Absolute free energies of hydration (ΔG hyd) for more than 500 neutral and charged compounds have been computed, using Poisson−Boltzmann (PB) and Generalized Born (GB) continuum methods plus a ...solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved procedures and protocols for protein−ligand binding calculations and virtual screening (docking). The best overall PBSA and GBSA results, in comparison with experimental ΔG hyd values for small molecules, were obtained using MSK, RESP, or ChelpG charges obtained from ab initio calculations using 6-31G* wave functions. Correlations using semiempirical (AM1BCC, AM1CM2, and PM3CM2) or empirical (Gasteiger-Marsili and MMFF94) methods yielded mixed results, particularly for charged compounds. For neutral compounds, the AM1BCC method yielded the best agreement with experimental results. In all cases, the PBSA and GBSA results are highly correlated (overall r 2 = 0.94), which highlights the fact that various partial charge models influence the final results much more than which continuum method is used to compute hydration free energies. Overall improved agreement with experimental results was demonstrated using atom-based constants in place of a single surface area term. Sets of optimized SA constants, suitable for use with a given charge model, were derived by fitting to the difference in experimental free energies and polar continuum results. The use of optimized atom-based SA constants for the computation of ΔG hyd can fine-tune already reasonable agreement with experimental results, ameliorate gross deficiencies in any particular charge model, account for nonoptimal radii, or correct for systematic errors.
Despite the non-contact underwater explosion phenomena (UNDEX) have been studied for decades and several numerical methods have been proposed in literature, its effects on military structures, ...especially composite ones, are even nowadays matter of research. In early design phases, it is not always possible to verify the shock resistance of hull structures modelling the whole phenomenon, in which fluid, gas and solid properties must be properly set in a fully coupled fluid-structure interaction (FSI) numerical model. These ones are extremely complex to set, computationally demanding and certainly not suitable for everyday design practice. In this paper, a simplified finite element (FE) model, easy to use in an early design phase, is proposed. Both, the structure and the fluid are simulated. In this approximation, the fluid behaviour is simplified, using special finite elements, available in a commercial software environment. This choice reduces the computational time and numerical efforts avoiding the problem of combining computational fluid dynamics (CFD) and FE domains and equations in a fully coupled fluid-structure interaction model. A typical parallel body block of a minesweeper is modelled, using two-dimensional multi-layered shell elements to properly account for the composite materials behaviour. For the fluid instead, three dimensional volumetric elements, directly coupled to the structural elements, are placed. In addition, the same calculation is performed, modelling separately fluid in the CFD environment and structures in the finite element one. Thus, realizing a fully coupled fluid-structure interaction model. The results obtained by applying both numerical models are compared with the structural response measured on board of a composite ship during a full-scale shock test. The simplified proposed procedure provides results in satisfactory agreement with experiments, allowing the validation of the model. Approximations are discussed and differences with the real phenomenon and fully coupled CFD+FE method are shown, providing a better understanding of the phenomena. Eventually, the modelling strategy has been considered a valuable and cost-effective tool for the concept and preliminary design of composite structures subject to underwater explosions.
The arrival of infected travelers from endemic regions can trigger sustained autochthonous transmission of mosquito-borne pathogens in Europe. In 2007 a Chikungunya outbreak was observed in central ...Italy, mostly affecting two villages characterised by a high density of Aedes albopictus. The outbreak was mitigated through intervention strategies reducing the mosquito abundance. Ten years later, in 2017, sustained Chikungunya transmission was documented in both central and southern Italy. The proposed analysis identifies suitable reactive measures for the containment and mitigation of future epidemics by combining epidemiological modeling with a health economic approach, considering different arrival times of imported infections and possible delays in the notification of cases. Obtained estimates suggest that, if the first notification will occur in the middle of the mosquito breeding season, the combination of larvicides, adulticides and breeding sites removal represents the optimal strategy. In particular, we found that interventions implemented in 2007 were cost-effective, with about 3200 prevented cases, 1450 DALYs averted and €13.5 M saved. Moreover, larvicides are proven to be more cost beneficial in early summer and warmer seasons, while adulticides should be preferred in autumn and colder seasons. Our results provide useful indications supporting urgent decision-making of public health authorities in response to emerging mosquito-borne epidemics.
Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous ...genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in
-deficient PC.
This study was designed to evaluate the role of epidural methadone-lidocaine in cancer pain combined or not to epidural dexamethasone.
In all, 72 cancer patients, 32- to 67-year-old were randomized ...to six groups (n=12) and prospectively studied to examine analgesia and adverse effects for 3 weeks. Patients received single-dose protocol epidural test drugs: Control group (CG) received epidural 40-mg lidocaine diluted to 10-ml volume with saline. Dexamethasone group (DG) 40-mg lidocaine plus 10-mg dexamethasone. The 2.5MetG 2.5-mg epidural methadone with 40-mg lidocaine; the 5MetG, 5-mg epidural methadone plus 40-mg lidocaine, the 7.5MetG, 7.5-mg epidural methadone plus 40-mg lidocaine and finally the 7.5Met-DexG, 7.5-mg methadone with 40-mg lidocaine and 10-mg dexamethasone.
Groups CG, DG and 2.5MetG were similar regarding analgesia and side effects. Patients from 5MetG and 7.5MetG took 3 ± 1 and 5 ± 1 days, respectively, to restart oral morphine. Patients from 7.5MetDG took 14 ± 2 to restart oral morphine (P<0.001). Daily somnolence and appetite improved in the 7.5MetDG during 2-week evaluation (P<0.005). Fatigue improved for both DG and 7.5MetDG during 2-week evaluation (P<0.005). By the third week of evaluation, all patients were similar.
Epidural methadone plus lidocaine resulted in dose-dependent analgesia, further improved by epidural dexamethasone, which also improved fatigue.
Influenza A(H3N2), A(H1N1)pdm09 and B viruses co-circulated in Europe in 2014/15. We undertook a multicentre case-control study in eight European countries to measure 2014/15 influenza vaccine ...effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. General practitioners swabbed all or a systematic sample of ILI patients. We compared the odds of vaccination of ILI influenza positive patients to negative patients. We calculated adjusted VE by influenza type/subtype, and age group. Among 6,579 ILI patients included, 1,828 were A(H3N2), 539 A(H1N1)pdm09 and 1,038 B. VE against A(H3N2) was 14.4% (95% confidence interval (CI): -6.3 to 31.0) overall, 20.7% (95%CI: -22.3 to 48.5), 10.9% (95%CI -30.8 to 39.3) and 15.8% (95% CI: -20.2 to 41.0) among those aged 0-14, 15-59 and ≥60 years, respectively. VE against A(H1N1)pdm09 was 54.2% (95%CI: 31.2 to 69.6) overall, 73.1% (95%CI: 39.6 to 88.1), 59.7% (95%CI: 10.9 to 81.8), and 22.4% (95%CI: -44.4 to 58.4) among those aged 0-14, 15-59 and ≥60 years respectively. VE against B was 48.0% (95%CI: 28.9 to 61.9) overall, 62.1% (95%CI: 14.9 to 83.1), 41.4% (95%CI: 6.2 to 63.4) and 50.4% (95%CI: 14.6 to 71.2) among those aged 0-14, 15-59 and ≥60 years respectively. VE against A(H1N1)pdm09 and B was moderate. The low VE against A(H3N2) is consistent with the reported mismatch between circulating and vaccine strains.
Abstract
The increasing use of medical marijuana highlights the importance of developing a better understanding of cannabinoid metabolism. Phytocannabinoids, including ∆
9
-tetrahydrocannabinol ...(THC), are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. The lipophilic nature of cannabinoids necessitates mechanism(s) to facilitate their intracellular transport to metabolic enzymes. Here, we test the central hypothesis that liver-type fatty acid binding protein (FABP1) mediates phytocannabinoid transport and subsequent inactivation. Using X-ray crystallography, molecular modeling, and
in vitro
binding approaches we demonstrate that FABP1 accommodates one molecule of THC within its ligand binding pocket. Consistent with its role as a THC carrier, biotransformation of THC was reduced in primary hepatocytes obtained from FABP1-knockout (FABP1-KO) mice. Compared to their wild-type littermates, administration of THC to male and female FABP1-KO mice potentiated the physiological and behavioral effects of THC. The stark pharmacodynamic differences were confirmed upon pharmacokinetic analyses which revealed that FABP1-KO mice exhibit reduced rates of THC biotransformation. Collectively, these data position FABP1 as a hepatic THC transport protein and a critical mediator of cannabinoid inactivation. Since commonly used medications bind to FABP1 with comparable affinities to THC, our results further suggest that FABP1 could serve a previously unrecognized site of drug-drug interactions.
•Titanate nanotubes (TTNT) were modified with 3-aminopropyltriethoxysilane (APTES).•Effects of TTNT sodium content and solvent on APTES grafting efficiency were studied.•Aqueous ethanol was a more ...efficient reaction medium for functionalization of TTNT.•Within aqueous ethanol TTNT with low sodium content were more efficiently grafted.•Grafting of APTES on TTNT surface occurs through Ti–O–Si primary chemical bonding.
One of the major challenges in the development of nanocomposites based on a polymer matrix and highly polar ceramic nanofillers is the lack of the compatibility between these two components. In order to improve the chemical interaction between titanate nanotubes (TTNT) and polymer matrix, such as nylon 11,3-aminopropyltriethoxysilane (APTES) was grafted onto TTNT. The effects of the TTNT chemical composition i.e. sodium content and solvent type on the grafting silane efficiency were thoroughly studied through CHN elemental analysis, Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), surface area and zeta potential measurements. The present study brings evidences supporting aqueous ethanol as more efficient reaction medium for TTNT functionalization with APTES, independent of the sodium content of nanotubes, when compared with pure water. It is also worth noting that within aqueous ethanol medium, TTNT with low sodium content are more efficiently grafted than TTNT with high sodium content. Successful APTES grafting decreases concentration of the hydroxyl groups on TTNT surfaces and enables its future application for the fabrication of nylon 11 nanocomposites.
Exertional compartment syndrome of the forearm is a rare pathology, occurring almost exclusively in motorcycle racers. The results of endoscopic techniques are similar to those of open fasciotomies, ...but they are less invasive and leave smaller scars. The aim of our study was to present a new endoscopic technique for superficial fasciotomy using the Agee® system and to describe the results. This was a single-center, retrospective descriptive study of 21 patients (36 forearms) operated on between 2006 and 2016. All patients but one were competitive motorcycle racers. The mean operating time was 38.2min (standard deviation (SD), 10.5min). The QuickDASH score was 23.3±10.2% preoperatively versus 1±2% postoperatively (mean±SD). Among the 18 patients who came back for a follow-up visit after 4.9±2.7 years, 17 (94%) were satisfied or very satisfied. The mean time before returning to sport was 4.3 weeks (SD, 1.8 weeks), 9 patients (50%) at the same level as before surgery, 8 (44%) at a higher level, and one at a lower level. There were a few minor complications (superficial vascular lesions, hematoma, transitory hypoesthesia) and symptoms recurred in two patients. Our technique yields outcomes similar to those of other published endoscopic procedures and allows early return to sport. It has the advantage of being based on the Agee endoscope, which is commonly used to treat carpal tunnel syndrome, making the procedure easy to master.
Le syndrome des loges d’effort de l’avant-bras est une pathologie rare et presque exclusive aux sportifs motocyclistes. Les résultats des techniques endoscopiques sont comparables à ceux des fasciotomies à ciel ouvert, tout en étant moins invasives et réalisant des cicatrices moins importantes. L’objectif de notre étude était de présenter une nouvelle technique endoscopique de fasciotomie superficielle utilisant l’endoscope d’Agee®, et d’en présenter les résultats. Nous avons réalisé une étude de cohorte rétrospective monocentrique. Trente-six avant-bras chez 21 patients ont été opérés entre 2006 et 2016. Tous sauf un pratiquaient les sports mécaniques en compétition. Le recul moyen était de 4,9±2,7 ans chez les 18 patients revus. Le temps opératoire moyen était de 38,2±10,5minutes. Le score QuickDASH était de 23,3±10,2 % en préopératoire contre 1±2 % en post-opératoire, 94 % des patients étaient satisfaits ou très satisfaits. Le sport était repris en 4,3±1,8 semaines: 50 % (n=9) au même niveau, 44 % (n=8) à un niveau supérieur et un à un niveau inférieur. Quelques complications mineures ont été notées (lésions veineuses superficielles, hématomes et hypoesthésies transitoires), et 2 récidives des symptômes. Notre technique donne des résultats comparables à ceux des autres techniques endoscopiques publiées, et une reprise sportive rapide. Elle a l’avantage d’utiliser l’endoscope Agee®, outil courant du traitement endoscopique des syndromes du canal carpien. La courbe d’apprentissage est rapide, car utilisant ce matériel déjà maîtrisé.
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