Background: beta blockers of three generations are first-line drugs in the treatment of chronic heart failure (CHF). However, to date there is no clear understanding of the effect of beta blockers on myocardial energy metabolism disorders in CHF. The aim of the study: to conduct a study of beta-blockers of different generations on myocardial energy metabolism in the experimental CHF. Methods: CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically – new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, metoprolol - 15 mg/kg, Nebivolol -10 mg/kg, Carvedilol 50 mg/kg, Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined - ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, NAD-dependent malate dehydrogenase (NAD-MDH) activity. Results: traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties - Carvedilol and, especially, Nebivalol and Hypertril improved myocardial energy metabolism. Conclusions: obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF.

Hemicellulose is one of the most important natural polysaccharides in nature. Hemicellulose from different sources varies in chemical composition and structure, which in turn affects the modification effects and industrial applications. Grain and oil by-products (GOBP) are important raw materials for hemicellulose. This article reviews the modification methods of hemicellulose in GOBP. The effects of chemical and physical modification methods on the properties of hemicellulose biomaterials were evaluated. The potential applications of GOBP hemicellulose in films, hydrogel, Three-dimensional (3D) printing and adsorbent are discussed. Future research directions and recommendations are also proposed to provide theoretical foundations and technical support for the efficient utilization of these by-products.

The authors propose a novel approach for a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while preserving animal life. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate-calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity, signs of neurological deficits (paresis, paralysis, etc.), as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds.

The intranasal route of drug administration is characterized by high bioavailability and is considered promising for rapid delivery of drugs with systemic action to the central nervous system, bypassing the blood-brain barrier. This is particularly important for the use of neuroprotective drugs in the treatment of brain tissue damage in infants caused by the effects of intrauterine hypoxia. Creation of new dosage forms for neonatology with the use of software and mathematical technologies in pharmaceutical development allows to create cerebroprotective drugs with controlled pharmaco-technological properties, thus reducing time and resources for necessary research. We developed a formulation of a new nasal gel formulation with Angiolin using Box-Benken experiment design for the therapy of prenatal CNS damage. It was found that the consistency properties of the nasal gel were significantly influenced by the gelling agent and mucoadhesive component - sodium salt of carboxymethylcellulose. We have optimized the composition of nasal gel formulation with Angiolin using the formed models and relationships between the factors. The optimized composition of the obtained nasal gel has satisfactory parameters of thixotropic properties. The developed 1% gel for neuroprotection with Angiolin meets all the requirements for harmlessness and safety to drug forms of this group - low toxicity, absence of local irritant and allergic effect.

Quebec is the third-largest wine grape producing province in Canada, and the industry is constantly expanding. Traditionally, 90% of the grapevine cultivars grown in Quebec were rustic or semi-rustic and largely dominated by winter hardy interspecific hybrid Vitis sp. cultivars. Over the years, the winter protection techniques adopted by growers and climate changes have offered an opportunity to establish V. vinifera L. cultivars (e.g. Pinot Noir). We characterized the virome of leafroll-infected interspecific hybrid cultivar and compared it to the virome of V. vinifera cultivar to support and facilitate the transition of the industry. A dsRNA sequencing method was used to sequence symptomatic and asymptomatic grapevine leaves of different cultivars. The results suggested a complex virome in terms of composition, abundance, richness, and phylogenetic diversity. Three viruses, grapevine Rupestris stem pitting-associated virus, grapevine leafroll-associated virus (GLR) 3 and 2 and hop stunt viroid (HSVd) largely dominated the virome. However, their presence and abundance varied among grapevine cultivars. The symptomless grapevine cultivar Vidal was frequently infected by multiple virus and viroid species and different strains of the same virus, including GLR virus 3 and 2. Our data shows that viruses and viroids associated with the highest number of grapevines expressing symptoms included HSVd, GLR3 and GLR2, in gradient order. However, co-occurrence analysis revealed that the presence of GLR species was randomly associated with the development of virus-like symptoms. These findings and their implication for grapevine leafroll disease management were discussed.

المستخلص تصنيع لقاح مكون من الحمض النووي الريبوزي الرسول الخاص بالبروتينات المسئولة عن انتاج البروتينات نيورامنيديز والهيم اجليوتونين لفيروسي الانفلونزا الخنازير والطيورمحاط بجزيئات دهنية بحجم النانوميتر عدوى انفلونزا الخنازير وانفلونزا الطيور مشكلة خطيرة تؤرق العالم كله هذه الايام خصوصا انها مميتة لكثير من اطفال العالم . بعد فترة التعافي من الاصابة تتكون المناعة المكتسبة ضدها لمدة عام تقريبا. هذه الانفلونزا تسبب تسمم فيروسي في الدم بالاضافة للالتهاب الرئوي وهذامن بين اكبرالاسباب للوفاة بين الاطفال قبل سن عامين عالميا بشكل مباشر. الهدف من الدراسة هو انتاج لقاح الحمض النووي الريبوزي الرسول من نوع الام بالنانوتكنولوجي لبروتينات الهيم اجليوتونين والنيورامنيديز الموجودة على سطح هذه الفيروسات التي تساعدتها في الاتصاق بالعائل الذي ستتكاثر داخل خلاياه بالجهاز التنفسي. هذه الدراسة دراسة استكشافية ومن خلالها استطاعنا تصميم هذا اللقاح باستعمال نظام توصيل للقاح بالنانوتكنولوجي حجم جزيئاته 70نانوميمتر. اللقاح الجديد اظهر فاعلية بنسبة 60% واظهر فاعلية حيوية مقاربة واثار جانبية اقل بالمقارنة باللقاحات المتوفرة حاليا بالسوق الدوائي ضد هذا النوع من الفيروسات الوبائية. ABSTRACT Background: Worldwide, Swine and Avian influenza, or the H1N1 and H5N1 serotypes of the Influenza A virus, is a highly contagious illness. In recent years, the global incidence of mortality rate has surpassed 284,000 fatalities. Aim of the study: The production of mRNA vaccine lipid nanoparticles (LNP) to combat the deadly strains of Avian and Swine influenza (H1N1 and H5N1 of the influenza A serotype). Methodology: Polymerase chain reaction (PCR) was used to clone genes of interest encoding Haemagglutinin (HA) and Neuraminidase (NA) of Influenza A virus strains (H5N1 and H1N1) known as Avian flu and Swine flu, respectively. The genes were then inserted using the EcoR1, BAM Hind II restriction endonuclease type II, and Ligase enzyme into the pET-21(+) transcription vector plasmid. On the other hand, the hybrid transcription vectors were mixed with T7 RNA polymerase and ribonucleotides within a test tube after being linearized using EcoR II. Following their purification via reversed-phase high-performance liquid chromatography (RP-HPLC), the mRNAs of the HA and NA were encased in 70 nm LNPs and subjected to reverse-phase high-performance liquid chromatography (RP-HPLC). Lastly, immunogenicity studies were performed in stages 1/2 of randomized human and preclinical clinical trials. Results: The bivalent vaccination had around 63% efficacy in preclinical studies and approximately 60% efficacy in randomized human clinical trials. As shown by the ELISA test, strong neutralizing antibodies against HA were prevalent. Conclusion: The current study is a promising effort because of the development of the novel LNP-mRNA vaccine, which could lower the incidence of Avian and Swine flu infectious disorders.

Deep Eutectic Solvents (DESs) show promising abilities for the delamination of multilayer packaging films that are used in food packaging and in pharmaceutical blister packs. Due to the complexity of their structure, the recycling of these materials is a challenging task, leading to the easiest or cheapest option, landfilling. Towards the development of ‘green’ solvents for the efficient waste management and recycling, the conducted research focuses on the preparation of a range of hydrophobic and hydrophilic DES based on carboxylic acids. Also, their chemical and physical characterization, such as DSC, rheometer and density measurements, was followed for the determination of their properties. The laminate packaging waste products that were tested were Al/PE, PE/Al/PET, Al/PE/paper and PVC/PE/Al. Different batches of solvent systems were tested based on various naturally derived aliphatic and aromatic organic compounds as well as amino acids. The separated films were collected and studied further for the examination of the delamination extend. Results showed full or partial delamination of some materials as well as challenges of solvent systems. Variables such as temperature, agitation rate, mixing time and solvents ratios were monitored and collected during the design of experimental process. The results showed that the used DESs can offer an efficient, low-energy, affordable and green option for the delamination tested packaging materials.

Cybersecurity is a crucial concern for local governments, as they serve as the primary interface between public and government services, managing sensitive data and critical infrastructure. While technical safeguards are integral to cybersecurity, the role of well-structured policy is equally important, as it provides structured guidance to translate technical requirements into actionable protocols. This study reviews local governments’ cybersecurity policies to provide a comprehensive assessment of how these policies align with NIST CSF, which is a widely adopted and commonly used cybersecurity assessment framework. The review offers local governments a mirror to reflect on their cybersecurity stance, identifying potential vulnerabilities and areas needing urgent attention. The study further extends to developing a cybersecurity policy framework, which local governments can use as a strategic tool. It provides valuable information on crucial cybersecurity elements that local governments must incorporate into their policies to protect confidential data and critical infrastructure.

The release of the active substance from the matrix modified-release tablets based on Kollidon®SR and chitosan depends on its solubility in the dissolution medium and on the composition of the matrix-forming polymers. The study is based on new oral matrix tablets based on Kollidon®SR and chitosan, formulated to optimize the low oral bioavailability of chlorzoxazone, a non-steroidal anti-inflammatory drug, a class II Biopharmaceutical Classification System. Nine types of chlorzoxazone matrix tablets were obtained using the direct compression method, and their combination at 1:1, 1:2, 1:3 chlorzoxazone/ excipients, 20%-40% (w/w) Kollidon®SR, 3-7% (w/w) chitosan and the auxiliary substances were formulated in constant concentrations. Pharmaco-technical characterization included the analysis of flowability and compressibility properties (flow time, friction coefficient, angle of repose, Hausner ratio, Carr Index), and of pharmaco-chemical characteristics (mass and dose uniformity, thickness, diameter, mechanical strength, Friability, degree of softening, in vitro release profile) of the tablets. Based on the initial evaluation of the pharmaco-technical analysis, pharmaco-chemical characteristics, and in vitro release profile, only three matrix tablet formulations (F1b, F2b, and F3b) were further tested. They were evaluated through Fourier-transform infrared spectrometry, X-ray Diffraction, thermogravimetry, differential scanning calorimetry, and in vitro dissolution tests. The three formulations were comparatively studied regarding the release kinetics of active substances using in vitro release testing. The results were analyzed by fitting into four representative mathematical models for the modified release oral formulations. In vitro kinetic study reveals a complex mechanism of release occurring in the first (0 - 2 hours) and second (2.0 hours – 36 hours) steps of drug release. Two factors have been calculated to assess the release profile of chlorzoxazone: f1 - the similarity factor and f2 - the factor difference. The results have shown that both Kollidon®SR and chitosan may be used as matrix-forming agents when combined with chlorzoxazone. In vitro dissolution tests revealed the F2b sample, data suggesting a faster drug release. The three formulations showed optimum pharmaco-technical properties and in vitro kinetic study, and they had tremendous potential to be used in oral pharmaceutical products for the controlled delivery of chlorzoxazone.

Adjunctive treatment of periodontitis lacks solutions allowing enough time for wound healing in the periodontal pockets by avoiding a fast re-colonization. Such a solution might be an antibiotic containing formulation with a controlled release over weeks. Here, a recently described minocycline containing approach is qualified for further clinical development by focusing on proof-of-concept, systemic burden, resistance development and degradation studies. Animal studies were done in two different (mouse-chamber, rat Porphyromonas gingivalis challenging) models, including effects on inflammation markers, bone loss and bone structure. Also, serum concentrations of minocycline after local application were determined by HPLC-MS/MS. The resistance status of bacterial clinical isolates against minocycline was investigated and the degradation of the formulation was characterized by laser scanning- and scanning electron microscopy. Animal studies clearly demonstrated the applicability of the new formulation in the investigated models. Inflammation markers decreased dosage dependent and reduced bone loss compared to non-treated group was observed. Thereby, the systemic burden of the antibiotic was neglectable. Minocycline is still effective against oral pathogens; resistance development was not seen. The biodegradable thread was first swollen and subsequently degraded over weeks. The results support the continued clinical development of this new formulation. A phase I clinical trial is planned to further evaluate its safety and efficacy.

In the last years, different biotechnological approaches were developed to reduce the indiscriminate use of chemical fertilizers and pesticides and enhance plant growth and health. The most attractive, safe, and environmentally mild alternatives include those based on plant beneficial microorganisms. After a long period of studies on isolation, selection, and characterisation of plant-beneficial microorganisms, the main lines of research have been oriented to optimising the fermentation processes to produce high-quality and large volumes of biomass/spores and their further formulation. However, further well-structured schemes for improvement of all main steps of the production of bio-formulates should be developed following the ideas based on “healthy soil-healthy plants-healthy humans”.

Global crop yields are estimated to be reduced by 30–40% per year on account of plant pests and pathogens. Agricultural insect pests raise concerns about constraining global food security and climate changes contributing to the rise of infestation. The current management relies on plant breeding, associated or not with transgenes and chemical pesticides. Both approaches face serious technology obsolescence on the field due to resistance breakdown or development of insecticide resistance. The need for new Modes of Action (MoA) approaches in managing crop health grows each year, driven by market demands to reduce economic losses and phytosanitary requirements to meet the consumer perception. Disabling pest genes by sequence-specific expression silencing is considered a promising tool in the development of environment and health respectful biopesticides. The specificity conferred by long dsRNA-base solutions give support to minimizing effects on off-targeted genes in the insect pest genome and the target gene in non-target organisms (NTOs). In this review, we summarize the current status of gene silencing by RNA interference (RNAi) for agricultural control. More specifically, we focus on the engineering, development and application of gene silencing to control Lepidoptera by the employment of non-transforming dsRNA technologies. Despite some delivery and stability drawbacks of topical applications, we reviewed works showing convincing proof-of-concept results that point to imminent innovative solutions. Considerations about the regulamentation of the ongoing research on dsRNA-based pesticides to produce commercialized products for exogenous application are discussed. Academic and industry initiatives reveal a worthy effort to accomplish controlling Lepidoptera pests with this new mode of action to provide more sustainable and reliable technologies to field management. New data on genomics of this taxon encourage the increment of a customized target genes portfolio. As a case of study, we illustrate how dsRNA and associated methodologies could be applied to control an important Lepidopteran coffee pest.

Orodispersible film (ODF) is one of the novel formulations that have been currently made available that disintegrates rapidly in the mouth without the requisite for water and offer several benefits over conventional oral solid dosage formulations. This delivery system serves as a discreet and convenient mode of administration, especially in patients who have dysphagia, fluid restriction, being beneficial to pediatric, geriatric, and bedridden patients. A novel sildenafil ODF containing sildenafil citrate is formulated to be used in patients with erectile dysfunction (ED). This review discusses the advantages of ODF in improving compliance and satisfaction in these patients and describes the bioequivalence and stability studies of sildenafil ODF. This formulation offers unique benefit to patients with ED by improving their acceptance, compliance, and respecting their privacy. Moreover, the comparison of pharmacokinetic parameters between the sildenafil ODF administered with and without water and the conventional film-coated tablet were similar. It also demonstrated reliable performance that yielded a consistent product, meeting all specifications at release and after three weeks of storage under stressed conditions (60oC). Sildenafil ODF warrants improved ease of intake, taste, portability, storage, and compliance among ED patients, making it the potential most preferred formulation and drug of choice.

Probiotic feed additives have attracted considerable research interest in recent years because the effectiveness of probiotics can differ across microbial strains and the supplemented macroorganisms. The present study was conducted on 16 lambs divided into two groups (C - control and E - experimental). The examined lambs were aged 11 days at the beginning of the experiment and 40 days at the end of the experiment. The diet of group E lambs was supplemented with a multi-strain probiotic formulation (Lactobacillus plantarum AMT14, Lactobacillus plantarum AMT4, Lactobacillus rhamnosus AMT15, and Bifidobacterium animalis AMT30), whereas group C lambs did not receive the probiotic additive. At the beginning of the experiment (day 0) and on experimental days 15 and 30, blood was sampled from the jugular vein to determine and compare: phagocytic activity (PHAGOTEST) and oxidative metabolism (PHAGOBURST) of peripheral blood granulocytes and monocytes by flow cytometry. An analysis of the phagocytic activity of granulocytes and monocytes revealed significantly higher levels of phagocytic activity (expressed as the percentage of phagocytic cells and mean fluorescence intensity) in lambs administered the multi-strain probiotic formulation than in the control group. The probiotic feed additive also exerted a positive effect on the oxidative metabolism of both granulocytes and monocytes (expressed as the percentage of oxidative metabolism and mean fluorescence intensity) after stimulation with Escherichia coli bacteria and with PMA (4-phorbol-12-β-myristate-13-acetate).

In a previous work by the author it was shown that the Koopman-von Neumann formulation of classical mechanics (KvN) exhibits quantum interference. As such it was there claimed that KvN ought to be considered as a proper quantum mechanical theory in a similar sense as ordinary non-relativistic quantum mechanics (OQM) is. In this article this claim is made manifest by showing that KvN and OQM can be taken as merely inequivalent representations resulting from one and the same quantization scheme. Of course, as the typical notion of quantization necessitates the canonical commutation relations (CCR) to hold, which they do not in KvN, the concept needs to be properly revised. To justify such a revision the typical reasons for necessitation the CCR, reductionism and quantization as 'turning brackets to commutators', are examined and found insufficient.

In this paper, we generalize the problems of finding simple polygons with the minimum area, maximum perimeter and maximum number of vertices so that they contain a given set of points and their angles are bounded by $\alpha+\pi$ where $\alpha$ ($0\leq\alpha\leq \pi$) is a parameter. We also consider the maximum angle of each possible simple polygon crossing a given set of points, and derive an upper bound for the minimum of these angles. The correspondence between the problems of finding simple polygons with the minimum area and maximum number of vertices is investigated from a theoretical perspective. We formulate the three generalized problems as nonlinear programming models, and then present a Genetic Algorithm to solve them. Finally, the computed solutions are evaluated on several datasets and the results are compared with those from the optimal approach.

Besides the Lagrangian and the Eulerian descriptions, the motion of a body can also be expressed relative to the present configuration of the body, known as the relative motion description. It is interesting to consider such a relative motion description in general to formulate the basic system of field equations for solid bodies. In doing so, when the time increment from the present state is small enough, the nonlinear constitutive equations can be linearized relative to the present state so that the resulting system becomes linear. This will be done for thermoelastic materials with a brief comment on the exploitation of entropy principle in general. Relative Lagrangian formulation is based on the well-known ``small-on-large'' idea, and can be implemented for solving problems with large deformation in successive incremental manner. Some applications of such a formulation in numerical simulations are briefly reviewed.

Maize mosaic virus (MMV) is a plant virus that is transmitted by the corn planthopper, Peregrinus maidis Ashmead (Hemiptera: Delphacidae) in a persistent and propagative manner. MMV is the causal agent for mosaic disease that can cause significant loss in corn yield. Management is focused on controlling insect vector population. The molecular mechanisms of virus transmission by the insect vector are not fully understood. Previously, we identified a receptor for MMV, the P. maidis syntaxin 18 (PmStx18). PmStx18 interacts with the viral glycoprotein and potentially facilitates MMV recognition and entry into the vector, enabling virus proliferation. Stx18 is a key component of the vesicular trafficking machinery and also plays a critical role in neurotransmitter release in insects. In this work, we investigated the expression of PmStx18 in different developmental stages and major parts of the insect vector. Primers were designed to generate templates for synthesis of double-stranded RNA fragments. A 374-bp amplicon was selected and gene-specific sequences were flanked by T7 promoter sequences for in vitro transcription. Results showed a significant difference in the expression of Stx18 in the different developmental stages of P. maidis but not between male and female adults and major body parts. In vitro transcription products indicated optimal reaction conditions and protocol suitability. The findings establish the initial steps for developing RNAi-based approach in controlling MMV transmission by targeting Syntaxin-18 in P. maidis. Further investigations are needed to evaluate the efficacy of this approach.

Phytophthora. infestans is a well known late blight causing oomycetes pathogen. It evolves and adapts to the host background and new fungicide molecules rapidly within a few years of their release, may be due to the predominance of transposable elements in its genome. Frequent and huge applications of fungicides cause environmental concerns. Here we developed target specific RNA interference based molecules, that are capable of effectively reducing the late blight infection. cDNA microarray expression data was used for the selection of genes involved in the early stage of infection process, sporulation etc. The in vitro synthesis of double stranded RNA molecule, targeting SDH, EF-1α, GPI-HAM344, PLD-3 and HSP-90 encoding genes revealed the reduction in growth, sporulation and symptom expression, which were subsequently assessed by culture bioassay, detached leaf assay and topical application methods. The multiple genes targeted dsRNA nano clay sprayed plants showed enhanced disease resistance (4% disease severity) and least sporulation (<1x103), compared to naked dsRNA spray. Use of nano clay was assumed to be involved in the effective delivery, protection and boosting the action of RNAi in potato plants. A significant difference in the growth, sporulation count, disease severity and reduced expression of the genes and confocal microscopy imaging authenticates the effects of SIGS on late blight disease progression. Our research demonstrated that topical dsRNA nano clay spray under the open-air environment could be an alternative to chemical fungicides and transgenic approaches as a novel plant protection strategy for late blight in an environmentally friendly manner.

A relativistic positioning system is a set of four emitters broadcasting their proper times by means of light signals. The four emitter times received at an event constitute the emission coordinates of the event. Covariant quantities associated with relativistic positioning systems are analysed relatively to an observer in Minkowski space-time by splitting them in their relative space-like and time-like components. The location of a user in inertial coordinates from a standard set of emission data (emitted times and satellite trajectories) is solved in the underlying 3+1 formalism. The analytical location solution obtained by Kleusberg for the GPS system is recovered and interpreted in a Minkowskian context.

The active form of fingolimod (FTY720; FT) is a sphingosine-1-phosphate receptor agonist with potential ocular applications. The goal of the present study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. FT-NE formulations were prepared with homogenization followed by probe sonication method. The lead FT-NE formulation (0.15% and 0.3% w/v loading), comprising soybean oil as lipid and Tween® 80 and Poloxamer 188 as surfactants, was further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature post-filtration through polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release, compared with the control FT solution (FT-S), over 24 h. The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.

The unexploited unification of general relativity and quantum mechanics (QM) prevents the proper understanding of the micro- and macroscopic world. Here we put forward a mathematical approach that introduces the problem in terms of negative curvature manifolds. We suggest that the oscillatory dynamics described by wave functions might take place on hyperbolic continuous manifolds, standing for the counterpart of QM’s Hilbert spaces. We describe how the tenets of QM, such as the observable A, the autostates ψa and the Schrodinger equation for the temporal evolution of states, might work very well on a Poincaré disk equipped with rotational groups. This curvature-based approach to QM, combined with the noncommutativity formulated in the language of gyrovectors, leads to a mathematical framework that might be useful in the investigation of relativity/QM relationships. Furthermore, we introduce a topological theorem, termed the punctured balloon theorem (PBT), which states that an orientable genus-1 surface cannot encompass disjoint points. PBT suggests that hyperbolic QM manifolds must be of genus ≥ 1 before measuring and genus zero after measuring. We discuss the implications of PBT in gauge theories and in the physics of the black holes.

The combination of nanoemulgel and phytochemistry has resulted in several recent discoveries in the field of the topical delivery systems. The present study aimed to prepare turmeric (Curcuma longa) and neem (Azadirachta indica) based nanoemulgel against microbial infection as topical drug delivery. Olive oil (oil phase), Tween 80 (surfactant), and PEG600 (co-surfactant) were used for the preparation of nanoemulsion. Carbopol 934 was used as gelling agent to convert the nanoemulsion to nanoemulgel and promote to control the release of biological properties of turmeric and neem. The nanoemulsion were characterized based on particle size distribution, PDI values and compatibility using FTIR analysis. In contrast, the nanoemulgel was evaluated based on pH, viscosity, spreadability, plant extract and excipients compatibility or physical state, in-vitro study, ex-vivo mucoadhesive study, antimicrobial properties and stability. The resulting nanoemulsion was homogeneous, stable during the centrifugation process, with the smallest droplets and low PDI values. FTIR analysis also confirmed good compatibility and absence of phase separation between the oil substance, surfactant, co-surfactant with both plant extracts. The improved nanoemulgel also demonstrated a smooth texture, good consistency, pH, desired viscosity, ex-vivo mucoadhesive strength with highest spreadability, and an 18-hour in-vitro drug release study. Additionally, it exhibited better antimicrobial properties against different microbial strain. Stability studies also revealed that the product had good rheological properties and physicochemical state for a period of over 3 months. The present study has affirmed that turmeric and neem based nanoemulgel as a promising alternative for microbial infection particularly associated by microorganisms via topical application.

The recent years various, there huge interest to improve the efficiency of smart electronic and optoelectronic devices via developing emerging materials and printing technologies. However, printing technologies becomes one of the most interesting areas for researcher over a convenient coating method because it not only helps to improve the efficiency of device but also help for rapid, reproducible, and low-cost production which open as a new window for mass production for commercial use. Inkjet printing technology has become the most attractive among various printing technologies due to which it is acceptable in most of scientific and various of industrial applications. This review paper presents an overview of the investigations on formulation of the ink, fabrication, and the applications of conductive polymer via inkjet printing for variety of devices including supercapacitors, sensors, electrochromic devices, and patterning of conductive polymers on flexible substrates. The review covers the different conducting polymer explored for supercapacitors, sensors, electrochromic devices, and patterning of conductive polymers, their ink formulation, inkjet printing process and their keys features. This review also presented future perspectives for inkjet printing technology for advanced electronic, optoelectronic, and other conductive polymer-based devices. We believe this review provides new direction to next generation conductive polymer-based devices for various applications.

The production, processing of agricultural products results in massive generation of waste, which has an environmental impact. In current study on the node of valorisation of the processed waste, orange and banana peel waste are utilized for the production of biscuits. The fortified biscuits were analysed for proximate and sensory analysis. The fibre content of the fortified biscuits increases several folds. From the sensory score the proportion of biscuits with 7.5% and 10% has undesirable quality parameters, whereas up to 5% concentration all the parameters are more desirable. Fortifying biscuits with orange and banana peel powder may be an excellent source of dietary fibre and an enhanced valorisation technique.

Gasca D herbal formulation is an antidiabetic medicine for the management of diabetes mellitus produced exclusively from natural ingredients. The level of some essential elements (Copper, chromium, Cobalt, Iron, Manganese, Nickel and zinc) and toxic (Cadmium, Arsenic, Mercury, and Lead) heavy metals were determined using microwave plasma-atomic emission spectrometry (MP-AES). The aim of this study is to evaluate the levels of essential and toxic heavy metals and also identify bioactive compounds present in Gasca D herbal formulation. The result shows no traces of Lead, Mercury, Zinc, Arsenic and Zinc, Iron was found to have highest concentration 67.16 + 7.5 µg/g and Cadmium lowest concentration 0.4 + 0.03µg/g. GC-MS analysis of Gasca D herbal formulation revealed the presence of 14 biologically active compounds which include N-Formyl-beta-alanine, Paromomycin, 3,4-Altrosan, Benzamide, 1,3,4-Thiadiazol-2-amine, Carbamodithioic acid, Carbonic acid, alpha-D-Glucopyranoside, Ethyl isocyanide, 2-Propanesulfinic acid, Propanamide, 2-Butenenitrile, Dicyclopropyl carbinol, Isoxazolidine, 1,5-Hexadiene 10-Azido-1-decanethiol. Conclusion: The result indicates that the mean levels of toxic metals in Gasca D herbal formulation were below WHO permissible levels. Gasca D herbal formulation also contains various bioactive compounds that can have various medicinal application which can be used for the treatment of various diseases.

The main purpose of our research is the evaluation of the efficacity of solvent polarity on phenolic composition, as well as the antibacterial, and antioxidant activities of extract of Moroccan Mentha aquatica L., leaves. To attempt these objectives, the HPLC-DAD was used to identify the biomolecules. The total amount of phenolic and flavonoid content was determined using the Folin-Ciocalteu and aluminum trichloride processes as well as the DPPH, RP, and TAC tests were used to evaluate the antioxidant capabilities. In addition, by employing both in vitro and in silico analysis through the microdilution method, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extracts were assessed against multidrug-resistant bacteria. Furthermore, the High-Performance Liquid Chromatography (HPLC) analysis indicated that all extracts of M. aquatica were abundant in noteworthy phytochemical compounds, especially gallic acid, vanillic acid, chlorobenzoic acid, quercetin, and kaempferol. Furthermore, the results indicated that the total phenolic content was higher in hydroethanolic extract (62.19 ± 1.19 mg GAE/g DW) in contrast to the acetonic and aqueous extracts (22.22 ± 0.64, and 22.44± 0.57 mg GAE/g DW) respectively. Similarly, the aqueous ethanol extract contained the greatest flavonoid concentration, with values of 29.15± 0.09 mg QE/g DW when compared with the other extracts. The seam extract poses excellent antioxidant power with an IC50 of 0.06 ± 0.00 mg/mL for the DPPH test, and lower RP with EC50 of 80± 0.00 µg/ml when compared with acetonic and aqueous extract (370± 0.00 and 460± 0.01 µg/mL) respectively. Moreover, the hydroethanolic extract has a high level of TAC 75.09± 2.00 mg EAA/g DW, followed by aqueous extract carrying a value of 28.53 ± 1.36 mg EAA/g DW. The antibacterial capacity is ranged between 0.78 ± 0.05 mg/mL and 12.60 ± 0.00 mg/L. The results of the in-silico study demonstrated that quercetin, vanillic acid, and naringenin components contribute to the antioxidant capability. While gallic acid, kaempferol, and quercetin components are attributed to the antibacterial capacity.

Autonomous search is an ongoing cycle of sensing, statistical estimation and motion control with objective to find and localise targets in a designated search area. Traditionally, the theoretical framework for autonomous search combines the sequential Bayesian estimation with the information theoretic motion control. This paper formulates autonomous search in the framework of possibility theory. Although the possibilistic formulation is slightly more involved than the traditional, it provides means for quantitative modelling and reasoning in the presence of epistemic uncertainty. This feature is demonstrated in the paper in the context of partially known probability of detection, expressed as an interval value. The paper presents an elegant Bayes-like solution to sequential estimation, with the reward function for motion control defined to take into account the epistemic uncertainty. The advantages of the proposed search algorithm are demonstrated by numerical simulations.

This article proposes a novel formulation of quantization, which considers the Koopman-von Neumann formulation (KvN) and ordinary non-relativistic quantum mechanics (OQM) as unitarily inequivalent representations of the same underlying structure. The approach is grounded in the notion that contextuality, rather than occurrence if Plank's constant, is the fundamental aspect of quantum mechanics. The motivation for this novel view arises from the limitations of traditional approaches to quantization, combined with previous research demonstrating contextuality in KvN. Using a representation-theoretic approach, both KvN and OQM are regarded as valid quantum theories, separated by a superselection rule.

The allocation for the use of Deconcentration Funds focuses on the seven priority health programs listed in the Regulation of the Minister of Health for the Republic of Indonesia. Therefore, this study aims to formulate a budget allocation for deconcentration funds in the health sector. Secondary data were analyzed using reports from the Ministry of Health for five years (2014-2018) on the Human Development Index (HDI), population, area, number of health workers, as well as amount and percentage for the realization of deconcentration funds. The results showed that the variables which had a significant effect were the number of districts/cities, the area, and HDI, while those without a significant effect were population, the number of health workers, and the percentage of budget realization. Political factors and regional commitment to implementing as well as using the budget were shown to also affect the deconcentration of funds both from the central and regional sources. Generally, deconcentration funds are used for non-physical tasks, including coordinating and synchronizing planning, facilitation, technical guidance, training, outreach, supervision, investigations and surveys, direction, and control. Based on the results, the budget allocation for deconcentration funds for health development needs to be calculated according to regional capacities by considering the number of districts/cities, land area, and the HDI.

Formulation is an ancient concept, although the word has been used only recently. The first formulations made our civilization advance by inventing bronze, steel, and gunpowder; then, it was used in medieval alchemy. When chemistry became a science and with the golden age of organic synthesis, the second formulation period began. This made it possible to create new chemical species and new combinations “à la carte.” However, the research and developments were still carried out by trial and error. Finally, the third period of formulation history began after World War II, when the properties of a system were associated with its ingredients and the way they were assembled or combined. Therefore, the formulation and the systems’ phenomenology were related to the generation of some synergy to obtain a commercial product. Winsor’s formulation studies in the 1950s were enlightening for academy and industries that were studying empirically surfactant-oil-water (SOW) systems. One of its key characteristics was how the interfacial interaction of the adsorbed surfactant with oil and water phases could be equal by varying the physicochemical formulation of the system. Then, Hansen’s solubility parameter in the 1960s helped to reach a further understanding of the affinity of some substances to make them suitable to oil and water phases. In the 1970s, researchers such as Shinoda and Kunieda, and different groups working in Enhanced Oil Recovery (EOR), among them Schechter and Wade’s group at the University of Texas, made formulation become a science by using semiquantitative correlations to attain specific characteristics in a system (e.g., low oil-water interfacial tension, formulation of a stable O/W or W/O emulsion, or high-performance solubilization in a bicontinuous microemulsion system at the so-called optimum formulation). Nowadays, over 40 years of studies with the hydrophilic-lipophilic deviation equation (HLD) have made it feasible for formulators to improve products in many different applications using surfactants to attain a target system using HLD in its original or its normalized form, i.e., HLDN. Thus, it can be said that there is still current progress being made towards an interdisciplinary applied science with numerical guidelines. In the present work, the state-of-the-art of formulation in multiphase systems containing two immiscible phases like oil and water, and therefore systems with heterogeneous or micro-heterogeneous interfaces, is discussed. Surfactants, from simple to complex or polymeric, are generally present in such systems to solve a wide variety of problems in many areas. Some significant cases are presented here as examples dealing with petroleum, foods, pharmaceutics, cosmetics, detergency, and other products occurring as dispersions, emulsions, or foams, that we find in our everyday lives.

In this paper, a local meshless method (LMM) based on radial basis functions (RBFs) is utilized for the numerical solution of various types of PDEs, due to the flexibility with respect to geometry and high order of convergence rate. In case of global meshless methods, the two major deficiencies are the computational cost and the optimum value of shape parameter. Therefore, research is currently focus towards localized radial basis function approximations, as the local meshless method is proposed here. The local meshless procedures is used for spatial discretization whereas for temporal discretization different time integrators are employed. The proposed local meshless method is testified in terms of efficiency, accuracy and ease of implementation using regular and irregular domains.

We present a generalized state-space model formulation particularly motivated by an online scheduling perspective. Through these proposed generalizations, we enable a natural way to handle routinely encountered disturbances and a rich set of corresponding counter-decisions. Thereby, greatly simplifying and extending the possible application of mathematical programming based online scheduling solutions to diverse application settings.

The study was conducted to prepare juice blend by using Orange, Carrot and Tiger-nut juices. Fully mature raw Orange, Tiger-nut and Carrot were processed into juice forms and combined in different ratios which were analyzed for their composition and Consumer’s acceptability. The analysis showed that the juice with higher Orange juice content had higher levels of acidity. This implies that they would last longer as they are not susceptible to spoilage by most organisms. The Juice with higher orange juice content was also found to be very rich in Vitamin C, due to inherent high amount of Vitamin C in raw Orange Fruit. However, it scored lowest in terms of general acceptability because the raw fruit was purchased separately and there’s a likelihood some of the Orange used in the Juice preparation were sour. This led to a sour taste in this Juice blend. The Juice blend that contained equal proportions of all three juices was the most acceptable to the consumers in terms of color, taste and Nutritional composition. It gave equal amounts of the unique properties of each fruit and provided a unique color and taste that was very appealing to the panelists. This product makes it possible to properly utilize these fruits, reduce post harvest losses, cater to different health needs of the consumers and ensure food security. It is recommended that further work should be done on antioxidant properties, other fruit blends and storage stability of the beverage to determine the shelf-life.

Starting from the analysis of the lack of positivity of the Cattaneo heat equation, the article addresses the thermodynamic relevance of the positivity constraint in irreversible thermodynamics, than is at least as important as the entropic constraints. The fulfillment of this condition in hyperbolic models leads to the parametrization of the concentration fields with respect to internal variables associated with the microscopic dynamics. Using Brownian motion theory as a landmarking example for deriving macroscopic transport equations from the equations of motion at the particle/molecular level, we discuss two typical problems involving hydrodynamic interactions at microscale: surface chemical reactions at a solid interface of a diffusing reactant, and mass-balance equations in a complex viscoelastic fluid, in which the physics of the interaction leads either to the overcome the parabolic diffusion model or to consider the parametrization of the concentration with respect to the degrees of freedom associated with the relaxation dynamics of the solvent fluid.

Epoxy matrix composites reinforced with high-performance fibers such as carbon, Kevlar, and glass, exhibit excellent specific stiffness and strength in many mechanical applications. However, these composites are disappointingly non-recyclable and are usually disposed of in landfill sites, with no realistic prospect for biodegradation in reasonable time. In contrast, moldable composites with carbonized elastomeric matrices developed in the last decades possess attractive mechanical properties in final net-shape products and can also be incinerated or recycled. Many carbon and inorganic fillers have recently been evaluated to adjust the properties of carbonized elastomeric composites. Renewable organic fillers such as human or animal hair offer an attractive fibrous material with substantial potential for reinforcing composites with elastomeric matrices. Samples of unidirectional fiber composites (with hair volume fraction up to 7 %) and quasi-isotropic short fiber composites (with hair volume fraction up to 20 %) of human hair-reinforced nitrile butadiene rubbers (HH-NBR) were produced in the peroxide-cured and carbonized states. The samples were characterized using SEM, Raman spectroscopy and photoacoustic microscopy. Mechanical tests were performed in tension using a miniature universal testing machine. The expected effect of fiber reinforcement on the overall mechanical performance has been demonstrated for both cured and carbonized composites. Considerable enhancement of the elastic modulus (up to 10 times), ultimate tensile strength (up to 3 times) and damage tolerance was achieved. The evidence of satisfactory interfacial bonding between hair and rubber was confirmed by SEM imaging of fracture surfaces. The suitability of photoacoustic microscopy was assessed for 3D reconstruction of the fiber sub-system spatial distribution and non-destructive testing.

Ellagic acid, a polyphenolic compound present in fruits and berries, has recently been object of extensive research for its antioxidant activity, which might be useful for the prevention and treatment of cancer, cardiovascular pathologies, and neurodegenerative disorders. Its protective role justifies numerous attempts to include it in functional food preparations and in dietary supplements not only to limit the unpleasant collateral effects of chemotherapy. However, ellagic acid use as chemopreventive agent has been debated because of its poor bioavailability associated to low solubility, limited permeability, first pass effect, and interindividual variability in gut microbial transformations. To overcome these drawbacks, various strategies for oral administration including solid dispersions, micro-nanoparticles, inclusion complexes, self-emulsifying systems, polymorphs have been proposed. Here, we have listed an updated description of pursued micro/nanotechnological approaches focusing on the fabrication processes and the features of the obtained products, as well as on the positive results yielded by in vitro and in vivo studies in comparison to the raw material. The micro/nano-sized formulations here described might be exploited for pharmaceutical delivery of this active, as well as for the production of nutritional supplements or for the enrichment of novel foods.

This paper proposed an explicit and simple representation of velocity fluctuation and the Reynolds stress tensor in terms of the mean velocity field. The proposed turbulence equations are closed. The proposed formulations reveal that the mean vorticity is the key source of producing turbulence. It is found that there are no velocity fluctuation and turbulence if there were no vorticity. As a natural consequence, the laminar- turbulence transition condition was obtained in a rational way.

The focus of this paper is on supply chain strategy formulation. A conceptual theory approach is used for investigating and identifying the relationship between multiple elements, dimensions, forces and factors that influence and affect the supply chain strategy formulation in Greenfield context, specific to the slate mining industry. The research study involved secondary data review and series of 20 qualitative interviews, followed by 2 group discussions, one with mining and transportation experts external to the supply chain and one group discussion with supply chain internal experts. Through critical analysis, a number of problems emerge and the process of addressing these problems, results in a new framework for evaluating the relationship between business and supply chain strategy, specific to Greenfield project and integration design context.

Despite multiple classical outcomes arising from the quantum Rayleigh conversions of photons underlying the propagation of optical waves through dielectric media and the ensuing light-matter interactions, this quantum process has been largely ignored. Several of its outcomes are considered in this article from a physical perspective, e.g., inter-quadrature coupling of photons, phase-dependent amplification in optical directional couplers and related polarization rotation, phase-shifting of weak signals in the optically linear regime, location-dependent coupling coefficient for refractive index gratings, etc. A correct identification of these effects will enable useful design and operation of integrated photonic functional devices.

We discuss the optimal control formulation for enhancement and denoising of satellite multiband images and propose to take it in the form of an L1-control problem for quasi-linear parabolic equation with non-local p[u]-Laplacian and with a cost functional of a tracking type. The main characteristic feature of the considered class of parabolic problems is the fact that the variable exponent p(t,x) and the anisotropic diffusion tensor D(t,x) are not well predefined a priori, but instead these characteristic non-locally depend on a solution of this problem, i.e., pu=p(t,x,u) and Du=D(t,x,u). We prove the existence of optimal pairs with sparse L1-controls using for that the indirect approach and a special family of approximation problems.

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg PE, DSPC, cholesterol, and DSPE-PEG-2000, and the mean size of the RTL was in the range of 114 to 133 nm, as measured by NTA. The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three i.v. injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.

The objective of this work was to determine the antimicrobial properties of an allium-based antimicrobial formulation named VEG’LYS (https://phytoauxilium.com/) on the growth of plant pathogenic microorganisms such as fungi, oomycetes, and bacteria. Two anthracnose-related species of the fungal genus Colletotrichum, C. gloeosporioides, and C. fragariae, the oomycete Phytophthora cactorum and the bacterium Xanthomonas fragariae associated with strawberry plants and two fungi Alternaria dauci and Botrytis cinerea, associated with carrot plants were tested in vitro. In in planta experiments, A. dauci and B. cinerea were used.. VEG’LYS inhibited the growth of all plant pathogens tested. We found that both curative and preventive in planta treatments with VEG’LYS inhibited the growth of A. dauci and B. cinerea in carrot. Furthermore, after spraying VEG’LYS on carrot plants the expression of the Pathogenesis-related (PR) 10 gene correlated with the magnitude of infection both in treated and untreated plants. Additionally, it has been shown, that the field application of VEG’LYS on strawberry plants results in a reduction of bacterial and fungal pathogens of strawberry fruits stored in refrigerator. In summary, VEG’LYS is a potential resistance inducer that seems to be suitable for use in both curative and preventive treatments to reduce the diseases and rotting of fruits and vegetables caused by different plant pathogens.

This paper gives a new unified formula for the Newtonian fluids valid for all pipe flow regimes from laminar to the fully rough turbulent. It includes laminar, unstable sharp jump from laminar to turbulent, and all types of the turbulent regimes: smooth turbulent regime, partial non-fully developed turbulent and fully developed rough turbulent regime. The formula follows the inflectional form of curves as suggested in Nikuradse’s experiment rather than monotonic shape proposed by Colebrook and White. The composition of the proposed unified formula consists of switching functions and of the interchangeable formulas for laminar, smooth turbulent and fully rough turbulent flow. The proposed switching functions provide a smooth and a computationally cheap transition among hydraulic regimes. Thus, the here presented formulation represents a coherent hydraulic model suitable for engineering use. The model is compared to existing literature models, and shows smooth and computationally cheap transitions among hydraulic regimes.

The aim of this study was to synthesize and optimize polylactide-co-glycolide (PLGA) nanoparticles loaded with rifampicin (RIF), with a given size and high loading rate, using the central composite design (CCD) method. CCD was used to investigate the influence of independent factors such as PLGA:RIF ratio, type of PLGA, type and concentration of surfactants, power and duration of homogenization, and type of organic solvent and its ratio to the aqueous phase on the dependent physicochemical characteristics of the nanoparticles. The optimized nanoparticles were investigated using scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Comparative evaluation of the drug release kinetics was carried out using different pH and different setups: flow cuvette (USP 4 apparatus) and Franz diffusion cuvette. In addition, the mucoadhesive properties and mycobacterial activity of PLGA-RIF NPs were studied.

Red mud (RM), a bauxite residue, contains hazardous radioactive wastes and alkaline material and poses severe surface water and groundwater contamination risks, necessitating recycling. Pretreated RM can be used to make adsorbents for water treatment. However, its performance is affected by many factors, resulting in a nonlinear correlation and coupling relationship. This study aimed to identify the best formula for an RM adsorbent using a mathematical model that examines the relationship between 11 formulation types (e.g., pore-assisting agent, component modifier, and external binder) and nine properties (e.g., specific surface area, wetting angle, and Zeta potential, among others). This model was built using a back-propagation neural networks(BP) based on single-factor experimental data and orthogonal test data. The model trained and predicted the established network structure to obtain the optimal adsorbent formula. The RM particle adsorbents had a pH of 10.16, specific surface area(BET) of 48.92 m2·g−1, pore volume of 2.10 cm3·g−1, compressive strength(ST)) of 1.12 KPa, and 24-h immersion pulverization rate(η_m) of 3.72%. In the removal of total phosphorus in flotation tailings backwater, it exhibited a good adsorption capacity (Q)and total phosphorous removal rate(η) of 48.63 mg·g−1 and 95.13%, respectively.

Background: Sungkai plant (Peronema canescens Jack.) is one of the medicinal plants widely grown in Indonesia. In recent years, Sungkai (Peronema canescens Jack) leaves have sparked particular interest for their health benefits. In this study, microencapsulation was conducted on an ethanol extract of Sungkai leaves (Peronema canescens Jack.) using three types of coating materials (maltodextrin, inulin, and Arabic gum) at various concentrations. Objectives: to determine the best microencapsulation formulation using maltodextrin, inulin, and Arabic gum at various concentrations.  Methods: Microencapsulation was performed using the extrusion method. Characterization of the best microencapsulant was done by measuring physico-chemical, morphological, and IR properties, and antioxidant activity testing was done using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Results: Microencapsulant A1 has better physico-chemical properties compared to other microencapsulant samples. The results of the morphological analysis of sample A1 using SEM showed a smooth surface with a slightly round shape, as well as minimal wall folds and cracks, indicating that the product has good stability. The results of the functional group analysis of sample A1 using FTIR also showed that the ethanol extract of Sungkai leaves was well encapsulated. Conclusions: The best formulation to make microencapsulant of ethanol extract of Sungkai leaves is formulation A1 using Arabic gum dressing material.

Utilization of medicine derived from plants has been documented in various traditional systems of medicines throughout the world for different diseases. Therefore, the current research work was carried out to evaluate the phytochemical and biological potential of Ficus carica L ethanolic leaf extract. For this purpose, physicochemical and phytochemical analysis, total phenolic and flavonoids contents was performed. Antioxidant potential was determined by FRAP, DPPH and H2O2 assay. Proteinase inhibition, heat induced hemolysis and BSA denaturation assay was carried out for inflammation. Antiglycation potential was assessed by fructosamine assay, Congo-red assay and estimation of free carbonyl groups. In-vivo antidiabetic, anti-obesity, effect on liver and kidney were investigated by high fat high sugar diet model. FTIR, HPLC and LCMS/MS analysis was performed to find out the compounds. Tablet based formulation was developed using wet granulation method and tested for physicochemical parameters. Results shows that total phenolic and flavonoids content was (333 mg GAE/g) and (123 mg RE/g) respectively, H2O2 assay shows 35.6% free radical inhibition potential, DPPH assay shows (IC50) inhibitory concentration at 0.58 mg/mL, and 88.769 µg/g Fe2SO4 solution FRAP values. Proteinase inhibition assay, Heat induced hemolysis and BSA-denaturation assay shows percentage inhibition of 28 ± 0.01, 55 ± 0.03 and 51.2 ± 0.05 respectively. In Antiglycation activity β-amyloid formation assay shows absorption of 0.017, Fructosamine assay shows inhibition of 19.4±0.06 and free carbonyl group estimation shows inhibition of 17.0±0.03. In in-vivo study FLE at (500 mg/kg) significantly decreased total bilirubin (p ≤ 0.001), decreased (p ≤ 0.05) alanine transferase, aspartate aminotransferase, alkaline phosphatase, decreased blood glucose, triglycerides and total cholesterol (p ≤ 0.01) while HDL (p ≤ 0.01) was significantly increased in comparison to obesity and diabetic-obesity groups. Different functional groups presence was confirmed by FTIR spectrum. HPLC analysis revealed the existence of ferulic acid, rutin, chlorogenic acid, coumarin and thymoquinone and these results are corelated by LC-MS/MS. Pre-compression characterization showed angle of repose (33.04°), bulk density (0.54 g/cm3), tapped density (0.73 g/cm3), compressibility index (35.179 %) and Hausner’s ratio (1.35), while the post-compression characterization showed weight variation 826±4.17 mg, thickness 10.50±0.25 kg/cm2, friability 0.57 %, and disintegration time 8.19 min. From the above results it is concluded that F. carica L. leaves extract has strong antioxidant, antidiabetic and hypolipidemic potential and can be used for an obesity and diabetes treatment.

In this paper a new monolithic Eulerian formulation in the framework of non-classical continuum is presented for the analysis of fluid-strucutre interaction problems. In this respect, Cosserat continuum theory taking into account the micro-rotational degrees of freedom of the particles is considered. Continuum description of the model and variational formulation of the governing flow dynamics for non-classical -fluid-structure interaction nCFSI is presented. The model is analyzed by computing a well known benchmark problem by Hecht and Pironneau [16]. The algorithmic description is presented and implemented using FreeFEM++. Code is validated with the benchmark solution of Turek and Hron [38] in case of flow around a flag attached with cylinder. New microstructral behavior of the solution is studied and numerical simulations and results are shown in the form of figures. Some interesting feature of the flow is observed and microstructural characteristics are discussed.

Background: The cumulative exposure of UV radiation can result in dangerous consequences such as skin burns, photoaging, and skin cancer, hence the importance of using photoprotective formulations. Currently, the formulations seek to be more efficient, innovative and reach a wider audience. Many sunscreens are vegan, and have antioxidant substances to ensure additional photochemoprotective action. To evaluate biological, functional, and mechanical characteristics of them on the skin, biometric and rheologic methods can be used. Objective: Evaluate biophysical, rheological and sensorial parameters of Face Care Facial Moisturizing Cream® (P1) and a vegan formulation (P2) by in vitro and in vivo tests. Methods: A UV scan experiment was performed covering the range of 250 to 400 nm. Sun Protection Factor (SPF) was evaluated by Mansur method. Rheological profiles were obtained using a MARS II (Haake®) controlled shear stress and gradient rheometer. Biophysical parameters were analyzed: skin sebum content, hydration level, transepidermal water loss, erythema and melanin level, skin color, and skin pH. The acceptance profile of the formulations by the volunteers was determined using a 9-point hedonic scale and a 5-point purchase intention test. Results: The formulations effectively absorbed light covering the UV radiation spectrum from UVA to UVB. The SPF of P1 was 25.21 and of P2 was 12.10 by in vitro tests. They had also pseudoplastic and thixotropic behavior, it can contribute to better spreadability and to form a protective film. Biometric tests showed an increase in hydration and skin sebum, decreased erythema, and maintenance of skin pH after application of both formulations. The products also had similarly good acceptance and purchase intention by the volunteers. Conclusion: The comparation of a commercialized product and a vegan test version showed very similar rheological and great acceptance profiles. Therefore, the vegan formulation is a good alternative to reach a different market.

This paper inquires on the options pricing modeling using Artificial Neural Networks to price Apple(AAPL) European Call Options. Our model is based on the premise that Artificial Neural Networks can be used as functional approximators and can be used as an alternative to the numerical methods to some extent, for a faster and an efficient solution. This paper provides a neural network solution for two financial models, the BlackScholes-Merton model, and the calibrated-Heston Stochastic Volatility Model, we evaluate our predictions using the existing numerical solutions for the same, the analytic solution for the Black-Scholes equation, COS-Model for Heston’s Stochastic Volatility Model and Standard Heston-Quasi analytic formula. The aim of this study is to find a viable time-efficient alternative to existing quantitative models for option pricing.

High-frequency neuroelectric signals like electroencephalography (EEG) or magnetoencephalography (MEG) provide a unique opportunity to infer causal relationships between local activity of brain areas. While causal inference is commonly performed through Classical Granger causality (GC) based on multivariate autoregressive models, this method may encounter important limitations (e.g. data paucity) in the case of high dimensional data from densely connected systems like the brain. Additionally, physiological signals often present long-range dependencies which commonly require high autoregressive model orders / number of parameters. We present a generalization of autoregressive models for GC estimation based on Wiener-Volterra decompositions with Laguerre polynomials as basis functions. In this basis, the introduction of only one additional global parameter allows to capture arbitrary long dependencies without increasing model order, hence retaining model simplicity, linearity and ease of parameters estimation. We validate our method in synthetic data generated from families of complex, densely connected networks and demonstrate superior performance as compared to classical GC. Additionally, we apply our framework to studying the directed human brain connectome through MEG data from 89 subjects drawn from the Human Connectome Project (HCP) database, showing that it is able to reproduce current knowledge as well as to uncover previously unknown directed influences between cortical and limbic brain regions.

Background: Patients with burn scars often suffer from a ‘vicious cycle’ in which their skin becomes dry and pruritus. This greatly reduces patients' quality of life, but there is no well-known mechanism yet, and the development of drugs for effective treatment is necessary. Objective: This study evaluated the efficacy and safety of cosmetic formulation containing arginine glutamate ion pair (named as RE:pair) on epidermal barrier function and reducing pruritus. Materials and Methods: A total of 20 patients [15 male and 5 female; average age 48.35 ± 13.13 years] participated in evaluating the effectiveness of using the RE:pair formula topically twice daily for up to 4 weeks after burn pruritus. Treatment efficacy was evaluated by Numerical Rating Scale (NRS) for itching and pain, transepidermal water loss (TEWL), skin hydration, Vancouver Scar Scale (VSS) evaluation, and the patient’s overall satisfaction. Results: This formula was well-tolerated, with significant relief of NRS for itching and pain score after 2nd weeks and 4th weeks of application (p &lt; 0.05). The itching score was high in some patients, and overall, it decreased significantly after 4 weeks compared to before application. Also, the personal pain score decreased after 4th weeks. Overall TEWL showed 35 % improvement after 4th week, and 52 % improvement was confirmed in arms and 19 % in legs. The overall improvement effect of skin hydration was also 45 % (p = 0.0012), and the improvement effect was 40 % (p = 0.0371) in areas including arms and 54 % (p = 0.0313) in areas including legs. All patient satisfactory evaluations were "excellent". Conclusions: RE:pair formula was safe and effective in improving skin barrier and itch relief, and if further studies are conducted, it can be used as an excellent topical treatment for post-burn scar that strengthens the skin barrier.

A large body of evidence, replicated in many mouse models of Alzheimer Disease (AD), demonstrated the therapeutic efficacy of oral rapamycin. Administration of m-TOR inhibitors (mTOR-Is), early after the clinical onset, greatly diminished cognitive impairment, amyloid angiopathy, intracellular beta Amyloid and neurofibrillary tangles load. The daily intake of rapamycin has always been 2.24g/Kg/24h. In humans the maximal tolerated oral dose is a few milligrams/day, and at this dosage patients are severely immunosuppressed. Thanks to rapalogs’ scarce CNS-related side effects, we administered intracerebroventricularly (ICV) high doses of the mTOR-I everolimus in a mouse model of AD (3xTg-AD) without significant systemic effects. The instability of the liquid formulation at body temperature (BT) made the treatment very short. Nevertheless, the efficacy of the treatment was high and much longer lasting than expected. In order to set up a thermostable, translational liquid formulation of mTOR-Is, we loaded everolimus in distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) micelles by the thin layer method. The formulation we obtained maintained over 95% of activity after 14 days at BT. We can envision short, potentially periodic ICV treatments in AD patients which replicate results obtained on animal models. The treatment could benefit also Tuberous Sclerosis and Multiple Sclerosis patients.

This article develops a duality principle and a related convex dual formulation suitable for a large class of models in physics and engineering. The results are based on standard tools of functional analysis, calculus of variations and duality theory. In particular, we develop applications to a model in non-linear elasticity.

The photoreduction of CO2 is an intriguing process, which allows the synthesis of fuels and chemicals. One of the limitations for CO2 photoreduction in the liquid phase is its low solubility in water. This point has been here addressed by designing a fully innovative concept of pressurized photoreactor, allowing operation up to 20 bar and applied to improve the productivity of this very challenging process. The photoreduction of CO2 in the liquid phase was performed using commercial TiO2 (Evonink P25), TiO2 obtained by flame spray pyrolysis (FSP) and gold doped P25 (0.2 wt% Au-P25) in the presence of Na2SO3 as hole scavenger (HS). The different reaction parameters (catalyst concentration, pH and amount of HS) have been addressed. The products in liquid phase were formic acid and formaldehyde. Moreover, for longer reaction time and with total consumption of HS, gas phase products formed (H2 and CO) after accumulation of significant amount of organic compounds in the liquid phase, due to their consecutive photoreforming. Enhanced CO2 solubility in water was achieved by adding a base (pH= 12-14). In basic environment, CO2 formed carbonates which further reduced to formaldehyde and formic acid and consequently formed CO/CO2+H2 in the gas phase through photoreforming. The deposition of small Au nanoparticles (3-5 nm) (NPs) onto TiO2 was found to quantitatively influence the products distribution and increase the selectivity towards gas phase products.

The use of metal oxide nanoparticles as an alternative antimicrobial agent has gained attention due to the increasing problem of antibiotic resistance. Understanding its properties and potential benefits can contribute to the development of more effective and sustainable treatments in veterinary medicine. The aim of this study was to characterize TiO2-NP formulations and evaluate their antibacterial and wound healing abilities. The diameters and zeta potentials were determined using the Zetasizer in conjunction with dynamic light scattering. The agar-well diffusion method, time-kill kinetic assay and crystal violet assay were used to evaluate their antimicrobial activities. Wound healing assays were conducted both in-vitro and in-vivo. The study demonstrated that TiO2-NP formulations exhibit significant antimicrobial properties against various bacterial strains such as S. aureus and E. coli. No measurable E. coli growth was observed within a 15-mins period following exposure to TiO2-NP formulations. The TiO2-NP formation can improve wound healing by enhancing cell migration and collagen formation in both in-vitro and in-vivo conditions. In summary, our study suggests that TiO2-NP has the potential for use as an antimicrobial agent for animal wound treatment due to its ability to suppress bacterial growth and biofilm formation, as well as to enhance wound healing.

The occurrence of bone-related disorders and diseases has increased dramatically in recent years around the world. Demineralized bone matrix (DBM) has been widely used as a bone implant due to its osteoinduction and bioactivity. However, the use of DBM is limited because it is a particulate material, which makes it difficult to manipulate and implant with precision, in addition, these particles are susceptible to migrate to other sites. To address this situation, DBM is commonly incorporated into a variety of carriers. An injectable scaffold has advantages over bone grafts or preformed scaffolds, such as the ability to flow and fill the bone defect. The aim of this research is to develop a DBM carrier with such viscoelastic properties to obtain an injectable bone substitute (IBS). The DBM carrier developed consisted of a PVA/glycerol network cross-linked with borax and reinforced with CaCO3 as a pH neutralizer, porosity generator, and source of Ca. The physicochemical properties were determined by the injectability test, FTIR, SEM, and TGA. Porosity, degradation, bioactivity, possible cytotoxic effect, and proliferation in osteoblasts were also determined. The results show that the developed material has great potential to be used in bone tissue regeneration

In this paper, we introduce a compressible formulation for dealing with 2D/3D compressible interfacial flows. The formulation is combined with an original monolithic solver, according to which a strong velocity-pressure coupling is achieved. The results show that the scheme can ensure accuracy and stability for various fluid flow scenarios: from the standard incompressible conditions to compressible flows, spanning both single-phase and two-phase flows.

Ocular pathologies present significant challenges in achieving effective therapeutic re-sults due to various anatomical and physiological barriers. Natural products, such as flavonoids, alone or in association with allopathic drugs, present many therapeutical actions, including anti-cancer, anti-inflammatory, and antibacterial action. However, their clinical employment is chal-lenging for scientists due to their low water solubility. In this study, we designed a liquid formu-lation based on rutin/sulfobutylether-β-cyclodextrin (RTN/SBE-β-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were de-termined by employing the SupraFit software on the Uv-vis titration experiment. A deep physical-chemical characterization of the RTN/SBE-β-CD inclusion complex was also performed; it con-firmed the predominant formation of a stable complex (Kc, 9660 M−1) in a 1:1 molar ratio, with high water solubility of 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), per-mitting the dissolution of the solid complex within 30 min. NMR studies revealed the involve-ment of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecu-lar modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains demonstrating a sig-nificant activity of the formulation to the free components.

High Vacuum Flat Plate Collectors (HVFPCs) are the only type of Flat Plate Thermal Collectors capable of producing thermal energy for middle-temperature applications (until 180 °C). As the trend of research plans to develop new Selective Solar Absorbers to extend the range of HVFPC application until 250 °C, it is necessary to correctly evaluate the collector efficiency up to such temperature to predict the energy production accurately. We propose an efficiency model for these collectors based on the selective absorber optical properties. The proposed efficiency model explicitly includes the radiative heat exchange with the ambient, which is the main source of thermal losses for evacuated collectors at high temperatures. It also decouples the radiative losses that depend on the optical properties of the absorber adopted from the other thermal losses due to HVFPC architecture. The model has been validated by applying it to MT-Power HVFPC manufactured by TVP-Solar, and it has been used to predict the efficiency and energy production of HVFPC equipped with new, optimized selective solar absorbers developed in recent years.

Glyphosate (G)-based herbicidal formulations, such as the most commonly used one, Roundup (R), are major pesticides used worldwide on food and feed. Pregnant women may thus be frequently exposed to R compounds. These are composed of G, which is declared as the active principle, and other products contained in formulations, named formulants, which have been declared as inerts and diluents by the manufacturers. These formulants have, in fact, been demonstrated to be much more toxic than G, in particular to placental and embryonic human cells. In this work, we thus compared the effect of G and R, using placental perfusion ex vivo. R, but not G alone, was demonstrated to alter the placental permeability of a known small model molecule, antipyrine. Similar results were observed for the fetal venous flow rate. The transfer of G alone increases with time, but is significantly decreased in presence of its formulants. The perfusion of R provokes a destruction of fetal vessels, as demonstrated by immunohistochemistry. Formulants obviously alter the fetal-placental circulation and placental integrity according to time of exposure. Therefore, G does not appear to be the main toxic agent of R. Formulants, although undeclared, include polyoxyethanolamines, PAHs, or heavy metals, and may be responsible for this toxicity. These compounds are also present in other pesticides. The progressive blood flow reduction due to the toxic compounds of formulations may diminish the nutrient supply to the fetus, alter the development, and may enhance the poisoning effects. Although these are preliminary results, they could at least partially explain some adverse pregnancy outcomes in mothers exposed to pesticides or other environmental pollutants. The debate on glyphosate alone is proven insufficient for the understanding of the toxicity.

We introduce the Concept-Model-Graph-View Cycle (CMGVC). The CMGVC facilitates coherent architecture analysis, reasoning, insight, and decision-making based on conceptual models that are transformed into a generic, robust graph data structure (GDS). The GDS is then transformed into multiple views of the model, which inform stakeholders in various ways. This GDS-based approach decouples the view from the model and constitutes a powerful enhancement of model-based systems engineering (MBSE). The CMGVC applies the rigorous foundations of Category Theory, a mathematical framework of representations and transformations. We show that modeling languages are categories, drawing an analogy to programming languages. The CMGVC architecture is superior to direct transformations and language-coupled common representations. We demonstrate the CMGVC to transform a conceptual system architecture model built with the Object Process Modeling Language (OPM) into dual graphs and a stakeholder-informing matrix that stimulates system architecture insight.

Atopic dermatitis (AD) is a chronic cutaneous inflammatory disorder, characterized by skin barrier disruption. Dermacare is a new cosmetic formulation which enhances moisturization, reinforces and repairs the skin barrier and prevents cutaneous microbiota imbalance. To demonstrate its safety and efficacy a prospective, open-label and multicenter study was carried out on patients diagnosed with mild to moderate AD. Transepidermal water loss (TEWL), clinical severity, Desquamation Index, Patient/Investigator Global Assessments, quality of life index and tolerance were assessed. Adverse events were recorded. Daily application of the new treatment was well tolerated, and adverse events were absent. After 14 days, TEWL showed a 36.7% significant decrease (p = 0.035). At the end of the 28-day Dermacare treatment, the Desquamation Index showed a reduction in 70% of patients; Eczema Area and Severity Index were reduced by 70.4% (p = 0.002); and skin irritation showed a significant reduction (p = 0.024). Likewise, Patient and Investigator Global Assessments reported a significant improvement in conditions and an overall global worsening when patients restarted their normal treatment. Parent’s Index of Quality of Life Index significantly increased by 36.4% (p < 0.05) with Dermacare. In conclusion, Dermacare’s regular use helped reduce the risk of relapse and extend the steroid-free treatment periods.

Linear state estimation (SE) formulation under a rectangular coordinate system has been proved to be applicable for real-time distribution network management. Micro phasor measurements’ model can be accommodated into this kind of SE easily. However, voltage magnitude, active power and reactive power measurements are transformed to linear measurements with large node voltage error. To cope with this issue, a linear state estimation under a polar coordinate system is adopted at the first stage to obtain accurate enough complex node voltage, and then nonlinear measurements are transformed to be linear with complex node voltage. At the second stage, linear SE under a rectangular coordinate system can be adopted to satisfy more strict network constraints. The proposed two-stage linear SE is validated on balanced 14, 33, 70,84, 119, 135 nodes network and IEEE 13, 34, 37,123 unbalanced test feeders.

This article develops duality principles applicable to originally non-convex primal variational formulations. More specifically, as a first application, we establish a convex dual approximate variational formulation for a non-linear Kirchhoff-Love plate model. The results are obtained through basic tools of functional analysis, calculus of variations, duality and optimization theory in infinite dimensional spaces. We emphasize such a convex dual approximate formulation obtained may be applied to a large class of similar models in the calculus of variations. Finally, in the last section, we present a duality principle and respective convex dual formulation for a Ginzburg-Landau type equation.

This article develops duality principles and related convex dual formulations suitable for the local optimization of non-convex primal formulations for a large class of models in physics and engineering. The results are based on standard tools of functional analysis, calculus of variations and duality theory. In particular, we develop applications to a Ginzburg-Landau type equation.

A number of studies have investigated different crustacean food stuffs, feeding methods, 18 and feeding behavior, but little attention has been given to the interaction between these aspects in 19 crustaceans. The aim of the present review is to update knowledge, and examine challenges and 20 opportunities in the development of formulated diets, as pelleted feed, which is vital for developing 21 better quality of seed or broodstock in hatcheries, and adaptation of hatchery product to the aqua- 22 culture environment, and production systems.

Geopolymer cement has been popularly studied nowadays compared to ordinary Portland cement because it demonstrated superior environmental advantages due to its lower carbon emissions and waste material utilization. This paper focuses on the formulation of geopolymer cement from nickel-laterite mine waste (NMW) and coal fly ash (CFA) as geopolymer precursors, and sodium hydroxide (SH) and sodium silicate (SS) as alkali activators. Different mix formulations of raw materials are synthesized to produce a geopolymer based from an I-optimal design and obtained different compressive strengths. A mixed formulation of 50% NMW and 50% CFA, SH-to-SS ratio of 0.5, and an activator-to-precursor ratio of 0.429 yielded the highest 28-day unconfined compressive strength (UCS) of 22.10 ± 5.40 MPa. Furthermore, using an optimized formulation of 50.12% NMW, SH-to-SS ratio of 0.516, and an activator-to-precursor ratio of 0.428, a UCS value of 36.30 ± 3.60 MPa was obtained. The result implies that the synthesized geopolymer material can be potentially used for concrete structures and pavers, pedestrian pavers, light traffic pavers, and plain concrete.

Vaginal ecosystem is a unique environment where, in physiological conditions, lactobacilli dominate. However, also pathogenic microbial species, responsible of vaginitis and vaginosis, can harbor vaginal microbiota. To extend the data published by De Seta and Larsen in Pathogens (2021), here we analyzed both the anti-Candida and anti-inflammatory properties of the vaginal gel formulation, Respecta® Balance Gel (RBG), commercialized as an adjuvant to treat vaginitis and vaginosis. We evaluated its activity by an in vitro model where a monolayer of A-431 vaginal epithelial cells was infected by Candida albicans in the presence of RBG or the placebo formulation (pRBG). Specifically, we tested the RBG capacity to counteract C. albicans virulence factors as well as their anti-inflammatory properties. Our results show that, unlike the placebo, RBG reduces ,reduces, C. albicans adhesion, its capacity to form hyphae and C. albicans-induced vaginal cell damage. Interestingly, both RBG and pRBG reduce LPS-induced IL-8 secretion (being RBG the most effective) demonstrating that also the placebo retains anti-inflammatory properties. By our experimental approach we highlight the possible role of farnesol on such effects, but we would like to point out that lactic acid, polydextrose and glycogen too must be relevant in the actual application. Taken together, our results show that RBG impairs C. albicans virulence and is able to reduce the inflammation in the vaginal environment, ultimately allowing the establishment of a balanced vaginal ecosystem.

The classical joint economic lot-sizing (JELS) policy in a single-vendor single-buyer system generates an equal production quantity in all cycles, where the input parameters remain static indefinitely. In this paper, a new two-echelon supply chain inventory model is developed involving a hybrid production system that simultaneously focuses on green and regular production methods with optimal allocation fraction of green and regular productions. Unlike the classical mathematical formulation, each cycle is independent from the previous one, and consequently, the input parameters can be adjusted to be responsive to the dynamic nature of demand rate and price fluctuation. A rigorous heuristic approach is used to derive a global optimal solution for a joint hybrid production system. The model accounts for carbon emissions from production and storage activities related to green and regular produced items along with transportation activity under a multi-level emission-taxing scheme. The results emphasize the significant impact of green production on emissions. That is, the higher the allocation fraction of green production the lower the total amount of emissions generated by the system, i.e., the system becoming more sustainable. Adopting a hybrid production method not only decreases the greenhouse gas (GHG) emissions dramatically, but also reduces the per unit time total cost when compared with regular production. One of the main findings is that the total system cost generated by the base closed-form formula of the proposed model is considerably lower than that of the existing literature i.e., 33.59% (16.13%) lower in the first cycle (subsequent cycles) when the regular production method is assumed. Moreover, the optimal production rate generated by the proposed model is the one that minimizes the emissions production function. Illustrative examples and special cases that reflect different realistic situations are compared to outline managerial insights.

: We evaluated the pharmaceutical properties of levofloxacin (LV) in the form of an orally disintegrating tablet (LVODT) to find a new usefulness of low frequency (LF) Raman spectroscopy. LVODT contained dispersed granules with diameters in the order of several hundred micrometers, which were composed of the active pharmaceutical ingredient (API), as confirmed by infrared (IR) microspectroscopy. On the contrary, the API and inactive pharmaceutical ingredients (non-APIs) were homogeneously distributed in LV tablet (LVT) formulations. Microscopic IR spectroscopy and thermal analyses showed that LVODT and LVT contained the API in different crystalline forms or environment around the API each other. Furthermore, powder X-ray diffraction showed that LVT contained a hemihydrate of the API, while LVODT showed a partial transition to the monohydrate form. This result was confirmed by microscopic LF Raman spectroscopy. Moreover, this method confirmed the presence of thin layers coating the outer edges of the granules that contained the API. Spectra obtained from these thin layers indicated the presence of titanium dioxide, suggesting that the layers coexisted with a polymer that masks the bitterness of API. The microscopic LF Raman spectroscopy results in this study indicated new applications of this method in pharmaceutical science.

Two meters is the ratio of the distance between two points according to the standard 1-meter ruler saved somewhere in France, and this comparative ratio is really equal to dimensionless number 2. We can easily repeat such comparative ratios for kilograms and any other quantities that modern physics believes they carry units. When we think about it, all physical quantities are dimensionless comparative ratios referred to standard units saved somewhere in France (never mind more complicated, derived units, they still depend on the particular items saved in France). Once this important fact is established for dimensional units, we realize how we should deal with dimensionless constants in physics: we need to determine one such constant by experiment, and then all other related dimensionless constants fall in place by simple ratios, just as has been done for dimensional units over many years in the past. For the forces of nature, we advocate the fine-structure constant as the dimensionless quantity that will serve as the baseline for other dimensionless constants representing the coupling of forces. Then, we can extend gravity in the atomic world and quantum physics into large-scale cosmology, both quite flawlessly.

The variable-length arbitrary Lagrange-Euler (ALE)-ANCF finite element, which employ nonrational interpolating polynomials, cannot exactly describe the rational cubic Bezier curves such as conic and circular curves. The rational absolute nodal coordinate formulation (RANCF) finite element, whose reference length (undeformed length) is constant, can exactly represent the rational cubic Bezier curves. A new variable-length finite element called the ALE-RANCF finite element, which is capable of accurately describe the rational cubic Bezier curves, is proposed by combining the desirable features of the ALE-ANCF and RANCF finite element. In order to control the reference length of ALE-RANCF element within a suitable range, element segmentation and merging schemes are proposed. It is demonstrated that exact geometry and mechanic is maintained after the ALE-RANCF element is divided into two shorter ones, and compared with the ALE-ANCF elements, there are smaller deviations and oscillations after two ALE-RANCF elements are merged into a longer one. Numerical examples are presented and the feasibility and advantages of the ALE-RANCF finite element are demonstrated.

We propose a new binary formulation of the Travelling Salesman Problem (TSP), with which we overcame the best formulation of the Vehicle Routing Problem (VRP) in terms of the minimum number of necessary variables. Furthermore, we present a detailed study of the constraints used and compare our model (GPS) with other frequent formulations (MTZ and native formulation). Finally, we have carried out a coherence and efficiency check of the proposed formulation by running it on a quantum annealing computer, D-Wave\_2000Q6.

This research aims to study the ultimate limit state (ULS) behaviour of stiffened panel under longitudinal compression by non-linear finite element method (NLFEM). There are different types of stiffeners being used in shipbuilding i.e. T-bar, flat-bar and angle-bar. However, this research focuses on the ultimate compressive strength behaviour of flat-bar stiffened panel. A total of 420 of reliable scenarios of flat-bar stiffened panel are selected for numerical simulation by ANSYS NLFEM. The ultimate strength behaviours obtained were used as data for the development of closed form shape empirical formulation. Recently, Kim et al. [1] proposed for advanced empirical formulation for T-bar stiffened panel and the applicability of the proposed formulation to flat-bar stiffened panel will be confirmed by this study. The accuracy of the empirical formulation obtained for flat-bar stiffened panel has been validated by FE simulation results of statistical analysis (R2 = 0.9435). The outcome obtained will be useful for ship structural designers in predicting the ultimate strength performance of flat-bar type stiffened panel under longitudinal compression.

Abstract: Currently, antibodies are major therapeutic modalities in biopharmaceutical research and development. Because of required high dose for certain clinical applications, antibodies are formulated at high protein concentration for convenience of administration, shipping and storage. We will describe the inter-molecular interactions that can occur in such a crowded environment of high protein concentration. Two types of repulsive interactions, i.e., electrostatic and excluded volume effects, and three types of attractive interactions, i.e., hydrophobic, electrostatic and cross-linking, need to be considered in such a crowded environments. We then show consequences of such inter-molecular interactions, leading to high viscosity, opalescence and phase separation of antibody solutions. Co-solvents are used to control the stability, structure and molecular interactions and thereby to alleviate these solution problems. Among various co-solvents, arginine has been extensively used to suppress protein-protein interactions at high protein concentration. Arginine weakly but extensively interacts with aromatic/hydrophobic groups as well as charged groups on proteins, leading to effective suppression of viscosity, opalescence and phase separation of antibody solution.

Diabetes is one of the metabolic syndromes that demands the great concern affecting millions of people all over the world. Viral infections were also considered as responsible for diabetes. Though, variety of medications for prevention and treatment of diabetes are available, numerous limitations are also prevailing that cannot be neglected. Precise drug-targetability, controlled drug-release, oral bioavailability, minimizing side effects are a few to consider. To address most of these shortcomings of traditional drug-delivery models, nanoformulation has been employed therein a wide range of nanoformulation models are developed. The pharmacology of a drug can be greatly enhanced through nanoformulation models in diabetes treatment in terms of enhanced bioavailability, prolonged and sustained drug-lease, maintain maximum drug concentration in serum, higher intestinal absorption, and protection from enzymatic degradation. In this review work, recently designed nanoformulation models for efficient insulin delivery and the other properties concerning diabetes such as reducing blood glucose level, total cholesterol, triglycerides, lipid profile, wound healing, elevating antioxidant enzymes etc. are discussed. Classification of the nanoformulation models is done based on the nature of the fabricating material employed in nanoformulation. This review may be helpful in designing a more efficient nanoformulation model for diabetes treatment.

The incidence of celiac disease and gluten intolerance has been significantly rising globally. Gluten-free product consumption registered a sudden rise also among tolerant people, due to psychosocial factors. Biscuits are popular, low-cost bakery foods, consumed by nearly everyone worldwide. The removal of gluten from the baked product causes some undesirable traits and different textures and tastes. The main goal consists of creating a food product with the same taste and texture as a product with gluten. Moreover, gluten-free bakery products are usually low-grade sources of protein and poor in dietary fiber. Quinoa is a source of TDF and valuable protein. In this study, quinoa flour was used as the main constituent in the formulation of gluten-free c to improve their nutritional properties. Six different recipes with different percentages of quinoa flour have been realized. The formulations were compared, by rheological analysis, of each other and with a wheat flour control shortbread. The recipes with rheological features more similar to control shortbread were subjected to a discrimination analysis and the preferred was characterized from a chemical-physical and sensorial point of view. The experimental shortbreads constituted a good compromise to exploit the good nutritional composition of quinoa maintaining an acceptable sensory profile.

The Simplified Spherical Harmonic (SPN) approximation was first introduced as a three-dimensional (3-D) extension of the plane-geometry Spherical Harmonic (PN) equations. A third order SPN (SP3) solver, recently implemented in the Nodal Expansion Method (NEM), has shown promising performance in the reactor core neutronics simulations. This work is focused on the development and implementation of the transport corrected interface and boundary conditions in NEM SP3 solver, following recent published work on the rigorous SPN theory for piecewise homogeneous regions. A streamlined procedure has been developed to generate the flux zero and second order/moment discontinuity factors (DFs) of the generalized equivalence theory to eliminate the error introduced by pin-wise homogenization. Moreover, several color set models with varying size and configuration are later explored for their capability of generating DFs that can produce results equivalent to that using the whole-core homogenization model for more practical implementations. The new developments are tested and demonstrated on the C5G7 benchmark. The results show that the transport corrected SP3 solver shows general improvements to power distribution prediction compared to the basic SP3 solver with no DFs or only zero order/moment DFs. The complete equivalent calculations using the DFs can almost reproduce transport solutions with high accuracy. The use of equivalent parameters from larger size color set models show better prediction in the whole-core calculations. By coupling different color set models DFs can offer the best accuracy at both eigenvalues and power distributions.

Neisseria gonorrhoeae is a strict human pathogen responsible for more than 100 million new sexually transmitted infections worldwide each year. Due to the global emergence of antibiotic resistance, the CDC recently listed N. gonorrhoeae as an urgent threat to public health. No vaccine is available in spite of the huge disease burden and the possibility of untreatable gonorrhea. The aim of this study is to investigate the immunogenicity of a novel whole-cell based inactivated gonococcal microparticle vaccine formulation loaded in dissolvable microneedles for transdermal administration. The nanotechnology-based vaccine formulation consists of inactivated whole-cell gonococci strain CDC-F62, spray dried and encapsulated into biodegradable cross-linked albumin matrix with sustained slow antigen release. The dry vaccine nanoparticles were then loaded in a dissolvable microneedle skin patch for transdermal delivery. The efficacy of the whole-cell microparticles vaccine formulation loaded in microneedles was assessed in vitro using dendritic ,cells and macrophages as well as in vivo mouse model. Antibody titers were measured using an ELISA and antigen-specific T lymphocytes were assessed in spleens and lymph nodes. Here we report that whole-cell based gonococcal microparticle vaccine loaded in dissolvable microneedles for transdermal administration induced significant increase in antigen-specific IgG antibody titers and antigen-specific CD4 and CD8 T lymphocytes in mice compared to gonococcal antigens in solution or empty microneedles. Significant increase in antigen-specific IgG antibody levels was observed at end of week 2 in groups that received the vaccine compared to the group receiving empty nanoparticles. The advantages of using formalin-fixed whole-cell gonococci that all immunogenic epitopes are covered and preserved from degradation. The spherical shaped micro and nanoparticles are biological mimics of gonococci, therefore present to the immune system as invaders but without the ability to suppress adaptive immunity. In conclusion, the transdermal delivery of microparticles vaccine via a microneedle patch was shown to be an effective system for vaccine delivery. The novel gonorrhea nanovaccine is cheap to produce in a stable dry powder and can be delivered in microneedle skin patch obviating the need for needle use or the cold chain.

The CRISPR-Cas9 system is an emerging therapeutic tool with the potential to correct diverse ge-netic disorders. However, for gene therapy applications an efficient delivery vehicle is required, capable of delivering the CRISPR-Cas9 components into the cytosol of the intended target cell population. Once there, the ribonucleoprotein complex (RNP) can be transported into the nucleus. Lipid nanoparticles (LNP) serve as promising candidates for delivery of CRISPR-Cas9 RNP. These delivery vehicles have been optimized for the delivery of nucleic acids, such as mRNA. Co-delivery of Cas9 encoding mRNA with the accompanying sgRNA leads to translation of the Cas9 protein and formation of the Cas9 RNP inside the cell. Only recently, direct delivery of the CRISPR-Cas9 RNP complexes has been explored, which requires adjustments to the LNP formulation. In this study, the importance of buffer composition and cationic charge during RNP and ssDNA en-trapment in LNP are demonstrated. After optimizing several formulation parameters, LNP were prepared that were colloidally stable in human plasma and efficiently deliver the SpCas9 RNP and ssDNA for HDR-correction in reporter cells. Under optimal formulation conditions, gene knock-out and gene correction efficiencies as high as 80% and 20%, respectively were achieved at nanomolar CRISPR-Cas9 RNP concentrations.

Broflanilide is a novel active ingredient from a unique insecticide class (IRAC Group 30) and was investigated as a control option against modern insecticide resistant strains of the common bed bug, Cimex lectularius. The susceptibility of technical grade broflanilide and efficacy of a broflanilide-based aerosol formulation (Earth Corp., Japan) were evaluated against five C. lectularius strains (MONH, SYD, DARL, PARRA, RIPPO). Results demonstrated that bed bugs had high susceptibility to broflanilide (RR50: SYD=1.22-fold, DARL=1.03-fold, PARRA=3.65-fold, RIPPO=2.77-fold), compared to the susceptible MONH strain. The aerosol showed high efficacy to adult bed bugs (97.5–100 % mortality to five strains after 24 hrs post-spray) and produced a notable decrease in egg hatch rates (MONH=9.7–23.4 %, PARRA=14.9–22.6 %). The aerosol also demonstrated high residual activity with 97.5–100% mortality in all five bed bug strains within 7 days exposure. The impact of different surface types upon aerosol residual efficacy was limited, although residues on a non-porous surface (tile) killed bed bugs slightly quicker than that on a porous surface (filter paper). The aerosol provided long residual activity to bed bugs, as 6-month-old residues were as equally efficacious to that of fresh residues. Bed bugs did not avoid surfaces treated with the aerosol. The high efficacy (including ovicidal efficacy), long residual activity, and non-avoidance of bed bugs on treated surfaces, demonstrated that broflanilide is highly suitable for modern bed bug management.

Human fungal pathogen Candida albicans causes oral infectious diseases such as oral thrush in immunocompromised patients with hyposalivation, diabetes mellitus, prolonged use of anti-biotics or immunosuppressive medicines and poor oral hygiene. An anti-fungal medication classified as a BCS class II drug, Clotrimazole has high permeability and low solubility in water. It is commercially available as lozenges, which do not uniformly distribute the drug within saliva for local therapy. This results in higher dose frequency and lower patient compliance. Therefore, in this study we proposed a niosomal based subgingival film formulation of clotrimazole for enhancing drug efficacy by improving drug solubilization capacity and improving patient compliance by prolonging the release of drug at the targeted site and reducing the dose frequency to show effective anti-fungal activity. The prepared niosomal film showed good entrapment efficiency and anti-fungal activity. Niosomal film showed better release pattern than drug loaded film.

Addressing the impacts of climate change requires, first of all, understanding the mechanisms driving changes, especially at regional scale. In particular, policymakers and other stakeholders need physically robust climate change information to drive societal responses to a changing climate. In this study, we analyse the late 21st century precipitation projections (2071-2100) over the Congo Basin under Representative Concentration Pathway (RCP) 8.5, from the Rossby Centre Regional Climate Model (RCM) RCA4. In particular, we examine the impact of the RCM formulation (reduction of turbulent mixing) on future projections, by comparing the results of the modified version (RCA4-v4) with those of the standard version (RCA4-v1) used in CORDEX (Coordinated Regional climate Downscaling EXperiment). The two RCM versions are driven by two global climate models participating in the Coupled Model Intercomparison Project phase 5 (CMIP5). Results show that seasonal precipitation is largely affected by modifications in the atmospheric column moisture convergence or divergence, in turn, associated with dynamic and thermodynamic effects. Projected decreased precipitation in the dry seasons is associated with an increased moisture divergence, driven by dynamic effects (changes in circulation). Precipitation is projected to overall increase in the wet seasons, related to both dynamic and thermodynamic effects, but with larger thermodynamic contribution (changes in specific humidity). By comparing the two model versions, we found that the formulation strongly influences precipitation projections as well as the boundary conditions (driving GCM). This result could be very informative in view to ensure models fitness for the purpose of future projections for decision-makers.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric acid-related diseases. Herein, we evaluated the pharmacokinetics (PKs) of single-dose and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy subjects (Part 1) and investigated the bioequivalence between fexuprazan 10 mg and 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, 1-sequence, and 2-period design, and Part 2 comprised a single-dose, 2×2 crossover design. Eight and 23 subjects completed Parts 1 and 2, respectively. In Part 1, multiple doses accumulated twice as much as single doses. In Part 2, the geometric mean ratios [90% confidence intervals] for maximum plasma concentration (Cmax) and area under the concentration–time curve from zero to the time of the last quantifiable concentration (AUClast) of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, which met bioequivalence criteria. Overall, favorable PK was observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

Coffee berry borer (CBB), Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae: Scolytinae), is the pest that causes the most economic damage to coffee crops. Chemical control of this insect is based on the use of insecticides that can affect the environment and nontarget organisms. Despite the fact that caffeine has shown potential as an insecticide, a caffeine-based product for field use is currently not available on the market. As a new alternative to control CBB and other coffee pests, such as Monalonion velezangeli, a caffeine-oleate was developed. The caffeine oleate formulation showed laboratory efficacy by causing mortality of more than 90% of CBB adults in preventive tests in which the insecticide was sprayed prior to insect attack on the coffee fruits. In the curative tests, in which spraying occurred after CBB infested the fruits, the formulation caused 77% mortality of the insects. Under controlled field conditions, the product kept CBB infestation below 20%, reducing the number of fruits attacked by the insect by up to 70%. In addition, no phytotoxic effects were observed in coffee plants. The insecticide was also effective against M. velezangeli causing 100% mortality. A caffeine oleate formulation that could be part of a strategy for integrated CBB management as well as other pests of coffee was developed. The components of the insecticide are food grade; the product would provide greater security to the coffee ecosystem and coffee growers.

It has been discovered that representing odd integers as modified binary expressions of the form $\sum \limits_{n > m}2^n + 2^m - 1$ for $m \geq 1$ helps in understanding the dynamics of Collatz-type sequences. Starting with the original Collatz sequence $3x + 1$, it is found that when the odd step is applied to an odd integer $\sum \limits_{n > m}2^n + 2^m - 1$, an even integer $3\left(\sum \limits_{n > m}2^{n}\right) + 2^{m + 1} + 2^m - 2$ is obtained, which is exactly once divisible by 2, unless the lowest index reduces to zero. This implies that the sequence alternates between odd and even steps $m$ times. This governs the dynamics of the Collatz-type sequences because the value of $m$ determines the number of times the integer can be divided by 2 in each even step. A shortcut method is developed based on this dynamics that states that the even integer after $m$ odd-even steps are completed is $\left(\left(\frac{3}{2}\right)^m \sum \limits_{n > m}2^n\right) + 3^m - 1$. A shortcut method of this magnitude has never been utilized anywhere. The shortcut method for the modified Collatz sequence $5x + 1$ is also presented.

Although there is a vast body of neuroscientific research on cognitive behavioral therapy (CBT), many therapists are confused about how to incorporate the evidence into their clinical practice. This narrative review translates neuroscientific research on CBT for depression into a therapist-friendly formulation model. Four brain networks that are particularly relevant to depression, including the Central Executive Network, Default mode Network, Salience Network, and Affective Network, were identified based on their interactions and described in relation to depressive symptoms. Additionally, it clarified how each CBT technique works on a brain map. Assessment, intervention selection, and patient psychoeducation based on this model will facilitate the clinical application of neuroscience in CBT.

A novel phase-field method based numerical approach to modeling the compaction process of sedi- ments is presented. Water-logged rock or soil sediments are deposited on the water basins over time and the increasing volume of the sediment compacts under its own weight and external pressure. Coupled evolution of mass conservation, Darcy flow, and the viscoelastic constitutive response, in conjunction with the evolution of porosity and permeability, make this problem highly non-linear and involve moving boundaries. We adopt a phase-field approach to represent the moving sediment interface, and the underlying multiphasic model permits for studying compaction in dynamically evolving sediments. This approach does not necessitate a change of domain sizes as is the case of existing traditional models of sedimentation but rather treats sedimentation growth as a problem of interface motion. We first model a classical compaction problem in 1D to compare with existing results in the literature, and then extend the framework to 2D to model the compaction process taking place under the influence of gravity. The model is then extensively applied to understand the effect of the sediment initial state and the sediment material properties on the compaction process and its spatiotemporal evolution. Lastly, a strong validation of our phase-field treatment results against predictions from traditional methods of solving open boundary sediment compaction problems, and a good agreement between the conventional understanding and the numerical predictions of porosity dependence on the fluid pore pressure for various cases of geological interest, are used to demonstrate the applicability and scalability of this novel numerical framework to model more advanced sediment compaction problems and geometries.

Intravitreal injection is the gold standard therapeutic option for posterior segment pathologies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine-Laponite (BRI/LAP) can be monitored non-invasively using vitreous imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterization was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF.

The Landauer principle supplies the estimation of the minimal mass of a particle which is capable to record/erase information within a thermal bath at the temperature of T. Particles lighter than ${\tilde{m}}_0=\frac{k_{B}Tln2}{c^2}$will not transform the information to the surrounding bodies and are well expected to be undetectable. The relation of the Landauer principle to the problem of “dark matter” is discussed. The maximal informational content of a particle at rest, estimated as $I_{max}=\frac{m_0{c}^2}{k_{B}Tkn2}$ is introduced. The Landauer principle also allows the estimation of minimal energy of the field which is capable to record/erase 1 bit of information in the surrounding at the temperature of T. The relativistic aspects of the Landauer principle and its relation to the relativistic transformation of temperature are addressed.

Despite past efforts towards therapeutical innovation, cancer remains a highly incident and lethal disease, with current treatments many times lacking efficiency and leading to severe side-effects. Hence, it is imperative to develop new, more efficient, and safer therapies. Bee venom has proven to have multiple and synergistic bioactivities, including antitumor effects. Nevertheless, some toxic effects have been associated with its administration. To tackle these issues, in this work, bee venom-loaded niosomes were developed, for cancer treatment. The vesicles had a small (150.4 ± 3.7 nm) and homogeneous (PDI of 0.162 ± 0.008) particle size, and revealed good therapeutic efficacy in in vitro gastric, colorectal, breast, lung, and cervical cancer models, with GI50 values between 12.37 ng/mL and 14.72 ng/mL. Additionally, they also revealed substantial anti-inflammatory activity, with an IC50 of 28.98 ng/mL, effects that have been reported to be complementary to direct antitumor activity. Finally, the niosomes' safety was assessed, both in vitro, on skin, liver and kidney cells, and ex vivo, in a HET-CAM assay, and results showed that compound encapsulation increased its safety. Hence, small and homogeneous bee venom-loaded niosomes were successfully developed, with substantial anticancer and anti-inflammatory effects, making them potentially promising primary or adjuvant cancer therapies.

Background: Functional beverages are ordinary foods with components or ingredients able to provide specific health effects other than purely nutritional effect. Aim: This study aims to formulate a new functional beverage obtained from the recovery of YoAlp® whey, a bovine fermented milk obtained using autochthonous starter cultures, added with Renetta Canada/Golden Delicious-Raspberry (YWL), Renetta Canada-Aronia (YWA) and Ravèntse (YWR) fruit juices to improve the functionality of the beverage. Methods: Microbiological analysis and chemical characterization, by a proteomic approach and spectrophotometric microassay, have been conducted on beverages to investigate the expected shelf-life and potential health promoting effects. Results: The microbiological assessment confirmed the safety of the beverages and the probiotic bacteria vitality over a shelf life of seven days. Biochemical analysis performed highlight the presence of different bioactive peptides (ACE inhibitory and antioxidant), and the betacasomorphin 9 (BCM-9), marker of A2 variant of β-casein typically present in Aosta Valley cattle breeds. Moreover, high amounts of total polyphenols, which concur to the antioxidant activity values observed, have been found. Furthermore, ACE inhibitory activity is well correlated to the bioactive peptides detected. Finally, a consumer test confirmed the YoAlp® whey-based beverages appreciation. Conclusions: The production of these beverages could represent a huge opportunity for Aosta Valley’s farms to increase their income and competitiveness, creating a circular economy by recovering a by-product like whey and following sustainability and healthy trends, which are driving the food sector.

The pharmacokinetic profile of fat-soluble vitamins A, E, K1, and D3 co-administered with liquid paraffin or water in an experimental rat model was investigated. Animals received a solution of the four vitamins orally through a probe, followed 10 minutes later by the administration of either the liquid paraffin product dissolved in water (Emuliquen Simple®) or water (control). Vitamin formulations were 20, 50, 0.30 and 0.10 mg/kg for vitamins A, E, K1, and D3, respectively. Blood samples were collected before dosing and at 0.17, 1, 2, 4, 8, and 24 hours post-dosing. Vitamin concentrations were quantified by liquid chromatography coupled with mass spectrometry. No relevant differences in the absorption of vitamins in terms of AUC0-last (area under the curve up to the last measurable concentration) or Cmax in the absence or presence of co-administration of the liquid paraffin product were observed. The difference of these parameters between the treatment groups for all vitamins was in the range of bioequivalence (≤ 20%). The liquid paraffin-based laxative product did not interfere with the absorption of vitamins A, E, K1, and D3 that are ingested in the diet, which is clinically relevant due to the high prevalence of functional constipation in children and adults.

In silico prediction of the in vivo efficacy of siRNA ionizable-lipid nanoparticles is desirable yet never achieved before. This study aims to computationally predict siRNA nanoparticles in vivo efficacy, which saves time and resources. A data set containing 120 entries was prepared by combining molecular descriptors of the ionizable lipids together with two nanoparticles formulation characteristics. Input descriptor combinations were selected by an evolutionary algorithm. Artificial neural networks, support vector machines and partial least squares regression were used for QSAR modeling. Depending on how the data set is split, two training sets and two external validation sets were prepared. Training and validation sets contained 90 and 30 entries respectively. The results showed the successful predictions of validation set log(dose) with R2val = 0.86 – 0.89 and 0.75 – 80 for validation sets one and two respectively. Artificial neural networks resulted in the best R2val for both validation sets. For predictions that have high bias, improvement of R2val from 0.47 to 0.96 was achieved by selecting the training set lipids lying within the applicability domain. In conclusion, in vivo performance of siRNA nanoparticles was successfully predicted by combining cheminformatics with machine learning techniques.

Analysis of Fatigue Strain, Fatigue Modulus and Fatigue Damage for the modeling of concrete plays a vital role in the evolution material behaviour which is heterogeneous and anisotropic in nature. In this paper, the Level-S nonlinear fatigue strain curve, fatigue modulus curve, residual strain curve of concrete in compression, tension, flexure and torsional fatigue loading were proposed using strain life approach. The parameters such as physical meaning, the ranges, and the impact on the shape of the curve were discussed. Then, the evolution model of fatigue modulus was established based on the fatigue strain evolution model, fatigue modulus evaluation model, residual strain evaluation model, secondary strain evaluation model. The hypothesis of fatigue modulus is inversely related with the fatigue strain amplitude. The fatigue evolution of concrete damages the bond between material grains, changed the orientation of structure of molecules and affects the elastic properties resulting in the reduction of material stiffness and modulus by utilizing strain life analysis, regarding stiffness degradation and inelastic deformation by formation of microcracking, macro cracking, cracking which is heterogeneous and anisotropic in nature . This paper presents the Fatigue Strain Life Model and analyses of fatigue strain, fatigue modulus and damage parameters of concrete which is capable of predicting stiffness degradation, inelastic deformation, strength reduction under fatigue loading. Hence, the obtainable results were compared with experimental results for the validation of the proposed model.

Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancer have been masked by high drug toxicities, adverse reactions, and resistance. Using nanocarriers like liposomes to overcome these unwanted effects has become very popular. This study aimed to formulate 1,3-bis tetrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and evaluate the stability, MFU release kinetics, in vitro and in vivo anticancer activities, and biodistribution. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticle (Rh0-LnP) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP) as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnP in vivo using inductively coupled plasma mass spec-trometry (ICP-MS). The mean hydrodynamic diameters of the blank LnP and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4o C and 25oC for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroids (IC50Zhubech = 3.4 ± 1.0μM vs IC50MFU = 6.8 ± 1.1μM) and organoids (IC50Zhubech = 9.8 ± 1.4μM vs IC50MFU = 42.3 ± 1.0μM) culture models. Confocal imaging confirmed high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor efficacy studies in PDX bearing mouse model revealed more than 9-fold decrease in mean tumor volumes in Zhu-bech treated (108 ± 13.5 mm3) compared to 5-FU treated (1,107 ± 116.2 mm3) animals respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

Intravitreal injections (IVTs) of corticosteroids as triamcinolone acetonide (TA) are frequently used for the treatment of many vitreous and retinal disorders. However, IVTs are related to severe ocular complications. Lately, a topical ophthalmic TA loaded liposomes formulation (TALF) was designed to transport TA into the posterior segment of the eye when instilled in the ocular surface. To evaluate the safety, tolerability, and biologic activity of TALF, an animal study and a phase I clinical assay was performed. Moreover, four patients with diabetic macular edema (DME) were treated with TALF in order to explore the biologic activity of the formulation. No inflammation, lens opacity, swelling or intraocular pressure rising were recorded after the instillation of TALF in any of the animal or clinical study. Mainly, mild and transient adverse events such as dry eye (30%) and burning (30%) were reported. TALF improves significantly visual acuity and diminishes central foveal thickness in patients with DME. The current data demonstrate the safety, tolerability, and biologic activity of TALF. It seems that TALF can be used topically to treat vitreous and retinal diseases that respond to TA such as DME, avoiding the use of corticosteroids IVTs and its associated hazards.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.