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The thermal efficiency for the pelletizing process is intrinsically linked to the diameter and humidity of the iron ore pellets, so that the sensing of the granulometric range in the formation of the pellets becomes essential to the flow of the pelletizing process in the steel industry; this paper presents the assembly of a computer vision system for the detection and segmentation of pellets aiming at the automation of the granulometric measurement, following its formation in the pelletizing disk, using the instance segmentation method to verify whether the particle granulometric distribution (PSD) is adequate for "real-time" applications. The system calculates the normal distribution of the diameter in millimeters, evaluating the normal curve and the standard deviation of the segmented pellets, using a deep neural network based on the You Only Look At CoefficienTs (YOLACT) network, adding speed and precision in the granulometric analysis. In the sample sets, the need for adjustment factors inherent to the pelletizing process became evident. This led to the establishment of the computer vision system, termed the Volumetric Correction Factor (VCF) and Visual Overlay Factor (VOF). The VCF is utilized to estimate the volume of pellets within the pelletizing disk during operation, while the VOF adjusts the millimeter-per-pixel (mpp) ratio. The results of the measurement system proved to be efficient in real-time granulometric measurement. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are circularized single-stranded ribonucleic acids that interacts with DNA, RNA, and proteins to play critical roles in cell biology. CircRNAs regulate microRNA content, gene expression, and may code for specific peptides. Indeed, circRNAs are differentially expressed in neurodegenerative disorders like Parkinson’s disease (PD), playing a potential role in the mechanisms of brain pathology. The RNA molecules with aberrant expression in the brain can cross the blood–brain barrier and reach the bloodstream, which enable their use as non-invasive PD disease biomarker. Promising targets with valuable discriminatory ability in combined circRNA signatures include MAPK9_circ_0001566, SLAIN1_circ_0000497, SLAIN2_circ_0126525, PSEN1_circ_0003848, circ_0004381, and circ_0017204. On the other hand, regular exercises are effective therapy for mitigating PD symptoms, promoting neuroprotective effects with epigenetic modulation. Aerobic exercises slow symptom progression in PD by improving motor control, ameliorating higher functions, and enhancing brain activity and neuropathology. These improvements are accompanied by changes circRNA expression, including hsa_circ_0001535 (circFAM13B) and hsa_circ_0000437 (circCORO1C). The sensitivity of current methods for detecting circulating circRNAs is considered a limitation. While amplification kits already exist for low-abundant microRNAs, similar kits are needed for circRNAs. Alternatively, the use of digital PCR can help overcome this constraint. The current review examines the potential use of circRNAs as non-invasive biomarkers of PD and to assess the effects of rehabilitation. Although circRNAs hold promise as targets for PD diagnosis and therapeutics, further validation is needed before their clinical implementation. [ABSTRACT FROM AUTHOR]

The article addresses the challenges of evaluating energy performance in different neighborhood settings under various energy efficiency measures and proposes a methodology for selecting appropriate solar strategies on a neighborhood scale. The study selects five representative neighborhoods from various climatic zones with different building and street layouts. The proposed methodology involves a systematic three-step multi-domain workflow for implementing energy efficiency measures and solar strategies in the existing neighborhoods. The first step involves typical energy performance simulation, the second step involves energy simulation using high performance building envelope, and the third step involves the addition of solar strategies in combination with retrofitting materials to achieve net-zero status. The results of the study show that modifying the building envelope leads to a significant reduction in energy consumption, with up to 60% reduction observed. The study also finds that the optimal mix of solar strategies depends strongly on the type of neighborhood, its street layouts, and the type of buildings. The article highlights the importance of considering these factors when implementing solar strategies on a neighborhood scale to achieve energy efficiency and net-zero status. It provides urban planners with a systematic decision-making approach to evaluate and optimize neighborhoods to achieve net-zero energy status. [ABSTRACT FROM AUTHOR]

Water quality monitoring networks (WQMNs) that capture both the temporal and spatial dimensions are essential to provide reliable data for assessing water quality trends in surface waters, as well as for supporting initiatives to control anthropogenic activities. Meeting these monitoring goals as efficiently as possible is crucial, especially in developing countries where the financial resources are limited and the water quality degradation is accelerating. Here, we asked if sampling frequency could be reduced while maintaining the same degree of information as with bimonthly sampling in the São Paulo State (Brazil) WQMN. For this purpose, we considered data from 2004 to 2018 for 56 monitoring sites distributed into four out of 22 of the state's water resources management units (UGRHIs, "Unidades de Gerenciamento de Recursos Hídricos"). We ran statistical tests for identifying data redundancy among two-month periods in the dry and wet seasons, followed by objective criteria to develop a sampling frequency recommendation. Our results showed that the reduction would be feasible in three UGRHIs, with the number of annual samplings ranging from two to four (instead of the original six). In both seasons, dissolved oxygen and Escherichia coli required more frequent sampling than the other analyzed parameters to adequately capture variability. The recommendation was compatible with flexible monitoring strategies observed in well-structured WQMNs worldwide, since the suggested sampling frequencies were not the same for all UGRHIs. Our approach can contribute to establishing a methodology to reevaluate WQMNs, potentially resulting in less costly and more adaptive strategies in São Paulo State and other developing areas with similar challenges. [ABSTRACT FROM AUTHOR]

Shortly after research regarding the sexual double standard began, mixed results were found, which may be due to inconsistent methodology and outdated definitions of the concept. Studies often use explicit or self-report measures to assess the endorsement of a sexual double standard. Some of these approaches are not only influenced by social desirability, but they may also not be able to fully capture a sexual double standard. This study addressed the endorsement of the sexual double standard using an implicit association test (IAT) and a sexual double standard self-report scale. Additionally, sociosexuality was used to measure openness to casual sex as a moderator variable. The sample included 209 Portuguese heterosexual cisgender young adults (112 women and 97 men, Mage 23.75). Both men and women showed low endorsement of an explicit sexual double standard. However, the IAT revealed women to strongly adhere to an implicit reverse sexual double standard, while men showed very minor endorsement. [ABSTRACT FROM AUTHOR]

Entanglement is assuming a central role in modern quantum many-body physics. Yet, for lattice gauge theories its certification remains extremely challenging. A key difficulty stems from the local gauge constraints underlying the gauge theory, which separate the full Hilbert space into a direct sum of subspaces characterized by different superselection rules. In this work, we develop the theoretical framework of entanglement witnessing for lattice gauge theories that takes this subtlety into account. We illustrate the concept at the example of a U(1) lattice gauge theory in 2+1 dimensions, without and with dynamical fermionic matter. As this framework circumvents costly state tomography, it opens the door to resource-efficient certification of entanglement in theoretical studies as well as in laboratory quantum simulations of gauge theories. [ABSTRACT FROM AUTHOR]

In this paper, we present various concepts concerning generalized fractional calculus, wherein the fractional order of operators is not constant, and the integral kernel depends on a function. We observe that in the case of variable order, the concepts are distinct, and we present relations between them. Formulas for approximating fractional derivatives are provided, involving only integer-order derivatives. Finally, we conclude the work with some simulations to exemplify the method. [ABSTRACT FROM AUTHOR]

Water quality monitoring networks (WQMNs) are essential to provide good data for management decisions. Nevertheless, some WQMNs may not appropriately reflect the conditions of the water bodies and their temporal/spatial dimensions, more particularly in developing countries. Also, some WQMNs may use more resources to attain management goals than necessary and can be improved. Here we analyzed the São Paulo State (Brazil) WQMN design in order to evaluate and increase its spatial representativeness based on cluster analysis and stratified sampling strategy focused on clear monitoring goals. We selected water resources management units (UGRHIs) representative of contrasting land uses in the state, with bimonthly data from 2004 to 2018 in 160 river/stream sites. Cluster analysis indicated monitoring site redundancy above 20% in most of the UGRHIs. We identified heterogeneous spatial strata based on land use, hydrological, and geological features through a stratified sampling strategy. We identified that monitoring sites overrepresented more impacted areas. Thus, the network is biased against determination of baseline conditions and towards highly modified aquatic systems. Our proposed spatial strategy suggested the reduction of the number of sites up to 12% in the UGRHIs with the highest population densities, while others would need expansions based on their environmental heterogeneity. The final densities ranged from 1.6 to 13.4 sites/1,000km2. Our results illustrate a successful approach to be considered in the São Paulo WQMN strategy, as well as providing a methodology that can be broadly applied in other developing countries. [ABSTRACT FROM AUTHOR]

The water ingress phenomenon in sandwich-structured composites used in the aerospace/aeronautical sector is a current issue. This type of defect can cause in the course of time several other defects at the boundary, such as corrosions, deformations, detachments. In fact, water may change its state of physical matter going towards the freeze–thaw cycle caused by the atmosphere re-entry of, e.g. space probes. In this work, the alveoli of a composite laminate have been filled with water, which was initially transformed into ice. By taking into account, the known quantity of water, the freeze–thaw cycle was simulated by Comsol Multiphysics® software, reproducing exactly the shape of the sandwich as well as the real conditions in which it was subsequently subjected in a climatic chamber. The experimental part consisted of monitoring the front side of the specimen by means of a thermal camera operating into the long-wave infrared spectrum, and by setting both the temperature and the relative humidity of the test chamber according to the values imposed during the numerical simulation step. It was found that the numerical and experimental temperature trends are in good agreement with each other since the model was built by following a physico-chemical point-of-view. It was also seen that the application of the independent component thermography (ICT) technique was able both to retrieve the positions of the defects (i.e. the water inclusions) and to characterize the defects in which a detachment (fabricated between the fibres and the resin) is present; the latter was realized above an inclusion caused by the water ingress. To the best of our knowledge, this is the first time that ICT is applied to satisfy this purpose. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the impact of increased shadow supply in integrated crop-livestock-forest systems on in vitro embryonic development and physiological parameters related to stress response in Nellore heifers (Bos indicus). For the study, animals (n = 16) were randomly divided into two groups and kept in areas with different afforestation systems, the integrated crop-livestock-forest (ICLF) and the integrated crop-livestock (ICL) system. The microclimate of the ICLF system provided better comfort conditions than ICL. No differences of respiratory rate, rectal temperature, cortisol, T3, T4, oocyte quality, and cleavage rate between the systems were verified. A higher blastocyst rate was observed in the ICLF (p < 0.05). The results demonstrate that Nellore heifers managed in ICLF during summer in Midwest of Brazil showed higher production of in vitro embryos, without typical changes in its physiological parameters. The results observed in the present study indicate that zebu females are able to respond satisfactorily to the intense heat conditions; however, we believe that the long period to which these animals are exposed to these conditions interferes in the oocyte competence and embryo development. [ABSTRACT FROM AUTHOR]

Most information sources in the current technological world are generating data sequentially and rapidly, in the form of data streams. The evolving nature of processes may often cause changes in data distribution, also known as concept drift, which is difficult to detect and causes loss of accuracy in supervised learning algorithms. As a consequence, online machine learning algorithms that are able to update actively according to possible changes in the data distribution are required. Although many strategies have been developed to tackle this problem, most of them are designed for classification problems. Therefore, in the domain of regression problems, there is a need for the development of accurate algorithms with dynamic updating mechanisms that can operate in a computational time compatible with today's demanding market. In this article, the authors propose a new bagging ensemble approach based on neural network with random weights for online data stream regression. The proposed method improves the data prediction accuracy as well as minimises the required computational time compared to a recent algorithm for online data stream regression from literature. The experiments are carried out using four synthetic datasets to evaluate the algorithm's response to concept drift, along with four benchmark datasets from different industries. The results indicate improvement in data prediction accuracy, effectiveness in handling concept drift, and much faster updating times compared to the existing available approach. Additionally, the use of design of experiments as an effective tool for hyperparameter tuning is demonstrated. [ABSTRACT FROM AUTHOR]

The growing concern about the environmental sustainability, the risk of natural resources depletion and the increase amount of wastes generation endorse the need to develop new materials, namely for the construction industry. However, both the technical performance and the environmental behaviour of new materials are key factors in their acceptance. In this work it was intended to evaluate the effect of aggregates substitution by different wastes in the concrete production. Wastes from local industries (biomass fly ashes and lime sludge) were used for replacing 50 and 100% of the natural fine aggregates. The fresh and hardened properties of the concrete samples were evaluated and the environmental eco-toxicity was assessed by bioassays using duckweed and microorganisms as biomarkers. Bioleaching tests were done with the same materials in order to evaluate the concrete effect in biological activity. The results showed that the addition of wastes to the concrete mix lead to a slight decrease in the compressive strength when fly ashes were used (3%), but 35% decrease when lime was the replacing waste. The duckweed grow did not show different performances between conventional concrete and concrete produced with fly ashes or lime sludge but bioleaching revealed possible negative effect in micro species when compared with control. In bacterial growth the effect was more evident with a significant different behaviour between the control and the concrete assays, but also with the traditional concrete showing a higher negative effect in the development of microorganisms. [ABSTRACT FROM AUTHOR]

In November 2019 givosiran became the second small interfering RNA (siRNA)-based drug to receive US Food and Drug Administration (FDA) approval, it has been developed for the treatment of acute intermittent porphyria (AIP), a disorder characterized by life-threatening acute neurovisceral attacks. The porphyrias are a group of disorders in which enzymatic deficiencies in heme production lead to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are involved in the neurovisceral attacks. Givosiran acts as a conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the physiological level to attenuate further neurotoxicity. Givosiran makes use of a new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine) molecules to the siRNA passenger strand. GalNac binds to the liver asialoglycoprotein receptor, favoring the internalization of these GalNac-conjugated siRNAs into the hepatic cells. In a phase I study, subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase III, multicenter, placebo-controlled randomized controlled trial. In preliminary results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA levels, and presented a safety profile that enabled further drug development. The clinical performance of givosiran revealed that suppression of ALAS1 by GalNac-decorated siRNAs represents an additional approach for the treatment of patients with AIP that manifests recurrent acute neurovisceral attacks. [ABSTRACT FROM AUTHOR]

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing process involves the binding of siRNA guide strand to 3′-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC) as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2 years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study. At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15 ± 2.14 μg/mL and 184 ± 159 μg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18 months. Additionally, the modified body mass index showed positive outcomes. Altogether, the data across phase I–III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug. [ABSTRACT FROM AUTHOR]

This paper deals with an opinion formation model, that obeys a nonlinear system of fractional-order differential equations. We introduce a virtual leader in order to attain a consensus. Sufficient conditions are established to ensure that the opinions of all agents globally asymptotically approach the opinion of the leader. We also address the problem of designing optimal control strategies for the leader so that the followers tend to consensus in the most efficient way. A variational integrator scheme is applied to solve the leader–follower optimal control problem. Finally, in order to verify the theoretical analysis, several particular examples are presented. [ABSTRACT FROM AUTHOR]

Purpose: Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast. Methods: To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. Results: Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. Conclusion: Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) has chemical properties that make it uniquely suitable as an intracellular and intercellular messenger. NO is produced by the activity of the enzyme nitric oxide synthases (NOS). There is substantial and mounting evidence that slight abnormalities of NO may underlie a wide range of neurodegenerative disorders. NO participates of the oxidative stress and inflammatory processes that contribute to the progressive dopaminergic loss in Parkinson's disease (PD). The present study aimed to evaluate in vitro and in vivo the effects of neuronal NOS-targeted siRNAs on the injury caused in dopaminergic neurons by the toxin 6-hidroxydopamine (6-OHDA). First, we confirmed (immunohistochemistry and Western blotting) that SH-SY5Y cell lineage expresses the dopaminergic marker tyrosine hydroxylase (TH) and the protein under analysis, neuronal NOS (nNOS). We designed four siRNAs by using the BIOPREDsi algorithm choosing the one providing the highest knockdown of nNOS mRNA in SH-SY5Y cells, as determined by qPCR. siRNA 4400 carried by liposomes was internalized into cells, caused a concentration-dependent knockdown on nNOS, and reduced the toxicity induced by 6-OHDA (p < 0.05). Regarding in vivo action in the dopamine-depleted animals, intra-striatal injection of siRNA 4400 at 4 days prior 6-OHDA produced a decrease in the rotational behavior induced by apomorphine. Finally, siRNA 4400 mitigated the loss of TH(+) cells in substantia nigra dorsal and ventral part. In conclusion, the suppression of nNOS enzyme by targeted siRNAs modified the progressive death of dopaminergic cells induced by 6-OHDA and merits further pre-clinical investigations as a neuroprotective approach for PD. [ABSTRACT FROM AUTHOR]

In this paper, we discuss the existence and uniqueness of solutions of a boundary value problem for a fractional differential equation of order α ∈ (2 , 3) , involving a general form of fractional derivative. First, we prove an equivalence between the Cauchy problem and the Volterra equation. Then, two results on the existence of solutions are proven, and we end with some illustrative examples. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P < 0.05), while miR-7 (0.5 fold, P < 0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal. [ABSTRACT FROM AUTHOR]

Chromatin is the template for the basic processes of replication and transcription, making the maintenance of chromosomal integrity critical for cell viability. To elucidate how dividing cells respond to alterations in chromatin structure, here we analyse the replication programme of primary cells with altered chromatin configuration caused by the genetic ablation of the HMGB1 gene, or three histone H1 genes. We find that loss of chromatin compaction in H1-depleted cells triggers the accumulation of stalled forks and DNA damage as a consequence of transcription–replication conflicts. In contrast, reductions in nucleosome occupancy due to the lack of HMGB1 cause faster fork progression without impacting the initiation landscape or fork stability. Thus, perturbations in chromatin integrity elicit a range of responses in the dynamics of DNA replication and transcription, with different consequences on replicative stress. These findings have broad implications for our understanding of how defects in chromatin structure contribute to genomic instability. [ABSTRACT FROM AUTHOR]

Indoor environmental conditions in classrooms, in particular temperature and indoor air quality, influence students' health, attitude and performance. In recent years, several studies regarding indoor environmental quality of classrooms were published and natural ventilation proved to have great potential, particularly in southern European climate. This research aimed to evaluate indoor environmental conditions in eight schools and to assess their improvement potential by simple natural ventilation strategies. Temperature, relative humidity and carbon dioxide concentration were measured in 32 classrooms. Ventilation performance of the classrooms was characterized using two techniques, first by fan pressurization measurements of the envelope airtightness and later by tracer gas measurements of the air change rate assuming different envelope conditions. A total of 110 tracer gas measurements were made and the results validated ventilation protocols that were tested afterward. The results of the ventilation protocol implementation were encouraging and, overall, a decrease on the CO concentration was observed without modifying the comfort conditions. Nevertheless, additional measurements must be performed for winter conditions. [ABSTRACT FROM AUTHOR]

The aim of this paper is to study certain problems of calculus of variations that are dependent upon a Lagrange function on a Caputo-type fractional derivative. This type of fractional operator is a generalization of the Caputo and the Caputo-Hadamard fractional derivatives that are dependent on a real parameter $$\rho $$ . Sufficient and necessary conditions of the first and second order are presented. The cases of integral and holonomic constraints are also considered. [ABSTRACT FROM AUTHOR]

Ten years after Fire and Melo's Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development. [ABSTRACT FROM AUTHOR]

Intervertebral disk degeneration is a progressive and debilitating disease with multifactorial causes. Nitric oxide (NO) might contribute to the cell death pathway. We evaluated the presence of the constitutive form of the neuronal NOS (nNOS) in both health and degenerated intervertebral disk through qPCR and immunohistochemistry. We also analyzed the potential role of nNOS modulation in the tail needle puncture model of intervertebral disk degeneration. Male Wistar rats were submitted to percutaneous disk puncture with a 21-gauge needle of coccygeal vertebras. The selective nNOS pharmacological inhibitor N -propyl- l-arginine (NPLA) or a nNOS-target siRNA (siRNAnNOShum_4400) was injected immediately after the intervertebral disk puncture with a 30-gauge needle. Signs of disk degeneration were analyzed by in vivo magnetic resonance imaging and histological score. We found that intact intervertebral disks express low levels of nNOS mRNA. Disk injury caused a 4 fold increase in nNOS mRNA content at 5 h post disk lesion. However, NPLA or nNOS-target siRNA slight mitigate the intervertebral disk degenerative progress. Our data show evidence of the nNOS presence in the intervertebral disk and its upregulation during degeneration. Further studies would disclose the nNOS role and its potential therapeutical value in the intervertebral disk degeneration. [ABSTRACT FROM AUTHOR]

The aim of this paper is to exhibit a necessary and sufficient condition of optimality for functionals depending on fractional integrals and derivatives, on indefinite integrals and on the presence of time delay. We exemplify with one example, where we find analytically the minimizer. [ABSTRACT FROM AUTHOR]

Mangiferin has high potential as a cancer chemopreventive agent; but readily available sources are scarce. Therefore, the concentration of mangiferin and its isomer, were quantitated in the leaves of five species of Coffee leaves from Brazil and Costa Rica respectively. The amount of total mangiferins in methanol extracts of the Brazilian species; was in the range 0.67-4.97 g/kg, whereas in the Costa Rican species, it lay in the range 0.85-4.01 g/kg. In 90 % of cases, mangiferin accounted for 80 % or more of total mangiferins; as opposed to isomangiferin. Infusion studies with powdered leaves of a commercial Brazilian species ( Coffea arabica) shows that the release of mangiferins is temperature dependent and that release at 100 °C (1.6 ± 0.06 g/kg) is instantaneous, but approximately 50 % less compared to prolonged methanol extraction (3.05 ± 0.16 g/kg). Consumption of Coffee leaf tea brews, as a natural source of mangiferins, may contribute significantly to elevated intake of these potentially health-promoting phenolic compounds. [ABSTRACT FROM AUTHOR]

In this paper, we present a new numerical method to solve fractional differential equations. Given a fractional derivative of arbitrary real order, we present an approximation formula for the fractional operator that involves integer-order derivatives only. With this, we can rewrite FDEs in terms of a classical one and then apply any known technique. With some examples, we show the accuracy of the method. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate whether a specific interleukin-1 receptor-associated kinase-4 ( IRAK4) gene polymorphism had any influence on the development of changes in maxillary sinus, particularly in the presence of etiological factors of dental origin. Materials and methods: The study population included 153 Portuguese Caucasians that were selected from a database of 504 retrospectively analysed computed tomography (CT) scans. A genetic test was performed, and a model was created through logistic analysis and regression coefficients. The statistical methodologies included were the independent Chi test, Fisher's exact test, binary logistic regression and the receiver operating characteristic (ROC) curve. Results: The estimated prevalence of IRAK4 gene polymorphism found in a Portuguese Caucasian population was 26.8 % (CI 95 %) [20.1, 34.7 %]. A model to predict the inflammatory response in the maxillary sinus in the presence etiological factors of dental origin was constructed. This model had the following as variables: previously diagnosed sinusitis, sinus pressure symptoms, cortical bone loss observed on CT, positive genetic test result and radiographic examination that revealed the roots of the teeth communication with the maxillary sinus, which are interpreted as risk factors. Conclusions: The constructed model should be considered an initial clinical tool. The area under the ROC curve found, AUC = 0.91, revealed that the model correctly predicts the outcome in 91.1 % of cases. Clinical relevance: The clinical relevance of this study lies in trying to achieve a potential tool (a model) that may assist the clinician in the implementation of suitable dental treatment plans in complex cases, with probable involvement of the maxillary sinus. [ABSTRACT FROM AUTHOR]

We present a method to solve fractional optimal control problems, where the dynamic control system depends on integer order and Caputo fractional derivatives. Our approach consists in approximating the initial fractional order problem with a new one that involves integer order derivatives only. The latter problem is then discretized, by application of finite differences, and solved numerically. We illustrate the effectiveness of the procedure with an example. [ABSTRACT FROM AUTHOR]

This study examined whether the cytokine interferon (IFN) gamma plays a role in the injury of SH-SY5Y cells caused by MPP(+) (1-methyl-4-phenylpyridinium). First of all, IFN-gamma sensitized cells to the neurotoxin MPP(+), as determined by MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide) assay. MPP(+)-injured cells showed higher reactive oxygen species (ROS) levels, which was reinforced by IFN-gamma. The injury triggered a marked expression of the neuronal NOS (nNOS) enzyme. L-NAME [N(ω)-nitro- l-arginine methyl ester, a non-specific NOS inhibitor] reestablished the cell viability after IFN-gamma challenging, and recovered cells from MPP(+) injury (95.0 vs. 84.7 %; P < 0.05). Seven-NI (7-nitroindazole, a nNOS inhibitor) protected cells against the injury by MPP(+) co-administered with IFN-gamma. Both inhibitors restrained the apoptosis of SH-SY5Y cells caused by MPP(+)/IFN-gamma. Regarding oxidative stress, L-NAME and 7-NI attenuated the increase in ROS levels caused by MPP(+) (45.3 or 48.4 vs. 87.9 %, P < 0.05). Indeed, L-NAME was more effective than 7-NI for reducing oxidative stress caused by MPP(+) under IFN-gamma exposition. The nNOS gene silencing by small-interfering RNAs recovered cells challenged by IFN-gamma (24 h), or MPP(+) (8 h). In conclusion, IFN-gamma sensitizes cells to MPP(+)-induced injury, also causing an increase in ROS levels. Pretreating cells with L-NAME or 7-NI reverts both the oxidative stress and apoptosis triggered by the neurotoxin MPP(+). Taking together, our data reinforce that IFN-gamma and NOS enzymes play a role in oxidative stress and dopaminergic cell death triggered by MPP(+). [ABSTRACT FROM AUTHOR]