Search results for: anti-browning agent

Authors: Jae Won Lee, Kyung Hyun Min, Hong Jae Lee, Sang Cheon Lee

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To date, imaging techniques have attracted much attention in medicine because the detection of diseases at an early stage provides greater opportunities for successful treatment. Consequently, over the past few decades, diverse imaging modalities including magnetic resonance (MR), positron emission tomography, computed tomography, and ultrasound (US) have been developed and applied widely in the field of clinical diagnosis. However, each of the above-mentioned imaging modalities possesses unique strengths and intrinsic weaknesses, which limit their abilities to provide accurate information. Therefore, multimodal imaging systems may be a solution that can provide improved diagnostic performance. Among the current medical imaging modalities, US is a widely available real-time imaging modality. It has many advantages including safety, low cost and easy access for patients. However, its low spatial resolution precludes accurate discrimination of diseased region such as cancer sites. In contrast, MR has no tissue-penetrating limit and can provide images possessing exquisite soft tissue contrast and high spatial resolution. However, it cannot offer real-time images and needs a comparatively long imaging time. The characteristics of these imaging modalities may be considered complementary, and the modalities have been frequently combined for the clinical diagnostic process. Biominerals such as calcium carbonate (CaCO3) and calcium phosphate (CaP) exhibit pH-dependent dissolution behavior. They demonstrate pH-controlled drug release due to the dissolution of minerals in acidic pH conditions. In particular, the application of this mineralization technique to a US contrast agent has been reported recently. The CaCO3 mineral reacts with acids and decomposes to generate calcium dioxide (CO2) gas in an acidic environment. These gas-generating mineralized nanoparticles generated CO2 bubbles in the acidic environment of the tumor, thereby allowing for strong echogenic US imaging of tumor tissues. On the basis of this previous work, it was hypothesized that the loading of MR contrast agents into the CaCO3 mineralized nanoparticles may be a novel strategy in designing a contrast agent for dual imaging. Herein, CaCO3 mineralized nanoparticles that were capable of generating CO2 bubbles to trigger the release of entrapped MR contrast agents in response to tumoral acidic pH were developed for the purposes of US and MR dual-modality imaging of tumors. Gd2O3 nanoparticles were selected as an MR contrast agent. A key strategy employed in this study was to prepare Gd2O3 nanoparticle-loaded mineralized nanoparticles (Gd2O3-MNPs) using block copolymer-templated CaCO3 mineralization in the presence of calcium cations (Ca2+), carbonate anions (CO32-) and positively charged Gd2O3 nanoparticles. The CaCO3 core was considered suitable because it may effectively shield Gd2O3 nanoparticles from water molecules in the blood (pH 7.4) before decomposing to generate CO2 gas, triggering the release of Gd2O3 nanoparticles in tumor tissues (pH 6.4~7.4). The kinetics of CaCO3 dissolution and CO2 generation from the Gd2O3-MNPs were examined as a function of pH and pH-dependent in vitro magnetic relaxation; additionally, the echogenic properties were estimated to demonstrate the potential of the particles for the tumor-specific US and MR imaging.

Keywords: calcium carbonate, mineralization, ultrasound imaging, magnetic resonance imaging

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Authors: Deyadeen Ali Alshibani

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In the literature, the multi-armed bandit problem as a statistical decision model of an agent trying to optimize his decisions while improving his information at the same time. There are several different algorithms models and their applications on this problem. In this paper, we evaluate the Regret-regression through comparing with Q-learning method. A simulation on determination of optimal treatment regime is presented in detail.

Keywords: optimal, bandit problem, optimization, dynamic programming

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Authors: Hadas Sopher, Davide Schaumann, Yehuda E. Kalay

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This paper addresses the shortcomings of architectural computation tools in representing human behavior in built environments, prior to construction and occupancy of those environments. Evaluating whether a design fits the needs of its future users is currently done solely post construction, or is based on the knowledge and intuition of the designer. This issue is of high importance when designing complex buildings such as hospitals, where the quality of treatment as well as patient and staff satisfaction are of major concern. Existing computational pre-occupancy human behavior evaluation methods are geared mainly to test ergonomic issues, such as wheelchair accessibility, emergency egress, etc. As such, they rely on Agent Based Modeling (ABM) techniques, which emphasize the individual user. Yet we know that most human activities are social, and involve a number of actors working together, which ABM methods cannot handle. Therefore, we present an event-based model that manages the interaction between multiple Actors, Spaces, and Activities, to describe dynamically how people use spaces. This approach requires expanding the computational representation of Actors beyond their physical description, to include psychological, social, cultural, and other parameters. The model presented in this paper includes cognitive abilities and rules that describe the response of actors to their physical and social surroundings, based on the actors’ internal status. The model has been applied in a simulation of hospital wards, and showed adaptability to a wide variety of situated behaviors and interactions.

Keywords: agent based modeling, architectural design evaluation, event modeling, human behavior simulation, spatial cognition

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Authors: Jared Beard, Ali Baheri

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As autonomous systems become more prominent in society, ensuring their safe application becomes increasingly important. This is clearly demonstrated with autonomous cars traveling through a crowded city or robots traversing a warehouse with heavy equipment. Human environments can be complex, having high dimensional state and action spaces. This gives rise to two problems. One being that analytic solutions may not be possible. The other is that in simulation based approaches, searching the entirety of the problem space could be computationally intractable, ruling out formal methods. To overcome this, approximate solutions may seek to find failures or estimate their likelihood of occurrence. One such approach is adaptive stress testing (AST) which uses reinforcement learning to induce failures in the system. The premise of which is that a learned model can be used to help find new failure scenarios, making better use of simulations. In spite of these failures AST fails to find particularly sparse failures and can be inclined to find similar solutions to those found previously. To help overcome this, multi-fidelity learning can be used to alleviate this overuse of information. That is, information in lower fidelity can simulations can be used to build up samples less expensively, and more effectively cover the solution space to find a broader set of failures. Recent work in multi-fidelity learning has passed information bidirectionally using “knows what it knows” (KWIK) reinforcement learners to minimize the number of samples in high fidelity simulators (thereby reducing computation time and load). The contribution of this work, then, is development of the bidirectional multi-fidelity AST framework. Such an algorithm, uses multi-fidelity KWIK learners in an adversarial context to find failure modes. Thus far, a KWIK learner has been used to train an adversary in a grid world to prevent an agent from reaching its goal; thus demonstrating the utility of KWIK learners in an AST framework. The next step is implementation of the bidirectional multi-fidelity AST framework described. Testing will be conducted in a grid world containing an agent attempting to reach a goal position and adversary tasked with intercepting the agent as demonstrated previously. Fidelities will be modified by adjusting the size of a time-step, with higher-fidelity effectively allowing for more responsive closed loop feedback. Results will compare the single KWIK AST learner with the multi-fidelity algorithm with respect to number of samples, distinct failure modes found, and relative effect of learning after a number of trials.

Keywords: multi-fidelity reinforcement learning, multi-fidelity simulation, safety validation, falsification

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Authors: Bassant M. M. Ibrahim, Doha H. Abou Baker, Ahmed Abd Elghafour

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Excessive exposure to heavy metals contributes to the occurrence of deleterious health problems that affect vital organs like the brain, liver, kidneys, and heart. The use of natural products that have antioxidant capabilities may contribute to the protection of these organs. In the present study, the essential oil of summer savory (Satureja hortensis) was used to evaluate its protective effects against lead acetate induced damaging effect on rats’ vital organs, due to its high contents of carvacrol, y-terpinene, and p-cymene. Forty female Wister Albino rats were classified into five equal groups, the 1st served as normal group, the 2nd served as positive control group was given lead acetate (60 mg/kg) intra-peritoneal (IP), the third to fifth groups were treated with calcium disodium (EDTA) as chelating agent and summer savory essential oil in doses of (50 and 100mg/kg) respectively. All treatments were given IP concomitant with lead acetate for ten successive days. At the end of the experiment duration electrocardiogram (ECG), an open field test for the evaluation of psychological state, rotarod test as for the evaluation of locomotor coordination ability as well as anti-inflammatory and oxidative stress biomarkers in serum and histopathology of vital organs were performed. The investigations in this study show that the protective effect of high dose of summer savory essential oil is more than the low dose and that the essential oil of summer savory is a promising agent that can contribute to the protection of vital organs against the hazardous damaging effects of lead acetate.

Keywords: brain, heart, kidneys, lead acetate, liver, protective, summer savory

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Authors: Neda Amidi Fazli, Farid Amidi Fazli

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Enriched fruits by minerals provide minerals which are needed to human body the minerals are used by body cells for daily activities. This paper indicates the result of mass transfer in fruit slices in 55% sucrose syrup in presence of calcium and phosphorus ions. Osmosis agent 55% (w/w) was prepared by solving sucrose in deionized water and adding calcium or phosphorus in 1 and 2% concentration. Dry matter, solid gain, water loss as well as weight reduction were calculated. Results showed that by increasing of calcium concentration in osmosis solution solid gain, water loss and weight reduction were increased in short experiment time in kiwi fruit but the parameters decreased in long experiment time by concentration increasing and rise of calcium concentration caused decrease of osmosis parameters in banana. In the case of phosphorus, increasing of ion concentration had adverse effect on all treatments, this may be due to different osmosis force that is created by two types of ions. The mentioned parameters decreased in all treatments by increasing of ion concentration. Highest mass transfer in kiwi fruit occurs when 1% calcium solution applied for 60 minutes, values obtained for solid gain, water loss and weight reduction were 42.60, 51.97, and 9.37 respectively. In the case of banana, when 2% phosphorus concentration was applied as osmosis agent for 60 minutes highest values for solid gain, water loss and weight reduction obtained as 21, 25.84, and 4.84 respectively.

Keywords: calcium, concentration, osmotic dehydration, phosphorus

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Authors: Said Belaaouad

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This study aimed to explore the quantitative structure-activity relationship (QSAR) of 1,2,4-Triazine-3(2H)-one derivative as a potential anticancer agent against breast cancer. The electronic descriptors were obtained using the Density Functional Theory (DFT) method, and a multiple linear regression techniques was employed to construct the QSAR model. The model exhibited favorable statistical parameters, including R2=0.849, R2adj=0.656, MSE=0.056, R2test=0.710, and Q2cv=0.542, indicating its reliability. Among the descriptors analyzed, absolute electronegativity (χ), total energy (TE), number of hydrogen bond donors (NHD), water solubility (LogS), and shape coefficient (I) were identified as influential factors. Furthermore, leveraging the validated QSAR model, new derivatives of 1,2,4-Triazine-3(2H)-one were designed, and their activity and pharmacokinetic properties were estimated. Subsequently, molecular docking (MD) and molecular dynamics (MD) simulations were employed to assess the binding affinity of the designed molecules. The Tubulin colchicine binding site, which plays a crucial role in cancer treatment, was chosen as the target protein. Through the simulation trajectory spanning 100 ns, the binding affinity was calculated using the MMPBSA script. As a result, fourteen novel Tubulin-colchicine inhibitors with promising pharmacokinetic characteristics were identified. Overall, this study provides valuable insights into the QSAR of 1,2,4-Triazine-3(2H)-one derivative as potential anticancer agent, along with the design of new compounds and their assessment through molecular docking and dynamics simulations targeting the Tubulin-colchicine binding site.

Keywords: QSAR, molecular docking, ADMET, 1, 2, 4-triazin-3(2H)-ones, breast cancer, anticancer, molecular dynamic simulations, MMPBSA calculation

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Authors: Morlu Stevens, Bareki Batlokwa

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The use of treated wastewater is widely employed to compensate for the scarcity of safe and uncontaminated freshwater. However, the existence of toxic heavy metal ions in the wastewater pose a health hazard to animals and the environment, hence, the importance for an effective technique to tackle the challenge. A multi-templated ion imprinted sorbent (Fe,Ni,Cu-IIP) for the simultaneous removal of heavy metal ions from waste water was synthesised employing molecular imprinting technology (MIT) via thermal free radical bulk polymerization technique. Methacrylic acid (MAA) was employed as the functional monomer, and ethylene glycol dimethylacrylate (EGDMA) as cross-linking agent, azobisisobutyronitrile (AIBN) as the initiator, Fe, Ni, Cu ions as template ions, and 1,10-phenanthroline as the complexing agent. The template ions were exhaustively washed off the synthesized polymer by solvent extraction in several washing steps, while periodically increasing solvent (HCl) concentration from 1.0 M to 10.0 M. The physical and chemical properties of the sorbents were investigated using Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD) and Atomic Force Microscopy (AFM) were employed. Optimization of operational parameters such as time, pH and sorbent dosage to evaluate the effectiveness of sorbents were investigated and found to be 15 min, 7.5 and 666.7 mg/L respectively. Selectivity of ion-imprinted polymers and competitive sorption studies between the template and similar ions were carried out and showed good selectivity towards the targeted metal ion by removing 90% - 98% of the templated ions as compared to 58% - 62% of similar ions. The sorbents were further applied for the selective removal of Fe, Ni and Cu from real wastewater samples and recoveries of 92.14 ± 0.16% - 106.09 ± 0.17% and linearities of R2 = 0.9993 - R2 = 0.9997 were achieved.

Keywords: ion imprinting, ion imprinted polymers, heavy metals, wastewater

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Authors: Swati Sundararajan, Asit B. Samui, Prashant S. Kulkarni

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Polymeric ionic liquids combine the properties of ionic liquids and polymers into a single material which has gained massive interest in the recent years. These ionic liquids offer several advantages such as high phase change enthalpy, wide temperature range, chemical and thermal stability, non-volatility and the ability to make them task-specific. Separation of CO2 is an area of critical importance due to the concerns over greenhouse gasses leading to global warming. Thermal energy storage materials, also known as phase change materials absorb latent heat during fusion process and release the absorbed energy to the surrounding environment during crystallization. These materials retain this property over a number of cycles and therefore, are useful for bridging the gap between energy requirement and use. In an effort to develop materials, which will help in minimizing the growing energy demand and environmental concerns, a series of dicationic poly(ethylene glycol) based polymeric ionic liquids were synthesized. One part of an acrylate of poly(ethylene glycol) was reacted with imidazolium quarternizing agent and the second part was reacted with triazolium quarternizing agent. These two different monomers were then copolymerized to prepare dicationic polymeric ionic liquid. These materials were characterized for solid-liquid phase transition and the enthalpy by using differential scanning calorimetry. The CO2 capture studies were performed on a fabricated setup with varying pressure range from 1-20 atm. The findings regarding the prepared materials, having potential dual applications in the fields of thermal energy storage and CO2 capture, will be discussed in the presentation.

Keywords: CO2 capture, phase change materials, polyethylene glycol, polymeric ionic liquids, thermal energy storage

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Authors: Amani Hassan Abu Atieh

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This study aims at examining the patterns of ideology reflected in the written discourse of women writers in the media of Jordan; Lana Mamkgh is taken as an example. This study critically analyzes the discursive, linguistic, and cognitive representations that she employs as an agent in the institutionalized discourse of the media. Grounded in van Dijk’s critical discourse analysis approach to Sociocognitive Discourse Studies, the present study builds a multilayer framework that encompasses van Dijk’s triangle: discourse, society, and cognition. Specifically, the study attempts to analyze, at both micro and macro levels, the underlying cognitive processes and structures, mainly ideology and discursive strategies, which are functional in the production of women’s discourse in terms of meaning, forms, and functions. Cognitive processes that social actors adopt are underlined by experience/context and semantic mental models on the one hand and social cognition on the other. This study is based on qualitative research and adopts purposive sampling, taking as an example a sample of an opinion article written by Lana Mamkgh in the Arabic Jordanian Daily, Al Rai. Taking her role as an agent in the public sphere, she stresses the National and feminist ideologies, demonstrating the use of assertive, evaluative, and expressive linguistic and rhetorical devices that appeal to the logic, ethics, and emotions of the addressee. Highlighting the agency of Jordanian writers in the media, the study sought to achieve the macro goal of dispensing political and social justice to the underprivileged. Further, the study seeks to prove that the voice of Jordanian women, viewed as underrepresented and invisible in the public arena, has come through clearly.

Keywords: critical discourse analysis, sociocognitive theory, ideology, women discourse, media

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Authors: Irit Rutman Halili, Tehila Zvulun, Natali Elgabsi, Revaya Cohen, Shlomo Sarig

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Active sand dunes (ASD) may cause significant damage to field crops and livelihood, and therefore, it is necessary to find a treatment that would enhance ADS soil stability. Biological soil crusts (biocrusts) contain microorganisms on the soil surface. Metabolic polysaccharides secreted by biocrust cyanobacteria glue the soil particles into aggregates, thereby stabilizing the soil surface. Filter cake powder (FCP) is a waste by-product in the final stages of the production of sugar from sugarcane, and its disposal causes significant environmental pollution. FCP contains high concentrations of polysaccharides and has recently been shown to be soil stability enhancing agent in ASD. It has been reported that adding FCP to the ASD soil surface by dispersal significantly increases the level of penetration resistance of soil biocrust (PRSB) nine weeks after a single treatment. However, it was not known whether a similar effect could be obtained by administering the FCP in liquid form by means of spraying. It has now been found that spraying a water solution of FCP onto the ASD soil surface significantly increased the level of penetration resistance of soil biocrust (PRSB) three weeks after a single treatment. These results suggest that FCP spraying can be used as a short-term soil stability-enhancing agent for ASD, while administration by dispersal might be more efficient over the long term. Finally, an additional benefit of using FCP as a soil stabilizer, either by dispersal or by spraying, is the reduction in environmental pollution that would otherwise result from the disposal of FCP solid waste.

Keywords: active sand dunes, filter cake powder, biological soil crusts, penetration resistance of soil biocrust

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Authors: Rahul Paul, Kedar Nath Das

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The paradigm of Reinforcement Learning (RL) has become prominent in training intelligent agents to make decisions in environments that are both dynamic and uncertain. The primary objective of RL is to optimize the policy of an agent in order to maximize the cumulative reward it receives throughout a given period. Nevertheless, the process of optimization presents notable difficulties as a result of the inherent trade-off between exploration and exploitation, the presence of extensive state-action spaces, and the intricate nature of the dynamics involved. Evolutionary Optimization Methods (EOMs) have garnered considerable attention as a supplementary approach to tackle these challenges, providing distinct capabilities for optimizing RL policies and value functions. The ongoing advancement of research in both RL and EOMs presents an opportunity for significant advancements in autonomous decision-making systems. The convergence of these two fields has the potential to have a transformative impact on various domains of artificial intelligence (AI) applications. This article highlights the considerable influence of EOMs in enhancing the capabilities of RL. Taking advantage of evolutionary principles enables RL algorithms to effectively traverse extensive action spaces and discover optimal solutions within intricate environments. Moreover, this paper emphasizes the practical implementations of EOMs in the field of RL, specifically in areas such as robotic control, autonomous systems, inventory problems, and multi-agent scenarios. The article highlights the utilization of EOMs in facilitating RL agents to effectively adapt, evolve, and uncover proficient strategies for complex tasks that may pose challenges for conventional RL approaches.

Keywords: machine learning, reinforcement learning, loss function, optimization techniques, evolutionary optimization methods

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Authors: Mini P. Singh, Jagat Ram, Archit Kumar, Tripti Rungta, Jasmine Khurana, Amit Gupta, R. K. Ratho

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Introduction: Human adenovirus is the most common agent involved in viral conjunctivitis. The clinical manifestations vary with different serotypes. The identification of the circulating strains followed by phylogenetic analysis can be helpful in understanding the origin and transmission of the disease. The present study aimed to carry out molecular epidemiology of the adenovirus types in the patients with conjunctivitis presenting to the eye centre of a tertiary care hospital in North India. Materials and Methods: The conjunctival swabs were collected from 23 suspected adenoviral conjunctivitis patients between April-August, 2014 and transported in viral transport media. The samples were subjected to nested PCR targeting hexon gene of human adenovirus. The band size of 956bp was eluted and 8 representative positive samples were subjected to sequencing. The sequences were analyzed by using CLUSTALX2.1 and MEGA 5.1 software. Results: The male: female ratio was found to be 3.6:1. The mean age of presenting patients was 43.95 years (+17.2). Approximately 52.1% (12/23) of patients presented with bilateral involvement while 47.8% (11/23) with unilateral involvement of the eye. Human adenovirus DNA could be detected in 65.2% (15/23) of the patients. The phylogenetic analysis revealed presence of serotype 8 in 7 patients and serotype 4 in one patient. The serotype 8 sequences showed 99-100% identity with Tunisian, Indian and Japanese strains. The adenovirus serotype 4 strains had 100% identity with strains from Tunisia, China and USA. Conclusion: Human adenovirus was found be an important etiological agent for conjunctivitis in our set up. The phylogenetic analysis showed that the predominant circulating strains in our epidemic keratoconjunctivitis were serotypes 8 and 4.

Keywords: conjunctivitis, human adenovirus, molecular epidemiology, phylogenetics

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Authors: Alex Kiselyov, Suehyun Cho, Darrell Harrington; Florent Cros, Olin Palmer, John Caputo, Michael Kardosh, Eran Oren, William Loudon, Michael Shpigelmacher

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Despite the most aggressive surgical and adjuvant therapeutic strategies, treatment of both pediatric and adult brainstem tumors remains problematic. Novel strategies, including targeted biologics, immunotherapy, and specialized delivery systems such as convection-enhanced delivery (CED), have been proposed. While some of these novel treatments are entering phase I trials, the field is still in need of treatment(s) that exhibits dramatically enhanced potency with optimal therapeutic ratio. Bionaut Labs has developed a modular microrobotic platform for performing localized delivery of diverse therapeutics in vivo. Our biocompatible particles (Bionauts™) are externally propelled and visualized in real-time. Bionauts™ are specifically designed to enhance the effect of radiation therapy via anatomically precise delivery of a radiosensitizing agent, as exemplified by temozolomide (TMZ) and Avastin™ to the brainstem gliomas of diverse origin. The treatment protocol is designed to furnish a better therapeutic outcome due to the localized (vs systemic) delivery of the drug to the neoplastic lesion(s) for use as a synergistic combination of radiation and radiosensitizing agent. In addition, the procedure is minimally invasive and is expected to be appropriate for both adult and pediatric patients. Current progress, including platform optimization, selection of the lead radiosensitizer as well as in vivo safety studies of the Bionauts™ in large animals, specifically the spine and the brain of porcine and ovine models, will be discussed.

Keywords: Bionaut, brainstem, glioma, local delivery, micro-robot, radiosensitizer

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Authors: Ashirgul Kozhagulova, Ainash Shabdirova, Galym Tokazhanov, Minh Nguyen

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The synthetic rocks have been advantageous over the natural rocks in terms of availability and the consistent studying the impact of a particular parameter. The artificial rocks can be fabricated using variety of techniques such as mixing sand and Portland cement or gypsum, firing the mixture of sand and fine powder of borosilicate glass or by in-situ precipitation of calcite solution. In this study, sodium silicate solution has been used as the cementing agent for the quartz sand. The molded soft cylindrical sandstone samples are placed in the gas-tight pressure vessel, where the hardening of the material takes place as the chemical reaction between carbon dioxide and the silicate solution progresses. The vessel allows uniform disperse of carbon dioxide and control over the ambient gas pressure. Current paper shows how the bonding material is initially distributed in the intergranular space and the surface of the sand particles by the usage of Electron Microscopy and the Energy Dispersive Spectroscopy. During the study, the strength of the cement bond as a function of temperature is observed. The impact of cementing agent dosage on the micro and macro characteristics of the sandstone is investigated. The analysis of the cement bond at micro level helps to trace the changes to particles bonding damage after a potential yielding. Shearing behavior and compressional response have been examined resulting in the estimation of the shearing resistance and cohesion force of the sandstone. These are considered to be main input values to the mathematical prediction models of sand production from weak clastic oil reservoir formations.

Keywords: artificial sanstone, cement bond, microstructure, SEM, triaxial shearing

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Authors: Seyed Reza Aghili, Tahereh Shokohi, Lotfollah Davoodi, Zahra Kashi, Azam Moslemi, Mahdi Abastabar, Iman Haghani, Sabah Mayahi, Asoudeh A.

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Introduction: In diabetic foot ulcers, if fungal agents such as Candida species penetrate into the cutaneous or depth of ulcer, can increase the degree of the wound and cause Candia infection and make it more difficult to heal. Material & Methods: A cross-sectional study was performed on 100 diabetic foot ulcer patients in 2020 in Sari, Iran. patient's data and wound grade were recorded in a questionnaire. Candida infection was diagnosed with direct microscopic examination and culture of samples. Colony-PCR molecular method was used for ITS region of DNA and then PCR-RFLP with Msp1 enzyme and using HWP1 specific gene to determine species of Candida agent. Results: Of 100 patients, the mean age 62.1 ± 10.8 years, 95% type 2 diabetes, 83%>10 years duration diabetes, 59% male, 66%> poor education level, 99% married, 52% rural, 95% neuropathic symptoms, 88% using antibiotics, 69%HbA1C >9%, and mean ulcer degree 2.6±1.05 were. Candida infection was seen in 13% of the deep tissue of the wound and 7% cutaneous around the wound. The predominant Candida isolated was C. parapsilosis (71.5%), C .albicans (14.3%). Fungal infections caused by mold fungi were not detected. There was a statistically significant relationship between yeast infection and gender, rural, HbA1C and ulcer degree. Conclusion: Mycological evaluations often are ignored. Candida parapsilosis is the most common infectious agent in these patients and may require specific treatment. Therefore, more attention of physicians to Candida infections particularly, early diagnosis and effective treatment can help faster recovery and prevent amputation.

Keywords: diabetic foot ulcer, candida infection, risk factors, c. parapsilosis

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Authors: Ichiro Takahashi

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One of the major assumptions of mainstream macroeconomics is the path independence of capital stock. This paper challenges this assumption by employing an agent-based approach. The simulation results showed the existence of multiple "quasi-steady state" equilibria of the capital stock, which may cast serious doubt on the validity of the assumption. The finding would give a better understanding of many phenomena that involve hysteresis, including the causes of poverty. The "market-clearing view" has been widely shared among major schools of macroeconomics. They understand that the capital stock, the labor force, and technology, determine the "full-employment" equilibrium growth path and demand/supply shocks can move the economy away from the path only temporarily: the dichotomy between the short-run business cycles and the long-run equilibrium path. The view then implicitly assumes the long-run capital stock to be independent of how the economy has evolved. In contrast, "Old Keynesians" have recognized fluctuations in output as arising largely from fluctuations in real aggregate demand. It will then be an interesting question to ask if an agent-based macroeconomic model, which is known to have path dependence, can generate multiple full-employment equilibrium trajectories of the capital stock in the super-long run. If the answer is yes, the equilibrium level of capital stock, an important supply-side factor, would no longer be independent of the business cycle phenomenon. This paper attempts to answer the above question by using the agent-based macroeconomic model developed by Takahashi and Okada (2010). The model would serve this purpose well because it has neither population growth nor technology progress. The objective of the paper is twofold: (1) to explore the causes of long-term business cycle, and (2) to examine the super-long behaviors of the capital stock of full-employment economies. (1) The simulated behaviors of the key macroeconomic variables such as output, employment, real wages showed widely diversified macro-economies. They were often remarkably stable but exhibited both short-term and long-term fluctuations. The long-term fluctuations occur through the following two adjustments: the quantity and relative cost adjustments of capital stock. The first one is obvious and assumed by many business cycle theorists. The reduced aggregate demand lowers prices, which raises real wages, thereby decreasing the relative cost of capital stock with respect to labor. (2) The long-term business cycles/fluctuations were synthesized with the hysteresis of real wages, interest rates, and investments. In particular, a sequence of the simulation runs with a super-long simulation period generated a wide range of perfectly stable paths, many of which achieved full employment: all the macroeconomic trajectories, including capital stock, output, and employment, were perfectly horizontal over 100,000 periods. Moreover, the full-employment level of capital stock was influenced by the history of unemployment, which was itself path-dependent. Thus, an experience of severe unemployment in the past kept the real wage low, which discouraged a relatively costly investment in capital stock. Meanwhile, a history of good performance sometimes brought about a low capital stock due to a high-interest rate that was consistent with a strong investment.

Keywords: agent-based macroeconomic model, business cycle, hysteresis, stability

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Authors: John T. Leman, James Gibson, Peter J. Bonitatibus

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There have been no potential clinically translatable developments of intravenous CT contrast materials over decades, and iodinated contrast agents (ICA) remain the only FDA-approved media for CT. Small molecule ICA used to highlight vascular anatomy have weak CT signals in large-to-obese patients due to their rapid redistribution from plasma into interstitial fluid, thereby diluting their intravascular concentration, and because of a mismatch of iodine’s K-edge and the high kVp settings needed to image this patient population. The use of ICA is also contraindicated in a growing population of renally impaired patients who are hypersensitive to these contrast agents; a transformative intravenous contrast agent with improved capabilities is urgently needed. Tantalum oxide nanoparticles (TaO NPs) with zwitterionic siloxane polymer coatings have high potential as clinically translatable general-purpose CT contrast agents because of (1) substantially improved imaging efficacy compared to ICA in swine/phantoms emulating medium-sized and larger adult abdomens and superior thoracic vascular contrast enhancement of thoracic arteries and veins in rabbit, (2) promising biological safety profiles showing near-complete renal clearance and low tissue retention at 3x anticipated clinical dose (ACD), and (3) clinically acceptable physiochemical parameters as concentrated bulk solutions(250-300 mgTa/mL). Here, we review requirements for general-purpose intravenous CT contrast agents in terms of patient safety, X-ray attenuating properties and contrast-producing capabilities, and physicochemical and pharmacokinetic properties. We report the current status of a TaO NP-based contrast agent, including chemical process technology developments and results of newly defined scaled-up processes for NP synthesis and purification, yielding reproducible formulations with appropriate size and concentration specifications. We discuss recent results of recent pre-clinical in vitro immunology, non-GLP high dose tolerability in rats (10x ACD), non-GLP long-term biodistribution in rats at 3x ACD, and non-GLP repeat dose in rats at ACD. We also include a discussion of NP characterization, in particular size-stability testing results under accelerated conditions (37C), and insights into TaO NP purity, surface structure, and bonding of the zwitterionic siloxane polymer coating by multinuclear (1H, 13C, 29Si) and multidimensional (2D) solution NMR spectroscopy.

Keywords: nanoparticle, imaging, diagnostic, process technology, nanoparticle characterization

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Authors: Yu Guan, Song Lu, Wei Yuan, Heping Zhang

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Gas fire extinguishing system is widely used due to its cleanliness and efficiency, and since its spray will be affected by many factors such as convection and obstacles in jetting region, so in order to evaluate its effectiveness, detecting concentration distribution in the jetting area is indispensable, which is commonly achieved by aspirating concentration detection technique. During the concentration measurement, the response time of detector is a very important parameter, especially for those fire-extinguishing systems with rapid gas dispersion. Long response time will not only underestimate its concentration but also prolong the change of concentration with time. Therefore it is necessary to analyze the factors influencing the response time. In the paper, an aspirating concentration detection method was introduced, which is achieved by using a small critical nozzle and a laminar flowmeter, and because of the response time is mainly related to the gas transport process from sampling site to the sensor, the effects of exhaust pipe size, gas flow rate, and gas concentration on its response time were analyzed. During the research, Bromotrifluoromethane (CBrF₃) was used. The effect of the sampling tube was investigated with different length of 1, 2, 3, 4 and 5 m (5mm in pipe diameter) and different pipe diameter of 3, 4, 5, 6 and 8 mm (3m in length). The effect of gas flow rate was analyzed by changing the throat diameter of the critical nozzle with 0.5, 0.682, 0.75, 0.8, 0.84 and 0.88 mm. The effect of gas concentration on response time was studied with the concentration range of 0-25%. The result showed that the response time increased with the increase of both the length and diameter of the sampling pipe, and the effect of length on response time was linear, but for the effect of diameter, it was exponential. It was also found that as the throat diameter of critical nozzle increased, the response time reduced a lot, in other words, gas flow rate has a great influence on response time. For the effect of gas concentration, the response time increased with the increase of the CBrF₃ concentration, and the slope of the curve was reduced.

Keywords: aspirating concentration detection, fire extinguishing, gaseous agent, response time

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Authors: Emad Kouhestani

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Background: Despite the enormous success of anterior cruciate ligament (ACL) reconstruction, acute neuropathic pain can develop postoperatively and is both distressing and difficult to treat once established. Pregabalin, as an anticonvulsant agent that selectively affects the nociceptive process, has been used as a pain relief agent. The purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the pain control effect of pregabalin versus placebo after ACL reconstruction. Method: A search of the literature was performed from inception to June 2022, using PubMed, Scopus, Google Scholar, Web of Science, Cochrane, and EBSCO. Studies considered for inclusion were RCTs that reported relevant outcomes (postoperative pain scores, or cumulative opioid consumption, adverse events) following the administration of pregabalin in patients undergoing ACL reconstruction. Result: Five placebo-controlled RCTs involving 272 participants met the inclusion criteria. 75 mg and 150 mg of oral pregabalin were used in included trials. Two studies used a single dose of pregabalin one hour before anesthesia induction. Two studies used pregabalin 1 hour before anesthesia induction and 12 hours after. One study used daily pregabalin 7 days before and 7 days after surgery. Out of five papers, three papers found significantly lower pain intensity and cumulative opioid consumption in the pregabalin group compared with the placebo group. However, a decrease in pain scores was found in all trials. Pregabalin administration was associated with dizziness and nausea. Conclusion: The use of pregabalin may be a valuable asset in pain management after ACL reconstruction. However, future studies with larger sample sizes and longer follow-up periods are required.

Keywords: pregabalin, anterior cruciate ligament, postoperative pain, clinical trial

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Authors: Sadie Namani, Lindita Ajazaj, Arjeta Zogaj, Vera Berisha, Bahrije Halili, Luljeta Hasani, Ajete Aliu

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Background: The outcome of bacterial meningitis is strongly related to the resistance of bacterial pathogens to the initial antimicrobial therapy. The objective of the study was to analyze the initial antimicrobial therapy, the resistance of meningeal pathogens and the outcome of adults bacterial meningitis cases. Materials/methods: This prospective study enrolled 46 adults older than 16 years of age, treated for bacterial meningitis during the years 2009 and 2010 at the infectious diseases clinic in Prishtinë. Patients are categorized into specific age groups: > 16-26 years of age (10 patients), > 26-60 years of age (25 patients) and > 60 years of age (11 patients). All p-values < 0.05 were considered statistically significant. Data were analyzed using Stata 7.1 and SPSS 13. Results: During the two year study period 46 patients (28 males) were treated for bacterial meningitis. 33 patients (72%) had a confirmed bacterial etiology; 13 meningococci, 11 pneumococci, 7 gram-negative bacilli (Ps. aeruginosa 2, Proteus sp. 2, Acinetobacter sp. 2 and Klebsiella sp. 1 case) and 2 staphylococci isolates were found. Neurological complications developed in 17 patients (37%) and the overall mortality rate was 13% (6 deaths). Neurological complications observed were: cerebral abscess (7/46; 15.2%), cerebral edema (4/46; 8.7%); haemiparesis (3/46; 6.5%); recurrent seizures (2/46; 4.3%), and single cases of thrombosis sinus cavernosus, facial nerve palsy and decerebration (1/46; 2.1%). The most common meningeal pathogens were meningococcus in the youngest age group, gram negative-bacilli in second age group and pneumococcus in eldery age group. Initial single-agent antibiotic therapy (ceftriaxone) was used in 17 patients (37%): in 60% of patients in the youngest age group and in 44% of cases in the second age group. 29 patients (63%) were treated with initial dual-agent antibiotic therapy; ceftriaxone in combination with vancomycin or ampicillin. Ceftriaxone and ampicillin were the most commonly used antibiotics for the initial empirical therapy in adults > 50 years of age. All adults > 60 years of age were treated with the initial dual-agent antibiotic therapy as in this age group was recorded the highest mortality rate (M=27%) and adverse outcome (64%). Resistance of pathogens to antimicrobics was recorded in cases caused by gram-negative bacilli and was associated with greater risk for developing neurological complications (p=0.09). None of the gram-negative bacilli were resistant to carbapenems; all were resistant to ampicillin while 5/7 isolates were resistant to cefalosporins. Resistance of meningococci and pneumococci to beta-lactams was not recorded. There were no statistical differences in the occurrence of neurological complications (p > 0.05), resistance of meningeal pathogens to antimicrobics (p > 0.05) and the inital antimicrobial therapy (one vs. two antibiotics) concerning group-ages in adults. Conclusions: The initial antibiotic therapy with ceftriaxone alone or in combination with vancomycin or ampicillin did not cover cases caused by gram-negative bacilli.

Keywords: adults, bacterial meningitis, outcomes, therapy

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Authors: Lacramioara Ochiuz, Aurelia Vasile, Iulian Stoleriu, Cristina Ghiciuc, Maria Ignat

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Topical administration of chemotherapeutic agents (eg. carmustine, bexarotene, mechlorethamine etc.) in local treatment of cutaneous T-cell lymphoma (CTCL) is accompanied by multiple side effects, such as contact hypersensitivity, pruritus, skin atrophy or even secondary malignancies. A known method of reducing the side effects of anticancer agent is the development of modified drug release systems using drug incapsulation in biocompatible nanoporous inorganic matrices, such as mesoporous MCM-41 silica. Mesoporous MCM-41 silica is characterized by large specific surface, high pore volume, uniform porosity, and stable dispersion in aqueous medium, excellent biocompatibility, in vivo biodegradability and capacity to be functionalized with different organic groups. Therefore, MCM-41 is an attractive candidate for a wide range of biomedical applications, such as controlled drug release, bone regeneration, protein immobilization, enzymes, etc. The main advantage of this material lies in its ability to host a large amount of the active substance in uniform pore system with adjustable size in a mesoscopic range. Silanol groups allow surface controlled functionalization leading to control of drug loading and release. This study shows (I) the amino-grafting optimization of mesoporous MCM-41 silica matrix by means of co-condensation during synthesis and post-synthesis using APTES (3-aminopropyltriethoxysilane); (ii) loading the therapeutic agent (carmustine) obtaining a modified drug release systems; (iii) determining the profile of in vitro carmustine release from these systems; (iv) assessment of carmustine release kinetics by fitting on four mathematical models. Obtained powders have been described in terms of structure, texture, morphology thermogravimetric analysis. The concentration of the therapeutic agent in the dissolution medium has been determined by HPLC method. In vitro dissolution tests have been done using cell Enhancer in a 12 hours interval. Analysis of carmustine release kinetics from mesoporous systems was made by fitting to zero-order model, first-order model Higuchi model and Korsmeyer-Peppas model, respectively. Results showed that both types of highly ordered mesoporous silica (amino grafted by co-condensation process or post-synthesis) are thermally stable in aqueous medium. In what regards the degree of loading and efficiency of loading with the therapeutic agent, there has been noticed an increase of around 10% in case of co-condensation method application. This result shows that direct co-condensation leads to even distribution of amino groups on the pore walls while in case of post-synthesis grafting many amino groups are concentrated near the pore opening and/or on external surface. In vitro dissolution tests showed an extended carmustine release (more than 86% m/m) both from systems based on silica functionalized directly by co-condensation and after synthesis. Assessment of carmustine release kinetics revealed a release through diffusion from all studied systems as a result of fitting to Higuchi model. The results of this study proved that amino-functionalized mesoporous silica may be used as a matrix for optimizing the anti-cancer topical therapy by loading carmustine and developing prolonged-release systems.

Keywords: carmustine, silica, controlled, release

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Authors: Tsuneyuki Namekata, Yoko Namekata

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It is known that the mean investment evolves from a very low initial value to some high level in the Continuous Prisoner's Dilemma. We examine how the cooperation level evolves from a low initial level to a high level in our Demographic Multi-level Donor-Recipient situation. In the Multi-level Donor-Recipient game, one player is selected as a Donor and the other as a Recipient randomly. The Donor has multiple cooperative moves and one defective move. A cooperative move means the Donor pays some cost for the Recipient to receive some benefit. The more cooperative move the Donor takes, the higher cost the Donor pays and the higher benefit the Recipient receives. The defective move has no effect on them. Two consecutive Multi-level Donor-Recipient games, one as a Donor and the other as a Recipient, can be viewed as a discrete version of the Continuous Prisoner's Dilemma. In the Demographic Multi-level Donor-Recipient game, players are initially distributed spatially. In each period, players play multiple Multi-level Donor-Recipient games against other players. He leaves offspring if possible and dies because of negative accumulated payoff of him or his lifespan. Cooperative moves are necessary for the survival of the whole population. There is only a low level of cooperative move besides the defective move initially available in strategies of players. A player may modify and expand his strategy by his recent experiences or practices. We distinguish several types of a player about modification and expansion. We show, by Agent-Based Simulation, that introducing only the modification increases the emergence rate of cooperation and introducing both the modification and the expansion further increases it and a high level of cooperation does emerge in our Demographic Multi-level Donor-Recipient Game.

Keywords: agent-based simulation, donor-recipient game, emergence of cooperation, spatial structure, TFT, TF2T

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Authors: Nusaiba Al-Nemrawi, Belal Al-Husein

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Methotrexate (MTX) is a stoichiometric inhibitor of dihydrofolate reductase, which is essential for DNA synthesis. MTX is a chemotherapeutic agent used for treating many types of cancer cells. However, cells’ resistant to MTX is very common and its pharmacokinetic behavior is highly problematic. of MTX within tumor cells, we propose encapsulation of antitumor drugs in nanoparticulated systems. Chitosan (CS) is a naturally occurring polymer that is biocompatibe, biodegradable, non-toxic, cationic and bioadhesive. CS nanoparticles (CS-NPs) have been used as drug carrier for targeted delivery. Titanium dioxide (TiO2), a natural mineral oxide, which is used in biomaterials due to its high stability and antimicrobial and anticorrosive properties. TiO2 showed a potential as a tumor suppressor. In this study a new formulation of MTX loaded in CS NPs (CS-MTX NPs) and coated with Titanium oxide (TiO2) was prepared. The mean particle size, zeta potential, polydispersity index were measured. The interaction between CS NPs and TiO2 NPs was confirmed using FTIR and XRD. CS-MTX NPs was studied in vitro using the tumor cell line MCF-7 (human breast cancer). The results showed that CS-MTX has a size around 169 nm and as they were coated with TiO2, the size ranged between and depending on the ratio of CS-MTX to TiO2 ratio used in the preparation. All NPs (uncoated and coated carried positive charges and were monodispersed. The entrapment efficacy was around 65%. Both FTIR and XRD proved that TiO2 interacted with CS-MTX NPs. The drug invitro release was controlled and sustained over days. Finally, the studied in vitro using the tumor cell line MCF-7 suggested that combining nanomaterials with anticancer drugs CS-MTX NPs may be more effective than free MTX for cancer treatment. In conclusion, the combination of CS-MTX NPs and TiO2 NPs showed excellent time-dependent in vitro antitumor behavior, therefore, can be employed as a promising anticancer agent to attain efficient results towards MCF-7 cells.

Keywords: Methotrexate, Titanium dioxide, Chitosan nanoparticles, cancer

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Authors: Norhan H. Mahdally, Bathini Thissera Riham A. ElShiekh, Noha M. Elhosseiny, Mona T. Kashef, Ali M. El Halawany, Mostafa E. Rateb, Ahmed S. Attia

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Multidrug-resistant (MDR) pathogens pose a global threat to healthcare settings. The exhaustion of the current antibiotic arsenal and the scarcity of new antimicrobials in the pipeline aggravate this threat and necessitate a prompt and effective response. This study focused on two major pathogens that can cause serious infections: carbapenem-resistant Acinetobacter baumannii (CRAB) and methicillin-resistant Staphylococcus aureus (MRSA). Multiple soil isolates were collected from several locations throughout Egypt and screened for their conventional and non-conventional antimicrobial activities against MDR pathogens. One isolate exhibited potent antimicrobial activity and was subjected to multiple rounds of fractionation. After fermentation and bio-guided fractionation, we identified pure microbial secondary metabolites with two scaffolds that exhibited promising effects against CRAB and MRSA. Scaling up and chemical synthesis of derivatives of the identified metabolite resulted in obtaining a more potent derivative, which we designated as 2HP. Cytotoxicity studies indicated that 2HP is well-tolerated by human cells. Ongoing work is focusing on formulating the new compound into a nano-formulation to enhance its delivery. Also, to have a better idea about how this compound works, a proteomic approach is currently underway. Our findings suggest that 2HP is a potential new broad-spectrum antimicrobial agent. Further studies are needed to confirm these findings and to develop 2HP into a safe and effective treatment for MDR infections.

Keywords: broad-spectrum antimicrobials, carbapenem-resistant acinetobacter baumannii, drug discovery, methicillin-resistant staphylococcus aureus, multidrug-resistant, natural products

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Authors: Affiah D. U., Katuri I. P., Emefiene M. E., Amienyo C. A.

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Broccoli (Brassica oleraceae L., var. italica) is one of the most important vegetables that is high in nutrients and bioactive compounds. It easily grown on a wide range of soil types and is adaptable to many different climatic conditions. This study was carried out within Jos North and environs in vitro to evaluate Neem (Azadirachta indica) leaves extract against Albugo candida, the causative agent of white blisters disease of broccoli. Through the survey, prevalence and incidence were accessed and a fluffy white growth symptom on the underside of leaves was also observed on the field. Infected leaves samples were collected from three different farms namely: Farin Gada, Naraguta, and Juth and the organism associated with the disease was isolated. Pathogenicity test carried out revealed the fungal isolate Albugo candida to be responsible for the disease. Antimicrobial susceptibility test was performed using agar well diffusion method to determine the minimum inhibitory concentrations of two extract of Azadirachta indica leaves against the organism. Ethanolic extract had the highest antifungal activities of 3.30±0.21 - 17.61± 0.11 while aqueous extract had the least antifungal activities of 0.00±0.00 - 13.23±0.12. The minimum inhibitory concentration of aqueous was 100 mg/ml while its minimum fungicidal concentration was at 200 mg/ml. For ethanol, the minimum inhibitory concentration was 50 mg/ml while its minimum fungicidal concentration was 100 mg/ml. Plants being less toxic in usage over synthetic or inorganic chemicals makes them easy to handle, easily accessible and renewable. Due to the biosafety of plant extracts and its availability since the plant-based extracts of the two different solvents were found to be effective against the test organism hence, it is recommended for in-depth research to make it readily available for control of other pathogens and pests.

Keywords: antifungal, biocontrol, broccoli, fungi

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Authors: Dmytro Symak

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Drying is a complex technologic, thermal and energy process. Energy cost of drying processes in many cases is the most costly stage of production, and can be over 50% of total costs. As we know, in Ukraine over 85% of Portland cement is produced moist, and the finished product energy costs make up to almost 60%. During the wet cement production, energy costs make up over 5500 kJ / kg of clinker, while during the dry only 3100 kJ / kg, that is, switching to a dry Portland cement will allow result into double cutting energy costs. Therefore, to study raw materials drying process in the manufacture of Portland cement is very actual task. The fine ferrous materials drying (small pyrites, red mud, clay Kyoko) is recommended to do by filtration method, that is one of the most intense. The essence of filtration method drying lies in heat agent filtering through a stationary layer of wet material, which is located on the perforated partition, in the "layer-dispersed material - perforated partition." For the optimum drying purposes, it is necessary to establish the dependence of pressure loss in the layer of dispersed material, and the values of heat and mass transfer, depending on the speed of the gas flow filtering. In our research, the experimentally determined pressure loss in the layer of dispersed material was generalized based on dimensionless complexes in the form and coefficients of heat exchange. We also determined the relation between the coefficients of mass and heat transfer. As a result of theoretic and experimental investigations, it was possible to develop a methodology for calculating the optimal parameters for the thermal agent and the main parameters for the filtration drying installation. The comparison of calculated by known operating expenses methods for the process of small pyrites drying in a rotating drum and filtration method shows to save up to 618 kWh per 1,000 kg of dry material and 700 kWh during filtration drying clay.

Keywords: drying, cement, heat and mass transfer, filtration method

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Authors: Paul J Yazaki, Michael Bouvet, John Shively

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Surgery for solid gastrointestinal (GI) cancers such as pancreatic, colorectal, and gastric adenocarcinoma remains the mainstay of curative therapy. Complete resection of the primary tumor with negative margins (R0 resection), its draining lymph nodes, and distant metastases offers the optimal surgical benefit. Real-time fluorescence guided surgery (FGS) promises to improve GI cancer outcomes and is rapidly advancing with tumor-specific antibody conjugated fluorophores that can be imaged using near infrared (NIR) technology. Carcinoembryonic Antigen (CEA) is a non-internalizing tumor antigen validated as a surface tumor marker expressed in >95% of colorectal, 80% of gastric, and 60% of pancreatic adenocarcinomas. Our humanized anti-CEA hT84.66-M5A (M5A) monoclonal antibody (mAb)was conjugated with the NHS-IRDye800CW fluorophore and shown it can rapidly and effectively NIRoptical imageorthotopically implanted human colon and pancreatic cancer in mouse models. A limitation observed is that these NIR-800 dye conjugated mAbs have a rapid clearance from the blood, leading to a narrow timeframe for FGS and requiring high doses for effective optical imaging. We developed a novel antibody-fluorophore conjugate by incorporating a PEGylated sidearm linker to shield or mask the IR800 dye’s hydrophobicity which effectively extended the agent’s blood circulation half-life leading to increased tumor sensitivity and lowered normal hepatic uptake. We hypothesized that our unique anti-CEA linked to the fluorophore, IR800 by PEGylated sidewinder, M5A-SW-IR800 will become the next generation optical imaging agent, safe, effective, and widely applicable for intraoperative image guided surgery in CEA expressing GI cancers.

Keywords: optical imaging, anti-CEA, cancer, fluorescence-guided surgery

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Authors: Jeanne Leblond, Warren Viricel, Amira Mbarek

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Although several products have reached the market, gene therapeutics are still in their first stages and require optimization. It is possible to improve their lacking efficiency by the use of carefully engineered vectors, able to carry the genetic material through each of the biological barriers they need to cross. In particular, getting inside the cell is a major challenge, because these hydrophilic nucleic acids have to cross the lipid-rich plasmatic and/or endosomal membrane, before being degraded into lysosomes. It takes less than one hour for newly endocytosed liposomes to reach highly acidic lysosomes, meaning that the degradation of the carried gene occurs rapidly, thus limiting the transfection efficiency. We propose to use a new pH-sensitive lipid able to change its conformation upon protonation at endosomal pH values, leading to the disruption of the lipidic bilayer and thus to the fast release of the nucleic acids into the cytosol. It is expected that this new pH-sensitive mechanism promote endosomal escape of the gene, thereby its transfection efficiency. The main challenge of this work was to design a preparation presenting fast-responding lipidic bilayer destabilization properties at endosomal pH 5 while remaining stable at blood pH value and during storage. A series of pH-sensitive lipids able to perform a conformational switch upon acidification were designed and synthesized. Liposomes containing these switchable lipids, as well as co-lipids were prepared and characterized. The liposomes were stable at 4°C and pH 7.4 for several months. Incubation with siRNA led to the full entrapment of nucleic acids as soon as the positive/negative charge ratio was superior to 2. The best liposomal formulation demonstrated a silencing efficiency up to 10% on HeLa cells, very similar to a commercial agent, with a lowest toxicity than the commercial agent. Using flow cytometry and microscopy assays, we demonstrated that drop of pH was required for the transfection efficiency, since bafilomycin blocked the transfection efficiency. Additional evidence was brought by the synthesis of a negative control lipid, which was unable to switch its conformation, and consequently exhibited no transfection ability. Mechanistic studies revealed that the uptake was mediated through endocytosis, by clathrin and caveolae pathways, as reported for previous lipid nanoparticle systems. This potent system was used for the treatment of hypercholesterolemia. The switchable lipids were able to knockdown PCSK9 expression on human hepatocytes (Huh-7). Its efficiency is currently evaluated on in vivo mice model of PCSK9 KO mice. In summary, we designed and optimized a new cationic pH-sensitive lipid for gene delivery. Its transfection efficiency is similar to the best available commercial agent, without the usually associated toxicity. The promising results lead to its use for the treatment of hypercholesterolemia on a mice model. Anticancer applications and pulmonary chronic disease are also currently investigated.

Keywords: liposomes, siRNA, pH-sensitive, molecular switch

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Authors: Zubi Sadiq, Ghazala Yaqub, Almas Hamid

Abstract:

We wish to report herein a very stimulating variation in Fischer indole reaction by adopting solvent and catalyst free conditions. A concise synthesis of dinitro tetrahydrocarbazole derivative 3 was introduced without the use of any accelerating agent at ambient temperature with fairly good yield. Product was fully corroborated by UV, FTIR, 1H NMR, 13C NMR, MS, and CHN analysis.

Keywords: fischer indole reaction, neutral medium, solvent free synthesis, tetrahydrocarbazole

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