Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.     

Ethylene and Nitric Oxide Involvement in the Regulation of Fe and P Deficiency Responses in Dicotyledonous Plants

Iron (Fe) and phosphorus (P) are two essential elements for plant growth. Both elements are abundant in soils but with poor availability for plants, which favor their acquisition by developing morphological and physiological responses in their roots. Although the regulation of the genes related to these responses is not totally known, ethylene (ET) and nitric oxide (NO) have been involved in the activation of both Fe-related and P-related genes. The common involvement of ET and NO suggests that they must act in conjunction with other specific signals, more closely related to each deficiency. Among the specific signals involved in the regulation of Fe- or P-related genes have been proposed Fe-peptides (or Fe ion itself) and microRNAs, like miR399 (P), moving through the phloem. These Fe- or P-related phloem signals could interact with ET/NO and confer specificity to the responses to each deficiency, avoiding the induction of the specific responses when ET/NO increase due to other nutrient deficiencies or stresses. Besides the specificity conferred by these signals, ET itself could confer specificity to the responses to Fe- or P-deficiency by acting through different signaling pathways in each case. Given the above considerations, there are preliminary results suggesting that ET could regulate different nutrient responses by acting both in conjunction with other signals and through different signaling pathways. Because of the close relationship among these two elements, a better knowledge of the physiological and molecular basis of their interaction is necessary to improve their nutrition and to avoid the problems associated with their misuse. As examples of this interaction, it is known that Fe chlorosis can be induced, under certain circumstances, by a P over- fertilization. On the other hand, Fe oxides can have a role in the immobilization of P in soils. Qualitative and quantitative assessment of the dynamic of known Fe- and P-related genes expression, selected ad hoc and involved in each of these deficiencies, would allow us to get a profound knowledge of the processes that regulate the responses to both deficiencies. The better knowledge of the regulation by ET of the responses to these deficiencies is necessary to properly understand the interactions between Fe and P. This will allow the obtention of more efficient varieties in the absorption of P and Fe, and the use of more rational management techniques for P and Fe fertilization. This will contribute to minimize the environmental impacts caused by the use of P and Fe fertilizers (Fe chelates) in agriculture and to adjust the costs for farmers, due to the high prices and/or scarcity of Fe and P fertilizers. This review aims to summarize the latest advances in the knowledge about Fe and P deficiency responses, analyzing the similarities and differences among them and considering the interactions among their main regulators, including some hormones (ethylene) and signaling substances (NO and GSNO) as well as other P- and Fe-related signals.     

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.     

Direct-Ink-Writing of Electroactive Polymers for Sensing and Energy Storage Applications

Considering the high levels of materials used in the fields of electronics and energy storage systems, it is increasingly necessary to take into consideration environmental impact. Thus, it is important to develop devices based on environmentally friendlier materials and/or processes, such as additive manufacturing techniques. In this work, poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) are prepared by direct-ink-writing (DIW) by varying solvent evaporation temperature and fill density percentage. Different morphologies for both polymers are obtained, including dense films and porous membranes, as well as different electroactive β-phase content, thermal and mechanical properties. The dielectric constant and piezoelectric d₃₃ coefficient for dense films reaches up to 16 at 1 kHz and 4 pC N⁻¹, respectively for PVDF-HFP with a fill density of 80 and a solvent evaporation temperature of 50 °C. Porous structures are developed for battery separator membranes in lithium-ion batteries, with a highest ionic conductivity value of 3.8 mS cm⁻¹ for the PVDF-HFP sample prepared with a fill density of 100 and a solvent evaporation temperature of 25 °C, the sample showing an excellent cycling performance. It is demonstrated that electroactive films and membranes can be prepared by direct-ink writing suitable for sensors/actuators and energy storage systems.     

A Methionine Chemical Shift Based Order Parameter Characterizing Global Protein Dynamics

Coupling of side chain dynamics over long distances is an important component of allostery. Methionine side chains show the largest intrinsic flexibility among methyl-containing residues but the actual degree of conformational averaging depends on the proximity and mobility of neighboring residues. The ¹³C NMR chemical shifts of the methyl groups of methionine residues located at long distances in the same protein show a similar scaling with respect to the values predicted from the static X-ray structure by quantum methods. This results in a good linear correlation between calculated and observed chemical shifts. The slope is protein dependent and ranges from zero for the highly flexible calmodulin to 0.7 for the much more rigid calcineurin catalytic domain. The linear correlation is indicative of a similar level of side-chain conformational averaging over long distances, and the slope of the correlation line can be interpreted as an order parameter of the global side-chain flexibility.     

Nitrogen dynamics during till and no-till pasture restoration sequences in Rondônia,Brazil

The clearing of tropical rain forest in the Amazon basin has created large areas of cattle pasture that are now declining in productivity. Practices adopted by ranchers to restore productivity to degraded pastures have the potential to alter soil N availability and gaseous N losses from soils. We examined how soil inorganic N pools, net N mineralization and net nitrification rates, nitrification potential and NO and N₂O emissions from soils of a degraded pasture responded to the following restoration treatments: (1) soil tillage followed by replanting of grass and fertilization, (2) no-till application of non-selective herbicide, planting of rice, harvest followed by no-till replanting of grass and fertilization, and (3) the same no-till sequence with soybeans instead of rice. Tillage increased soil NH₄⁺ and NO₃^? pools but NH₄⁺ and NO₃^? pools remained relatively constant in the control and no-till treatments. Cumulative rates of net N mineralization and net nitrification during the first 6 months after treatment varied widely but were hightest in the tilled treatment. Emissions of NO and N₂O fluxes increased with tillage and with N fertilization. There were no clear relationships among rates of N fertilizer application, net N mineralization, net nitrification, NO, N₂O and total N oxide emissions. Our results indicate that pasture restoration sequences involving tilling and fertilizing will increase emissions of N oxides, but the magnitude of the increase is likely to differ based on timing of fertilizer application relative to the presence of plants and the magnitude of plant N demand. Emissions of N oxides appear to be decreased by the use of restoration sequences that minimize reductions in pasture grass cover.     

Tetragonal structure, anionic vacancies and catalytic activity of SO4-ZrO2 catalysts for n-butane isomerization

An assessment of the influence of the crystal structure, surface hydroxylation state and previous oxidation/reduction pretreatments on the activity of sulfate-zirconia catalysts for isomerization of n-butane was performed using crystalline and amorphous zirconia supports. Different sulfation methods were used for the preparation of bulk and supported SO₄²⁻-ZrO₂ with monoclinic, tetragonal and tetragonal+monoclinic structures. Activity was important only for the samples that contained tetragonal crystals. The catalysts prepared from pure monoclinic zirconia showed negligible activity. SO₄²⁻-ZrO₂ catalysts prepared by sulfation of crystalline zirconia displayed sites with lower acidity and cracking activity than those sulfated in the amorphous state. Prereduction of the zirconia samples with H₂ was found to greatly increase the catalytic activity, and a maximum rate was found at a reduction temperature of 550–600 °C, coinciding with a TPR peak supposedly associated with the removal of lattice oxygen and the creation of lattice defects. A weaker dependence of catalytic activity on the density or type of surface OH groups on zirconia (before sulfation) was found in this work.

A model of active site generation was constructed in order to stress the dependence on the crystal structure and crystal defects. Current and previous results suggest that tetragonal structure in active SO₄²⁻-ZrO₂ is a consequence of the stabilization of anionic vacancies in zirconia. Anionic vacancies are in turn supposed to be related to the catalytic activity for n-butane isomerization through the stabilization of electrons from ionized intermediates.     

On reactive routing protocols in ZigBee wireless sensor networks

ZigBee is the primary standard solution for wireless sensor networks, implementing the Ad hoc On‐Demand Distance Vector (AODV) protocol in the network layer and supported by the standard IEEE 802.15.4. This study is focused on mesh topologies and the critical problems encountered when AODV is executed in conjunction with the Carrier Sense Multiple Access with Collision Avoidance protocol. These problems are mainly related to the packet overhead required to carry out route creation. To perform preliminary experiments to be able to implement AODV in a real network, a new metric is proposed herein. This metric uses fuzzy logic to help in the decision‐making process. The objective of the fuzzy routine is to determine, during the route‐discovery process, the best node to forward request/reply packets, with the aim of reducing packet overhead and energy consumption. Moreover, minor changes are also added to the discovery procedure of AODV to improve the performance of the route‐creation process. This intelligent version of AODV has provided promising experimental results, greatly reducing the number of packets required, with the consequent energy saving while selecting the best nodes to be part of the routes.     

An Algorithm Template for Domain-Based Parallel Irregular Algorithms

The parallelization of irregular algorithms has not been as widely studied as the one of regular codes. In particular, while there are many proposals of parallel skeletons and libraries very well suited to regular algorithms, this is not the case for irregular ones. This is probably due to the complexity of finding common patterns, behaviors and semantics in these algorithms. This is unfortunate, as the parallelization of irregular algorithms would benefit even more than that of regular codes from the higher degree of abstraction provided by skeletons. This work proposes to exploit the concept of domain defined on some property of the elements to process in order to enable the simple and effective parallelization of irregular applications. Namely, we propose to use such domains both to decompose the computations in parallel tasks and to detect and avoid conflicts between these tasks. A generic C++ library providing a skeleton for multicore systems built on this idea is described and evaluated. Our experimental results show that this library is a very practical tool for the parallelization of irregular algorithms with little programming effort.