained from Rate Equations, describing the dynamics of the swarm collective behaviour. In our experimental section, the Campus of the University of Alicante will be used to simulate our model. Three RFR antennas will be taken into account, one inside our Campus and the other two in its perimeter. Several tests, that show the convergence of the swarm towards the RFR, will be presented. In addition, the obtained RFR maps and the macroscopic behaviour of the swarm will be discussed.     

The Efficacy and Biopharmaceutical Properties of a Fixed-Dose Combination of Disulfiram and Benzyl Benzoate

Scabies and hair lice are parasitic diseases that affect human skin and hair, respectively. The incidence and resistances of these infections are increasing. Tenutex^® (disulfiram and benzyl benzoate emulsion) is an alternative to standard insecticides to avoid resistances. The aim of the work is to evaluate the transdermal absorption and the in vitro efficacy against scabies and hair lice after different exposition times. Dermatomed human skin was used to assess the dermal absorption using a validated High Performance Liquid Chromatography (HPLC) method. HEK001 keratinocytes were used to evaluate the cytotoxicity of benzyl benzoate. Only benzyl benzoate was able to cross the skin, but it did not show cytotoxicity at any of the tested concentrations. The product efficacy was tested on Psoroptes ovis after direct contact and after administration on sheep skin explants at different contact times. Permethrin/malathion-resistant strains of Pediculus humanis capitis adults and eggs were directly exposed to Tenutex, and the vitality and hatchability, respectively, were evaluated. The anti-scabies study demonstrated that exposure for 6 or 24 h completely eradicated the parasite. The pediculicidal activity of Tenutex exhibited superior efficacy than standard treatment on resistant lice. The positive results obtained suggest that Tenutex^® is a good treatment option, especially in drug resistance situations.     

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT_2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT_2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT_2A receptor-dependent head twitch behaviors or consistent changes in 5-HT_2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT_2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT_2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.     

EST79232 and EST79376, Two Novel Sigma-1 Receptor Ligands,Exert Neuroprotection on Models of Motoneuron Degeneration

Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded {"type":"entrez-protein","attrs":{"text":"EST79232","term_id":"558729011"}}EST79232 and {"type":"entrez-protein","attrs":{"text":"EST79376","term_id":"558729197"}}EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)^G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist {"type":"entrez-protein","attrs":{"text":"EST79376","term_id":"558729197"}}EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1^G93A mice. In contrast, the agonist {"type":"entrez-protein","attrs":{"text":"EST79232","term_id":"558729011"}}EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1^G93A mice. In vivo, Sig-1R ligand {"type":"entrez-protein","attrs":{"text":"EST79232","term_id":"558729011"}}EST79232 had a more potent effect on preventing MN degeneration than {"type":"entrez-protein","attrs":{"text":"EST79376","term_id":"558729197"}}EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration.