In vitro host response assessment of biomaterials for cardiovascular stent manufacture

The deployment of a vascular stent during angioplasty has greatly reduced the risks of restenosis. However, the presence of the device still induces a host response as well as a mechanical action on the blood vessel wall and an alteration of the haemodynamics. Platelet and inflammatory cells can adhere on the stent surface and be activated to produce biochemical signals able to stimulate an excessive proliferation of the smooth muscle cells with the consequent obstruction of the vessel lumen. For these reasons, the host response to two of the materials used in stent manufacture, stainless steel and diamond-like carbon, was investigated in vitro. The data showed that stainless steel induced a higher level of host response both in terms of platelet aggregation and macrophage activation. However, the spreading of inflammatory cells was more accentuated on diamond-like carbon. The inflammatory cells produced levels of platelet-derived growth factor, a key signal in smooth muscle cell proliferation, similar to stainless steel thus suggesting that carbon coatings may not be able to prevent restenosis.     

Modeling of multilayer microholographic data storage

We focus on the investigation of multilayer recording in microholographic data storage. We have developed a numerical model for calculating the electromagnetic scattering from thick microholographic gratings using the Born approximation and the direct volume integral. The signal-to-noise ratio and bit error rate were calculated to estimate the noise arising from interlayer and interhologram cross talk. Measurements were done to prove the validity of the model. The results of our calculations and the measurements show good agreement. We present the application of the model to the investigation of confocal filtering at the image plane and to the evaluation of positioning and wavelength tolerances.     

Microstructure and fatigue properties of friction stir welded high-strength steel plates

The weldability of high-strength steels (HSSs) is limited by their loss of strength, toughness and fatigue properties. In demanding applications, the fatigue properties of welds are among the strictest requirements. This paper presents a weldability analysis focusing on the microstructure and fatigue properties of 6?mm thick S690 and S355 HSS plates joined by friction stir welding. Their fatigue properties are compared to design recommendations and to fatigue properties obtained with other welding techniques. Results show that the high-quality friction stir welded steel joints outperform high-quality arc welds and FAT80 design recommendations. The fatigue strength of the friction stir welded joints is increased with material yield strength. The mechanisms governing crack initiation at different maximum stress levels are discussed.     

Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy

Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P₁ agonist, N‐methyl‐N‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P_1,5 agonist, N‐methyl‐N‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P_1,5 agonist 49 demonstrated comparable efficacy while S1P₁‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.     

Hydroperoxide formation during autoxidation of conjugated linoleic acid methyl ester

The aim of this study was to investigate whether hydroperoxides are formed in the autoxidation of conjugated linoleic acid (CLA) methyl ester both in the presence and absence of α‐tocopherol. The existence of hydroperoxide protons was confirmed by D₂O exchange and by chemoselective reduction of the hydroperoxide groups into hydroxyl groups using NaBH₄. These experiments were followed by nuclear magnetic resonance (NMR) spectroscopy. The ¹³C and ¹HNMR spectra of a mixture of 9‐hydroper‐oxy‐10‐trans,12‐cis‐octadecadienoic acid methyl ester (9‐OOH) and 13‐hydroperoxy‐9‐cis, 11‐trans‐octadecadienoic acid methyl ester (13‐OOH), which are formed during the autoxidation of methyl linoleate, were studied in detail to allow the comparison between the two linoleate hydroperoxides and the CLA methyl ester hydroperoxides. The ¹³CNMR spectra of samples enriched with one of the two linoleate hydroperoxide isomers were assigned using 2D NMR techniques, namely Correlated Spectroscopy (COSY), gradient Heteronuclear Multiple Bond Correlation (gHMBC), and gradient Heteronuclear Single Quantum Correlation (gHSQC). The ¹³C and ¹H NMR experiments performed in this study show that hydroperoxides are formed during the autoxidation of CLA methyl ester both in the presence and absence of α‐tocopherol and that the major isomers of CLA methyl ester hydroperoxides have a conjugated monohydroperoxydiene structure similar to that in linoleate hydroperoxides.     

P3 L: A structured high-level parallel language,and its structured support

The paper presents a parallel programming methodology that ensures easy programming, efficiency and portability of programs to different machines belonging to the class of the general-purpose, distributed-memory, MIMD architectures. The methodology is based on the definition of a new, high-level, explicitly parallel language, called P³ L, and of a set of static tools that automatically adapt the program features for each target architecture. P³ L does not require programmers to specify process activations, the actual parallelism degree, scheduling, or interprocess communications, i.e. all those features that need to be adjusted to harness each specific target machine. Parallelism is, on the other hand, expressed in a structured and qualitative way, by hierarchical composition of a restricted set of language constructs, corresponding to those forms of parallelism that are frequently encountered in parallel applications, and that can be efficiently implemented. The efficient portability of P³ L applications is guaranteed by the compiler along with the novel structure of the support. The compiler automatically adapts the program features for each specific architecture, using the costs (in terms of performance) of the low-level mechanisms exported by the architecture itself. In our methodology, these costs, along with other features of the architecture, are viewed through an abstract machine, whose interface is used by the compiler to produce the final object code.     

Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model

Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials.     

Carotenoids as antioxidants to prevent photooxidation

Carotenoids act as antioxidants in photooxidation by quenching singlet oxygen or triplet sensitizer. The antioxidant activities of β‐carotene, lutein and lycopene during photooxidation were investigated by following the formation of methyl linoleate isomeric hydroperoxides. The hydroperoxide formation and the isomeric distribution were determined using high‐performance liquid chromatography and post‐column detection with diphenyl‐1‐pyrenyl phosphine (DPPP). DPPP reacts with both the conjugated and nonconjugated hydroperoxides formed in photooxidation to give fluorescing DPPP‐oxides. Photooxidation with or without added β‐carotene, lutein and lycopene (10, 20 and 40 ppm) were carried out at +3 °C under 2000 lx. All the studied carotenoids were potential antioxidants during photooxidation and their antioxidant activities were concentration‐dependent. There were no significant differences in the antioxidant activities of lycopene and β‐carotene at a concentration of 10 ppm. At a concentration of 20 ppm β‐carotene was a better antioxidant than lycopene or lutein, and at a concentration of 40 ppm lycopene exerted a better antioxidant activity than β‐carotene or lutein. There were no significant differences between lycopene and lutein at a concentration of 20 ppm. The results also showed that carotenoids had no effect on the distribution of isomeric hydroperoxides indicating that the antioxidant mechanism of carotenoids during photooxidation does not involve hydrogen donation. All carotenoids were consumed during photooxidation. At a higher concentration (40 ppm) lycopene was more stable than the other tested carotenoids. That contributed most likely to it having a better antioxidant activity than β‐carotene and lutein.     

Maternal and Neonatal Polyunsaturated Fatty Acid Intake and Risk of Neurodevelopmental Impairment in Premature Infants

The N3 and N6 long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper neurodevelopment in early life. These fatty acids are passed from mother to infant via the placenta, accreting into fetal tissues such as brain and adipose tissue. Placental transfer of LCPUFA is highest in the final trimester, but this transfer is abruptly severed with premature birth. As such, efforts have been made to supplement the post-natal feed of premature infants with LCPUFA to improve neurodevelopmental outcomes. This narrative review analyzes the current body of evidence pertinent to neurodevelopmental outcomes after LCPUFA supplementation in prematurely born infants, which was identified via the reference lists of systematic and narrative reviews and PubMed search engine results. This review finds that, while the evidence is weakened by heterogeneity, it may be seen that feed comprising 0.3% DHA and 0.6% AA is associated with more positive neurodevelopmental outcomes than LCPUFA-deplete feed. While no new RCTs have been performed since the most recent Cochrane meta-analysis in 2016, this narrative review provides a wider commentary; the wider effects of LCPUFA supplementation in prematurely born infants, the physiology of LCPUFA accretion into preterm tissues, and the physiological effects of LCPUFA that affect neurodevelopment. We also discuss the roles of maternal LCPUFA status as a modifiable factor affecting the risk of preterm birth and infant neurodevelopmental outcomes. To better understand the role of LCPUFAs in infant neurodevelopment, future study designs must consider absolute and relative availabilities of all LCPUFA species and incorporate the LCPUFA status of both mother and infant in pre- and postnatal periods.     

Isoprene Emission Influences the Proteomic Profile of Arabidopsis Plants under Well-Watered and Drought-Stress Conditions

Isoprene is a small lipophilic molecule synthesized in plastids and abundantly released into the atmosphere. Isoprene-emitting plants are better protected against abiotic stresses, but the mechanism of action of isoprene is still under debate. In this study, we compared the physiological responses and proteomic profiles of Arabidopsis which express the isoprene synthase (ISPS) gene and emit isoprene with those of non-emitting plants under both drought-stress (DS) and well-watered (WW) conditions. We aimed to investigate whether isoprene-emitting plants displayed a different proteomic profile that is consistent with the metabolic changes already reported. Only ISPS DS plants were able to maintain the same photosynthesis and fresh weight of WW plants. LC–MS/MS-based proteomic analysis revealed changes in protein abundance that were dependent on the capacity for emitting isoprene in addition to those caused by the DS. The majority of the proteins changed in response to the interaction between DS and isoprene emission. These include proteins that are associated with the activation of secondary metabolisms leading to ABA, trehalose, and proline accumulations. Overall, our proteomic data suggest that isoprene exerts its protective mechanism at different levels: under drought stress, isoprene affects the abundance of chloroplast proteins, confirming a strong direct or indirect antioxidant action and also modulates signaling and hormone pathways, especially those controlling ABA synthesis. Unexpectedly, isoprene also alters membrane trafficking.