Search results for: orphan drug production
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 9326

Search results for: orphan drug production

7736 Designing Form, Meanings, and Relationships for Future Industrial Products. Case Study Observation of PAD

Authors: Elisabetta Cianfanelli, Margherita Tufarelli, Paolo Pupparo

Abstract:

The dialectical mediation between desires and objects or between mass production and consumption continues to evolve over time. This relationship is influenced both by variable geometries of contexts that are distant from the mere design of product form and by aspects rooted in the very definition of industrial design. In particular, the overcoming of macro-areas of innovation in the technological, social, cultural, formal, and morphological spheres, supported by recent theories in critical and speculative design, seems to be moving further and further away from the design of the formal dimension of advanced products. The articulated fabric of theories and practices that feed the definition of “hyperobjects”, and no longer objects describes a common tension in all areas of design and production of industrial products. The latter are increasingly detached from the design of the form and meaning of the same in mass productions, thus losing the quality of products capable of social transformation. For years we have been living in a transformative moment as regards the design process in the definition of the industrial product. We are faced with a dichotomy in which there is, on the one hand, a reactionary aversion to the new techniques of industrial production and, on the other hand, a sterile adoption of the techniques of mass production that we can now consider traditional. This ambiguity becomes even more evident when we talk about industrial products, and we realize that we are moving further and further away from the concepts of "form" as a synthesis of a design thought aimed at the aesthetic-emotional component as well as the functional one. The design of forms and their contents, as statutes of social acts, allows us to investigate the tension on mass production that crosses seasons, trends, technicalities, and sterile determinisms. The design culture has always determined the formal qualities of objects as a sum of aesthetic characteristics functional and structural relationships that define a product as a coherent unit. The contribution proposes a reflection and a series of practical experiences of research on the form of advanced products. This form is understood as a kaleidoscope of relationships through the search for an identity, the desire for democratization, and between these two, the exploration of the aesthetic factor. The study of form also corresponds to the study of production processes, technological innovations, the definition of standards, distribution, advertising, the vicissitudes of taste and lifestyles. Specifically, we will investigate how the genesis of new forms for new meanings introduces a change in the relative innovative production techniques. It becomes, therefore, fundamental to investigate, through the reflections and the case studies exposed inside the contribution, also the new techniques of production and elaboration of the forms of the products, as new immanent and determining element inside the planning process.

Keywords: industrial design, product advanced design, mass productions, new meanings

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7735 Minimization Entropic Applied to Rotary Dryers to Reduce the Energy Consumption

Authors: I. O. Nascimento, J. T. Manzi

Abstract:

The drying process is an important operation in the chemical industry and it is widely used in the food, grain industry and fertilizer industry. However, for demanding a considerable consumption of energy, such a process requires a deep energetic analysis in order to reduce operating costs. This paper deals with thermodynamic optimization applied to rotary dryers based on the entropy production minimization, aiming at to reduce the energy consumption. To do this, the mass, energy and entropy balance was used for developing a relationship that represents the rate of entropy production. The use of the Second Law of Thermodynamics is essential because it takes into account constraints of nature. Since the entropy production rate is minimized, optimals conditions of operations can be established and the process can obtain a substantial gain in energy saving. The minimization strategy had been led using classical methods such as Lagrange multipliers and implemented in the MATLAB platform. As expected, the preliminary results reveal a significant energy saving by the application of the optimal parameters found by the procedure of the entropy minimization It is important to say that this method has shown easy implementation and low cost.

Keywords: thermodynamic optimization, drying, entropy minimization, modeling dryers

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7734 Bis-Azlactone Based Biodegradable Poly(Ester Amide)s: Design, Synthesis and Study

Authors: Kobauri Sophio, Kantaria Tengiz, Tugushi David, Puiggali Jordi, Katsarava Ramaz

Abstract:

Biodegradable biomaterials (BB) are of high interest for numerous applications in modern medicine as resorbable surgical materials and drug delivery systems. This kind of materials can be cleared from the body after the fulfillment of their function that excludes a surgical intervention for their removal. One of the most promising BBare amino acids based biodegradable poly(ester amide)s (PEAs) which are composed of naturally occurring (α-amino acids) and non-toxic building blocks such as fatty diols and dicarboxylic acids. Key bis-nucleophilic monomers for synthesizing the PEAs are diamine-diesters-di-p-toluenesulfonic acid salts of bis-(α-amino acid)-alkylenediesters (TAADs) which form the PEAs after step-growth polymerization (polycondensation) with bis-electrophilic counter-partners - activated diesters of dicarboxylic acids. The PEAs combine all advantages of the 'parent polymers' – polyesters (PEs) and polyamides (PAs): Ability of biodegradation (PEs), a high affinity with tissues and a wide range of desired mechanical properties (PAs). The scopes of applications of thePEAs can substantially be expanded by their functionalization, e.g. through the incorporation of hydrophobic fragments into the polymeric backbones. Hydrophobically modified PEAs can form non-covalent adducts with various compounds that make them attractive as drug carriers. For hydrophobic modification of the PEAs, we selected so-called 'Azlactone Method' based on the application of p-phenylene-bis-oxazolinons (bis-azlactones, BALs) as active bis-electrophilic monomers in step-growth polymerization with TAADs. Interaction of BALs with TAADs resulted in the PEAs with low MWs (Mw2,800-19,600 Da) and poor material properties. The high-molecular-weight PEAs (Mw up to 100,000) with desirable material properties were synthesized after replacement of a part of BALs with activated diester - di-p-nitrophenylsebacate, or a part of TAAD with alkylenediamine – 1,6-hexamethylenediamine. The new hydrophobically modified PEAs were characterized by FTIR, NMR, GPC, and DSC. It was shown that after the hydrophobic modification the PEAs retain the biodegradability (in vitro study catalyzed by α-chymptrypsin and lipase), and are of interest for constructing resorbable surgical and pharmaceutical devices including drug delivering containers such as microspheres. The new PEAs are insoluble in hydrophobic organic solvents such as chloroform or dichloromethane (swell only) that allowed elaborating a new technology of fabricating microspheres.

Keywords: amino acids, biodegradable polymers, bis-azlactones, microspheres

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7733 Prioritization of Customer Order Selection Factors by Utilizing Conjoint Analysis: A Case Study for a Structural Steel Firm

Authors: Burcu Akyildiz, Cigdem Kadaifci, Y. Ilker Topcu, Burc Ulengin

Abstract:

In today’s business environment, companies should make strategic decisions to gain sustainable competitive advantage. Order selection is a crucial issue among these decisions especially for steel production industry. When the companies allocate a high proportion of their design and production capacities to their ongoing projects, determining which customer order should be chosen among the potential orders without exceeding the remaining capacity is the major critical problem. In this study, it is aimed to identify and prioritize the evaluation factors for the customer order selection problem. Conjoint analysis is used to examine the importance level of each factor which is determined as the potential profit rate per unit of time, the compatibility of potential order with available capacity, the level of potential future order with higher profit, customer credit of future business opportunity, and the negotiability level of production schedule for the order.

Keywords: conjoint analysis, order prioritization, profit management, structural steel firm

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7732 Production of Soy Yoghurt Using Soymilk-Based Lactic Acid Bacteria as Starter Culture

Authors: Ayobami Solomon Popoola, Victor N. Enujiugha

Abstract:

Production of soy-yogurt by fermentation of soymilk with lactic acid bacteria isolated from soymilk was studied. Soymilk was extracted from dehulled soybean seeds and pasteurized at 95 °C for 15 min. The soymilk was left to naturally ferment (temperature 40 °C; time 8 h) and lactic acid bacteria were isolated, screened and selected for yogurt production. Freshly prepared soymilk was pasteurized (95 °C, 15 min), inoculated with the lactic acid bacteria isolated (3% w/v starter culture) and incubated at 40 °C for 8 h. The yogurt produced was stored at 4 °C. Investigations were carried out with the aim of improving the sensory qualities and acceptability of soy yogurt. Commercial yogurt was used as a control. The percentage of soymilk inoculated was 70% of the broth. Soy-yoghurt samples produced were subsequently subjected to biochemical and microbiological assays which included total viable counts of fresh milk and soy-based yoghurt; proximate composition of functional soy-based yoghurt fermented with Lactobacillus plantarum; changes in pH, Titratable acidity, and lactic acid bacteria during a 14 day period of storage; as well as morphological and biochemical characteristics of lactic acid bacteria isolated. The results demonstrated that using Lactobacillus plantarum to inoculate soy milk for yogurt production takes about 8 h. The overall acceptability of the soy-based yogurt produced was not significantly different from that of the control sample. The use of isolate from soymilk had the added advantage of reducing the cost of yogurt starter culture, thereby making soy-yogurt, a good source of much desired good quality protein. However, more experiments are needed to improve the sensory qualities such as beany or astringent flavor and color.

Keywords: soy, soymilk, yoghurt, starter culture

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7731 Simultaneous Saccharification and Co-Fermentation of Paddy Straw and Fruit Wastes into Ethanol Production

Authors: Kamla Malik

Abstract:

For ethanol production from paddy straw firstly pretreatment was done by using sodium hydroxide solution (2.0%) at 15 psi for 1 hr. The maximum lignin removal was achieved with 0.5 mm mesh size of paddy straw. It contained 72.4 % cellulose, 15.9% hemicelluloses and 2.0 % lignin after pretreatment. Paddy straw hydrolysate (PSH) with fruits wastes (5%), such as sweet lime, apple, sapota, grapes, kinnow, banana, papaya, mango, and watermelon were subjected to simultaneous saccharification and co-fermentation (SSCF) for 72 hrs by co-culture of Saccharomyces cerevisiae HAU-1 and Candida sp. with 0.3 % urea as a cheap nitrogen source. Fermentation was carried out at 35°C and determined ethanol yield at 24 hours interval. The maximum production of ethanol was produced within 72 hrs of fermentation in PSH + sapota peels (3.9% v/v) followed by PSH + kinnow peels (3.6%) and PSH+ papaya peels extract (3.1 %). In case of PSH+ banana peels and mango peel extract the ethanol produced were 2.8 % and 2.2 % (v/v). The results of this study suggest that wastes from fruits that contain fermentable sugar should not be discarded into our environment, but should be supplemented in paddy straw which converted to useful products like bio-ethanol that can serve as an alternative energy source.

Keywords: ethanol, fermentation, fruit wastes, paddy straw

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7730 Life Cycle Assessment to Study the Acidification and Eutrophication Impacts of Sweet Cherry Production

Authors: G. Bravo, D. Lopez, A. Iriarte

Abstract:

Several organizations and governments have created a demand for information about the environmental impacts of agricultural products. Today, the export oriented fruit sector in Chile is being challenged to quantify and reduce their environmental impacts. Chile is the largest southern hemisphere producer and exporter of sweet cherry fruit. Chilean sweet cherry production reached a volume of 80,000 tons in 2012. The main destination market for the Chilean cherry in 2012 was Asia (including Hong Kong and China), taking in 69% of exported volume. Another important market was the United States with 16% participation, followed by Latin America (7%) and Europe (6%). Concerning geographical distribution, the Chilean conventional cherry production is focused in the center-south area, between the regions of Maule and O’Higgins; both regions represent 81% of the planted surface. The Life Cycle Assessment (LCA) is widely accepted as one of the major methodologies for assessing environmental impacts of products or services. The LCA identifies the material, energy, material, and waste flows of a product or service, and their impact on the environment. There are scant studies that examine the impacts of sweet cherry cultivation, such as acidification and eutrophication. Within this context, the main objective of this study is to evaluate, using the LCA, the acidification and eutrophication impacts of sweet cherry production in Chile. The additional objective is to identify the agricultural inputs that contributed significantly to the impacts of this fruit. The system under study included all the life cycle stages from the cradle to the farm gate (harvested sweet cherry). The data of sweet cherry production correspond to nationwide representative practices and are based on technical-economic studies and field information obtained in several face-to-face interviews. The study takes into account the following agricultural inputs: fertilizers, pesticides, diesel consumption for agricultural operations, machinery and electricity for irrigation. The results indicated that the mineral fertilizers are the most important contributors to the acidification and eutrophication impacts of the sheet cherry cultivation. Improvement options are suggested for the hotspot in order to reduce the environmental impacts. The results allow planning and promoting low impacts procedures across fruit companies, as well as policymakers, and other stakeholders on the subject. In this context, this study is one of the first assessments of the environmental impacts of sweet cherry production. New field data or evaluation of other life cycle stages could further improve the knowledge on the impacts of this fruit. This study may contribute to environmental information in other countries where there is similar agricultural production for sweet cherry.

Keywords: acidification, eutrophication, life cycle assessment, sweet cherry production

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7729 Characterization of Herberine Hydrochloride Nanoparticles

Authors: Bao-Fang Wen, Meng-Na Dai, Gao-Pei Zhu, Chen-Xi Zhang, Jing Sun, Xun-Bao Yin, Yu-Han Zhao, Hong-Wei Sun, Wei-Fen Zhang

Abstract:

A drug-loaded nanoparticles containing berberine hydrochloride (BH/FA-CTS-NPs) was prepared. The physicochemical characterizations of BH/FA-CTS-NPs and the inhibitory effect on the HeLa cells were investigated. Folic acid-conjugated chitosan (FA-CTS) was prepared by amino reaction of folic acid active ester and chitosan molecules; BH/FA-CTS-NPs were prepared using ionic cross-linking technique with BH as a model drug. The morphology and particle size were determined by Transmission Electron Microscope (TEM). The average diameters and polydispersity index (PDI) were evaluated by Dynamic Light Scattering (DLS). The interaction between various components and the nanocomplex were characterized by Fourier Transform Infrared Spectroscopy (FT-IR). The entrapment efficiency (EE), drug-loading (DL) and in vitro release were studied by UV spectrophotometer. The effect of cell anti-migratory and anti-invasive actions of BH/FA-CTS-NPs were investigated using MTT assays, wound healing assays, Annexin-V-FITC single staining assays, and flow cytometry, respectively. HeLa nude mice subcutaneously transplanted tumor model was established and treated with different drugs to observe the effect of BH/FA-CTS-NPs in vivo on HeLa bearing tumor. The BH/FA-CTS-NPs prepared in this experiment have a regular shape, uniform particle size, and no aggregation phenomenon. The results of DLS showed that mean particle size, PDI and Zeta potential of BH/FA-CTS NPs were (249.2 ± 3.6) nm, 0.129 ± 0.09, 33.6 ± 2.09, respectively, and the average diameter and PDI were stable in 90 days. The results of FT-IR demonstrated that the characteristic peaks of FA-CTS and BH/FA-CTS-NPs confirmed that FA-CTS cross-linked successfully and BH was encapsulated in NPs. The EE and DL amount were (79.3 ± 3.12) % and (7.24 ± 1.41) %, respectively. The results of in vitro release study indicated that the cumulative release of BH/FA-CTS NPs was (89.48±2.81) % in phosphate-buffered saline (PBS, pH 7.4) within 48h; these results by MTT assays and wund healing assays indicated that BH/FA-CTS NPs not only inhibited the proliferation of HeLa cells in a concentration and time-dependent manner but can induce apoptosis as well. The subcutaneous xenograft tumor formation rate of human cervical cancer cell line HeLa in nude mice was 98% after inoculation for 2 weeks. Compared with BH group and BH/CTS-NPs group, the xenograft tumor growth of BH/FA-CTS-NPs group was obviously slower; the result indicated that BH/FA-CTS-NPs could significantly inhibit the growth of HeLa xenograft tumor. BH/FA-CTS NPs with the sustained release effect could be prepared successfully by the ionic crosslinking method. Considering these properties, block proliferation and impairing the migration of the HeLa cell line, BH/FA-CTS NPs could be an important compound for consideration in the treatment of cervical cancer.

Keywords: folic-acid, chitosan, berberine hydrochloride, nanoparticles, cervical cancer

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7728 Design of a Dietetic Food: Case of Lebanese Kishk

Authors: Henri El Zakhem, Dona Shalhoub, Elias Atallah, Jessica Koura

Abstract:

Due to the increase of demand on dietetic food and the need for more types of diet food, the production of dietetic food is increasing and improving. This demand on dietetic food has triggered us to study the market in which we found that Kishk (Lebanese dairy product) diet is not available. Production of a low fat product which is diet Kishk was our concern. A strategy was followed to choose the right idea that will satisfy the need of the market. The whole process was studied and explained thoroughly. The percentage of fat was found to be 32.52 % in regular Kishk and 3.84 % in the diet Kishk produced. The new product has the advantage to be high in protein, low in fat.

Keywords: design and industrialization, dietetic, diet Kishk, fat

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7727 Comparative Assessment of a Distributed Model and a Lumped Model for Estimating of Sediments Yielding in Small Urban Areas

Authors: J.Zambrano Nájera, M.Gómez Valentín

Abstract:

Increases in urbanization during XX century, have brought as one major problem the increased of sediment production. Hydraulic erosion is one of the major causes of increasing of sediments in small urban catchments. Such increments in sediment yielding in header urban catchments can caused obstruction of drainage systems, making impossible to capture urban runoff, increasing runoff volumes and thus exacerbating problems of urban flooding. For these reasons, it is more and more important to study of sediment production in urban watershed for properly analyze and solve problems associated to sediments. The study of sediments production has improved with the use of mathematical modeling. For that reason, it is proposed a new physically based model applicable to small header urban watersheds that includes the advantages of distributed physically base models, but with more realistic data requirements. Additionally, in this paper the model proposed is compared with a lumped model, reviewing the results, the advantages and disadvantages between the both of them.

Keywords: erosion, hydrologic modeling, urban runoff, sediment modeling, sediment yielding, urban planning

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7726 Change of Substrate in Solid State Fermentation Can Produce Proteases and Phytases with Extremely Distinct Biochemical Characteristics and Promising Applications for Animal Nutrition

Authors: Paula K. Novelli, Margarida M. Barros, Luciana F. Flueri

Abstract:

Utilization of agricultural by-products, wheat ban and soybean bran, as substrate for solid state fermentation (SSF) was studied, aiming the achievement of different enzymes from Aspergillus sp. with distinct biological characteristics and its application and improvement on animal nutrition. Aspergillus niger and Aspergillus oryzea were studied as they showed very high yield of phytase and protease production, respectively. Phytase activity was measure using p-nitrophenilphosphate as substrate and a standard curve of p-nitrophenol, as the enzymatic activity unit was the quantity of enzyme necessary to release one μmol of p-nitrophenol. Protease activity was measure using azocasein as substrate. Activity for phytase and protease substantially increased when the different biochemical characteristics were considered in the study. Optimum pH and stability of the phytase produced by A. niger with wheat bran as substrate was between 4.0 - 5.0 and optimum temperature of activity was 37oC. Phytase fermented in soybean bran showed constant values at all pHs studied, for optimal and stability, but low production. Phytase with both substrates showed stable activity for temperatures higher than 80oC. Protease from A. niger showed very distinct behavior of optimum pH, acid for wheat bran and basic for soybean bran, respectively and optimal values of temperature and stability at 50oC. Phytase produced by A. oryzae in wheat bran had optimum pH and temperature of 9 and 37oC, respectively, but it was very unstable. On the other hand, proteases were stable at high temperatures, all pH’s studied and showed very high yield when fermented in wheat bran, however when it was fermented in soybean bran the production was very low. Subsequently the upscale production of phytase from A. niger and proteases from A. oryzae were applied as an enzyme additive in fish fed for digestibility studies. Phytases and proteases were produced with stable enzyme activity of 7,000 U.g-1 and 2,500 U.g-1, respectively. When those enzymes were applied in a plant protein based fish diet for digestibility studies, they increased protein, mineral, energy and lipids availability, showing that these new enzymes can improve animal production and performance. In conclusion, the substrate, as well as, the microorganism species can affect the biochemical character of the enzyme produced. Moreover, the production of these enzymes by SSF can be up to 90% cheaper than commercial ones produced with the same fungi species but submerged fermentation. Add to that these cheap enzymes can be easily applied as animal diet additives to improve production and performance.

Keywords: agricultural by-products, animal nutrition, enzymes production, solid state fermentation

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7725 Evaluation of Central Nervous System Activity of Synthesized 5, 5-Diphenylimidazolidine-2, 4-Dione Derivatives

Authors: Shweta Verma

Abstract:

Background: Epilepsy is a chronic non-communicable central nervous system (CNS) disorder which affects a large population of all ages. Different classes of drugs are used for the treatment of this neurological disorder, but due to augmented drug resistance and side effects, these drugs become incompetent. Therefore, we design the synthesis of ten new derivatives of Phenytoin. The moiety of Phenytoin was hybridized with different phenols by using three step approach. The synthesized molecules were then investigated for different physicochemical parameters, such as Log P values using diverse software programs and to predict the potential to cross the blood-brain barrier. Objective: The Phenytoin derivatives were designed, synthesized, and characterized to meet the structural necessities indispensable for antiepileptic activity. Method: Firstly, the chloroacetylation of the 5,5-diphenyl hydantoin was carried out, and then various substituted phenols were added to it. The synthesized compounds were characterized and evaluated for antianxiety activity by elevated plus maze method and antiepileptic activity by using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) models and neurotoxicity. Result: The number of derivatives of 5,5-diphenyl hydantoin was developed and optimized. The number of parameters was optimized which reveal that the compound containing chloro group such as C3 and C6 showed imperative potential when compared with the standard drug Diazepam. Other compounds containing nitro and methyl group were also found to possess activity. Conclusion: It was summarized that the new compounds of 5,5-diphenyl hydantoin derivatives were synthesized. The results of the data show that the compound containing chloro group is more potent for CNS activity. The new compounds have the probability of being optimized further to engender new scaffolds to treat various CNS disorders.

Keywords: phenytoin, parameters, CNS activity, blood-brain barrier, Log P, CNS active

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7724 Model Observability – A Monitoring Solution for Machine Learning Models

Authors: Amreth Chandrasehar

Abstract:

Machine Learning (ML) Models are developed and run in production to solve various use cases that help organizations to be more efficient and help drive the business. But this comes at a massive development cost and lost business opportunities. According to the Gartner report, 85% of data science projects fail, and one of the factors impacting this is not paying attention to Model Observability. Model Observability helps the developers and operators to pinpoint the model performance issues data drift and help identify root cause of issues. This paper focuses on providing insights into incorporating model observability in model development and operationalizing it in production.

Keywords: model observability, monitoring, drift detection, ML observability platform

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7723 An Integrated Power Generation System Design Developed between Solar Energy-Assisted Dual Absorption Cycles

Authors: Asli Tiktas, Huseyin Gunerhan, Arif Hepbasli

Abstract:

Solar energy, with its abundant and clean features, is one of the prominent renewable energy sources in multigeneration energy systems where various outputs, especially power generation, are produced together. In the literature, concentrated solar energy systems, which are an expensive technology, are mostly used in solar power plants where medium-high capacity production outputs are achieved. In addition, although different methods have been developed and proposed for solar energy-supported integrated power generation systems by different investigators, absorption technology, which is one of the key points of the present study, has been used extensively in cooling systems in these studies. Unlike these common uses mentioned in the literature, this study designs a system in which a flat plate solar collector (FPSC), Rankine cycle, absorption heat transformer (AHT), and cooling systems (ACS) are integrated. The system proposed within the scope of this study aims to produce medium-high-capacity electricity, heating, and cooling outputs using a technique different from the literature, with lower production costs than existing systems. With the proposed integrated system design, the average production costs based on electricity, heating, and cooling load production for similar scale systems are 5-10% of the average production costs of 0.685 USD/kWh, 0.247 USD/kWh, and 0.342 USD/kWh. In the proposed integrated system design, this will be achieved by increasing the outlet temperature of the AHT and FPSC system first, expanding the high-temperature steam coming out of the absorber of the AHT system in the turbine up to the condenser temperature of the ACS system, and next directly integrating it into the evaporator of this system and then completing the AHT cycle. Through this proposed system, heating and cooling will be carried out by completing the AHT and ACS cycles, respectively, while power generation will be provided because of the expansion of the turbine. Using only a single generator in the production of these three outputs together, the costs of additional boilers and the need for a heat source are also saved. In order to demonstrate that the system proposed in this study offers a more optimum solution, the techno-economic parameters obtained based on energy, exergy, economic, and environmental analysis were compared with the parameters of similar scale systems in the literature. The design parameters of the proposed system were determined through a parametric optimization study to exceed the maximum efficiency and effectiveness and reduce the production cost rate values of the compared systems.

Keywords: solar energy, absorption technology, Rankine cycle, multigeneration energy system

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7722 Analysis of Production Forecasting in Unconventional Gas Resources Development Using Machine Learning and Data-Driven Approach

Authors: Dongkwon Han, Sangho Kim, Sunil Kwon

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Unconventional gas resources have dramatically changed the future energy landscape. Unlike conventional gas resources, the key challenges in unconventional gas have been the requirement that applies to advanced approaches for production forecasting due to uncertainty and complexity of fluid flow. In this study, artificial neural network (ANN) model which integrates machine learning and data-driven approach was developed to predict productivity in shale gas. The database of 129 wells of Eagle Ford shale basin used for testing and training of the ANN model. The Input data related to hydraulic fracturing, well completion and productivity of shale gas were selected and the output data is a cumulative production. The performance of the ANN using all data sets, clustering and variables importance (VI) models were compared in the mean absolute percentage error (MAPE). ANN model using all data sets, clustering, and VI were obtained as 44.22%, 10.08% (cluster 1), 5.26% (cluster 2), 6.35%(cluster 3), and 32.23% (ANN VI), 23.19% (SVM VI), respectively. The results showed that the pre-trained ANN model provides more accurate results than the ANN model using all data sets.

Keywords: unconventional gas, artificial neural network, machine learning, clustering, variables importance

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7721 Use of Anti-Stick to Reduce Bitterness in Ultra Filtrated Chees-es(Single Packaged)

Authors: B. Khorram, M. Taslikh, R. Sattarzadeh, M. Ghazanfari

Abstract:

Bitterness is one of the most important problems in cheese processing industry all over the world. There are several reasons that bitterness may develop in cheese. With a few exceptions bitterness is generally associated with proteolysis. In this investigation, anti-stick as a neutral substance in proteolysis were considered and studied for reducing the problem. This vast survey was conducted in a big cheese production factory (in Neyshabur) and in the same procedure anti-stick as interested factor in cheeses packaging compared to standard cheeses production, one line productions (65200 packs with anti-stick were tested by 2953 persons for bitterness and another line was included the same procedure with standard cheese. In this investigate: 83% of standard packaging cheeses, compared with only28% of consumers cheese with anti-stick which confirmed bitterness. Although bitterness is generally associated with proteolysis and Microbial factors, Somatic cell, Starters play important role in generating bitterness in ultra filtrated cheeses, but based on the results the other factors such as anti-stick in packaging can be effective methods for reducing and removing unfavorable bitterness in cheese production.

Keywords: bitterness, uf cheese, anti-stick, single packaged

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7720 Co-Synthesis of Exopolysaccharides and Polyhydroxyalkanoates Using Waste Streams: Solid-State Fermentation as an Alternative Approach

Authors: Laura Mejias, Sandra Monteagudo, Oscar Martinez-Avila, Sergio Ponsa

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Bioplastics are gaining attention as potential substitutes of conventional fossil-derived plastics and new components of specialized applications in different industries. Besides, these constitute a sustainable alternative since they are biodegradable and can be obtained starting from renewable sources. Thus, agro-industrial wastes appear as potential substrates for bioplastics production using microorganisms, considering they are a suitable source for nutrients, low-cost, and available worldwide. Therefore, this approach contributes to the biorefinery and circular economy paradigm. The present study assesses the solid-state fermentation (SSF) technology for the co-synthesis of exopolysaccharides (EPS) and polyhydroxyalkanoates (PHA), two attractive biodegradable bioplastics, using the leftover of the brewery industry brewer's spent grain (BSG). After an initial screening of diverse PHA-producer bacteria, it was found that Burkholderia cepacia presented the highest EPS and PHA production potential via SSF of BSG. Thus, B. cepacia served to identify the most relevant aspects affecting the EPS+PHA co-synthesis at a lab-scale (100g). Since these are growth-dependent processes, they were monitored online through oxygen consumption using a dynamic respirometric system, but also quantifying the biomass production (gravimetric) and the obtained products (EtOH precipitation for EPS and solid-liquid extraction coupled with GC-FID for PHA). Results showed that B. cepacia has grown up to 81 mg per gram of dry BSG (gDM) at 30°C after 96 h, representing up to 618 times higher than the other tested strains' findings. Hence, the crude EPS production was 53 mg g-1DM (2% carbohydrates), but purity reached 98% after a dialysis purification step. Simultaneously, B. cepacia accumulated up to 36% (dry basis) of the produced biomass as PHA, mainly composed of polyhydroxybutyrate (P3HB). The maximum PHA production was reached after 48 h with 12.1 mg g⁻¹DM, representing threefold the levels previously reported using SSF. Moisture content and aeration strategy resulted in the most significant variables affecting the simultaneous production. Results show the potential of co-synthesis via SSF as an attractive alternative to enhance bioprocess feasibility for obtaining these bioplastics in residue-based systems.

Keywords: bioplastics, brewer’s spent grain, circular economy, solid-state fermentation, waste to product

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7719 Stochastic Frontier Application for Evaluating Cost Inefficiencies in Organic Saffron

Authors: Pawan Kumar Sharma, Sudhakar Dwivedi, R. K. Arora

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Saffron is one of the most precious spices grown on the earth and is cultivated in a very limited area in few countries of the world. It has also been grown as a niche crop in Kishtwar district of Jammu region of Jammu and Kashmir State of India. This paper attempts to examine the presence of cost inefficiencies in saffron production and the associated socio-economic characteristics of saffron growers in the mentioned area. Although the numbers of inputs used in cultivation of saffron were limited, still cost inefficiencies were present in its production. The net present value (NPV), internal rate of return (IRR) and profitability index (PI) of investment in five years of saffron production were INR 1120803, 95.67 % and 3.52 respectively. The estimated coefficients of saffron stochastic cost function for saffron bulbs, human labour, animal labour, manure and saffron output were positive. The saffron growers having non-farm income were more cost inefficient as compared to farmers who did not have sources of income other than farming by 0.04 %. The maximum value of cost efficiency for saffron grower was 1.69 with mean value of 1.12. The majority of farmers have low cost inefficiencies, as the highest frequency of occurrence of the predicted cost efficiency was below 1.06.

Keywords: saffron, internal rate of return, cost efficiency, stochastic frontier model

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7718 Time-dependent Association between Recreational Cannabinoid Use and Memory Performance in Healthy Adults: A Neuroimaging Study of Human Connectome Project

Authors: Kamyar Moradi

Abstract:

Background: There is mixed evidence regarding the association between recreational cannabinoid use and memory performance. One of the major reasons for the present controversy is different cannabinoid use-related covariates that influence the cognitive status of an individual. Adjustment of these confounding variables provides accurate insight into the real effects of cannabinoid use on memory status. In this study, we sought to investigate the association between recent recreational cannabinoid use and memory performance while correcting the model for other possible covariates such as demographic characteristics and duration, and amount of cannabinoid use. Methods: Cannabinoid users were assigned to two groups based on the results of THC urine drug screen test (THC+ group: n = 110, THC- group: n = 410). THC urine drug screen test has a high sensitivity and specificity in detecting cannabinoid use in the last 3-4 weeks. The memory domain of NIH Toolbox battery and brain MRI volumetric measures were compared between the groups while adjusting for confounding variables. Results: After Benjamini-Hochberg p-value correction, the performance in all of the measured memory outcomes, including vocabulary comprehension, episodic memory, executive function/cognitive flexibility, processing speed, reading skill, working memory, and fluid cognition, were significantly weaker in THC+ group (p values less than 0.05). Also, volume of gray matter, left supramarginal, right precuneus, right inferior/middle temporal, right hippocampus, left entorhinal, and right pars orbitalis regions were significantly smaller in THC+ group. Conclusions: this study provides evidence regarding the acute effect of recreational cannabis use on memory performance. Further studies are warranted to confirm the results.

Keywords: brain MRI, cannabis, memory, recreational use, THC urine test

Procedia PDF Downloads 197
7717 Exploring Managerial Approaches towards Green Manufacturing: A Thematic Analysis

Authors: Hakimeh Masoudigavgani

Abstract:

Since manufacturing firms deplete non-renewable resources and pollute air, soil, and water in greatly unsustainable manner, industrial activities or production of products are considered to be a key contributor to adverse environmental impacts. Hence, management strategies and approaches that involve an effective supply chain decision process in a manufacturing sector could be extremely significant to the application of environmental initiatives. Green manufacturing (GM) is one of these strategies which minimises negative effects on the environment through reducing greenhouse gas emissions, waste, and the consumption of energy and natural resources. This paper aims to explore what greening methods and mechanisms could be applied in the manufacturing supply chain and what are the outcomes of adopting these methods in terms of abating environmental burdens? The study is an interpretive research with an exploratory approach, using thematic analysis by coding text, breaking down and grouping the content of collected literature into various themes and categories. It is found that green supply chain could be attained through execution of some pre-production strategies including green building, eco-design, and green procurement as well as a number of in-production and post-production strategies involving green manufacturing and green logistics. To achieve an effective GM, the pre-production strategies are suggested to be employed. This paper defines GM as (1) the analysis of the ecological impacts generated by practices, products, production processes, and operational functions, and (2) the implementation of greening methods to reduce damaging influences of them on the natural environment. Analysis means assessing, monitoring, and auditing of practices in order to measure and pinpoint their harmful impacts. Moreover, greening methods involved within GM (arranged in order from the least to the most level of environmental compliance and techniques) consist of: •product stewardship (e.g. less use of toxic, non-renewable, and hazardous materials in the manufacture of the product; and stewardship of the environmental problems with regard to the product in all production, use, and end-of-life stages); •process stewardship (e.g. controlling carbon emission, energy and resources usage, transportation method, and disposal; reengineering polluting processes; recycling waste materials generated in production); •lean and clean production practices (e.g. elimination of waste, materials replacement, materials reduction, resource-efficient consumption, energy-efficient usage, emission reduction, managerial assessment, waste re-use); •use of eco-industrial parks (e.g. a shared warehouse, shared logistics management system, energy co-generation plant, effluent treatment). However, the focus of this paper is only on methods related to the in-production phase and needs further research on both pre-production and post-production environmental innovations. The outlined methods in this investigation may possibly be taken into account by policy/decision makers. Additionally, the proposed future research direction and identified gaps can be filled by scholars and researchers. The paper compares and contrasts a variety of viewpoints and enhances the body of knowledge by building a definition for GM through synthesising literature and categorising the strategic concept of greening methods, drivers, barriers, and successful implementing tactics.

Keywords: green manufacturing (GM), product stewardship, process stewardship, clean production, eco-industrial parks (EIPs)

Procedia PDF Downloads 581
7716 Enhanced Methane Production from Waste Paper through Anaerobic Co-Digestion with Macroalgae

Authors: Cristina Rodriguez, Abed Alaswad, Zaki El-Hassan, Abdul G. Olabi

Abstract:

This study investigates the effect on methane production from the waste paper when co-digested with macroalgal biomass as a source of nitrogen. Both feedstocks were previously mechanically pretreated in order to reduce their particle size. Methane potential assays were carried out at laboratory scale in batch mode for 28 days. The study was planned according to two factors: the feedstock to inoculum (F/I) ratio and the waste paper to macroalgae (WP/MA) ratio. The F/I ratios checked were 0.2, 0.3 and 0.4 and the WP/MA ratios were 0:100, 25:75, 50:50, 75:25 and 100:0. The highest methane yield (608 ml/g of volatile solids (VS)) was achieved at an F/I ratio of 0.2 and a WP/MA ratio of 50:50. The methane yield at a ratio WP/MA of 50:50 is higher than for single compound, while for ratios WP/MA of 25:75 and 75:25 the methane yield decreases compared to biomass mono-digestion. This behavior is observed for the three levels of F/I ratio being more noticeable at F/I ratio of 0.3. A synergistic effect was found for the WP/MA ratio of 50:50 and all F/I ratios and for WP/MA=50:50 and F/I=0.2. A maximum increase of methane yield of 49.58% was found for a co-digestion ratio of 50:50 and an F/I ratio of 0.4. It was concluded that methane production from waste paper improves significantly when co-digested with macroalgae biomass. The methane yields from co-digestion were also found higher that from macroalgae mono-digestion.

Keywords: anaerobic co-digestion, biogas, macroalgae, waste paper

Procedia PDF Downloads 367
7715 The Effects of Varying Nutrient Conditions on Hydrogen Production in PGR5 Deficient C. Reinhardtii Mutants

Authors: Samuel Mejorado

Abstract:

C. Reinahrdtii serves as one of the most promising organisms from which to obtain biological hydrogen. However, its production catalyst, [FeFe]-hydrogenase, is largely inhibited by the presence of oxygen. In recent years, researchers have identified a Proton Gradient Regulation 5 (PGR5) deficient mutant, which shows enhanced respiration and lower accumulations of oxygen within the system. In this research, we investigated the effects of varying nutrient conditions on PGR5 mutants' ability to produce hydrogen. After growing PGR5 mutants in varying nutrient conditions under 55W fluorescent lamps at 30℃ with constant stirring at 200 rpm, a common water displacement method was utilized to obtain a definitive volumetric reading of hydrogen produced by these mutants over a period of 12 days. After the trials, statistical t-tests and ANOVAs were performed to better determine the effect which nutrient conditions have on PGR5 mutants' ability to produce hydrogen. In this, we report that conditions of sulfur deprivation most optimally enhanced hydrogen production within these mutants, with groups grown under these conditions demonstrating the highest production capacity over the entire 12-day period. Similarly, it was found that when grown under conditions of nitrogen deprivation, a favorable shift towards carbon fixation and overall lipid/starch metabolism was observed. Overall, these results demonstrate that PGR5-deficient mutants stand as a promising source of biohydrogen when grown under conditions of sulfur deprivation. To date, photochemical characteristics of [FeFe]-hydrogenase in these mutants have yet to be investigated under conditions of sulfur deprivation.

Keywords: biofuel, biohydrogen, [FeFe]-hydrogenase, algal biofuel

Procedia PDF Downloads 145
7714 Lipid-Chitosan Hybrid Nanoparticles for Controlled Delivery of Cisplatin

Authors: Muhammad Muzamil Khan, Asadullah Madni, Nina Filipczek, Jiayi Pan, Nayab Tahir, Hassan Shah, Vladimir Torchilin

Abstract:

Lipid-polymer hybrid nanoparticles (LPHNP) are delivery systems for controlled drug delivery at tumor sites. The superior biocompatible properties of lipid and structural advantages of polymer can be obtained via this system for controlled drug delivery. In the present study, cisplatin-loaded lipid-chitosan hybrid nanoparticles were formulated by the single step ionic gelation method based on ionic interaction of positively charged chitosan and negatively charged lipid. Formulations with various chitosan to lipid ratio were investigated to obtain the optimal particle size, encapsulation efficiency, and controlled release pattern. Transmission electron microscope and dynamic light scattering analysis demonstrated a size range of 181-245 nm and a zeta potential range of 20-30 mV. Compatibility among the components and the stability of formulation were demonstrated with FTIR analysis and thermal studies, respectively. The therapeutic efficacy and cellular interaction of cisplatin-loaded LPHNP were investigated using in vitro cell-based assays in A2780/ADR ovarian carcinoma cell line. Additionally, the cisplatin loaded LPHNP exhibited a low toxicity profile in rats. The in-vivo pharmacokinetics study also proved a controlled delivery of cisplatin with enhanced mean residual time and half-life. Our studies suggested that the cisplatin-loaded LPHNP being a promising platform for controlled delivery of cisplatin in cancer therapy.

Keywords: cisplatin, lipid-polymer hybrid nanoparticle, chitosan, in vitro cell line study

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7713 Design and Control of an Integrated Plant for Simultaneous Production of γ-Butyrolactone and 2-Methyl Furan

Authors: Ahtesham Javaid, Costin S. Bildea

Abstract:

The design and plantwide control of an integrated plant where the endothermic 1,4-butanediol dehydrogenation and the exothermic furfural hydrogenation is simultaneously performed in a single reactor is studied. The reactions can be carried out in an adiabatic reactor using small hydrogen excess and with reduced parameter sensitivity. The plant is robust and flexible enough to allow different production rates of γ-butyrolactone and 2-methyl furan, keeping high product purities. Rigorous steady state and dynamic simulations performed in AspenPlus and AspenDynamics to support the conclusions.

Keywords: dehydrogenation and hydrogenation, reaction coupling, design and control, process integration

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7712 Development of 4-Allylpyrocatechol Loaded Self-Nanoemulsifying Drug Delivery System for Enhancing Water Solubility and Antibacterial Activity against Oral Pathogenic Bacteria

Authors: Pimpak Phumat, Sakornrat Khongkhunthian, Thomas Rades, Anette Müllertz, Siriporn Okonogi

Abstract:

Self-nanoemulsifying drug delivery systems (SNEDDS) containing 4-allylpyrocatechol (AP) extracted from Piper betle were developed to enhance water solubility of AP by using modeling and design (MODDE) program. The amount of AP in each SNEDDS formulation was determined by using high-performance liquid chromatography. The formulation consisted of 20% Miglyol®812N, 40 % Kolliphor®RH40, 30 % Maisine®35-1 and 10 % ethanol was found to be the best SNEDDS that provided the highest loading capacity of AP. (141.48±15.64 mg/g SNEDDS). The system also showed miscibility with water. The particle shape and size of the AP-SNEDDS after dispersing in water was investigated by using a transmission electron microscope and photon correlation spectrophotometer, respectively. The results showed that they were a spherical shape, having a particle size of 34.27 ± 1.14 nm with a narrow size distribution of 0.17 ± 0.04. The particles showed negative zeta potential with a value of -21.66 ± 2.09 mV. Antibacterial activity of AP-SNEDDS containing 1.5 mg/mL of AP was investigated against Streptococcus intermedius. The effect of this system on S. intermedius cells was observed by a scanning electron microscope (SEM). The results from SEM revealed that the bacterial cells were obviously destroyed. Killing kinetic study of AP-SNEDDS was carried out. It was found that the killing rate of AP-SNEDDS against S. intermedius was dose-dependent and the bacterial reduction was 79.86 ± 0.45 % within 30 min. In comparison with chlorhexidine (CHX), AP-SNEDDS showed similar antibacterial effects against S. intermedius. It is concluded that SNEDDS is a potential system for enhancing water solubility of AP. The antibacterial study reveals that AP-SNEDDS can be a promising system to treat bacterial infection caused by S. intermedius.

Keywords: SNEDDS, 4-allylpyrocathecol, solubility, antibacterial activity, Streptococcus intermedius

Procedia PDF Downloads 119
7711 Optimising Light Conditions for Recombinant Protein Production in the Microalgal Chlamydomonas reinhardtii Chloroplast

Authors: Saskya E. Carrera P., Ben Hankamer, Melanie Oey

Abstract:

The green alga C. reinhardtii provides a platform for the cheap, scalable, and safe production of complex proteins. Despite gene expression in photosynthetic organisms being tightly regulated by light, most expression studies have analysed chloroplast recombinant protein production under constant light. Here the influence of illumination time and intensity on GFP and a GFP-PlyGBS (bacterial-lysin) fusion protein expression was investigated. The expression of both proteins was strongly influenced by the light regime (6-24 hr illumination per day), the light intensity (0-450 E m⁻²s⁻¹) and growth condition (photoautotrophic, mixotrophic and heterotrophic). Heterotrophic conditions resulted in relatively low recombinant protein yields per unit volume, despite high protein yields per cell, due to low growth rates. Mixotrophic conditions exhibited the highest yields at 6 hrs illumination at 200µE m⁻²s⁻¹ and under continuous low light illumination (13-16 mg L⁻¹ GFP and 1.2-1.6 mg L⁻¹ GFP-PlyGBS), as these conditions supported good cell growth and cellular protein yields. A ~23-fold increase in protein accumulation per cell and ~9-fold increase L⁻¹ culture was observed compared to standard constant 24 hr illumination for GFP-PlyGBS. The highest yields under photoautotrophic conditions were obtained under 9 hrs illumination (6 mg L⁻¹ GFP and 2.1 mg L⁻¹ GFP-PlyGBS). This represents a ~4-fold increase in cellular protein accumulation for GFP-PlyGBS. On a volumetric basis the highest yield was at 15 hrs illumination (~2-fold increase L⁻¹ over the constant light for GFP-PlyGBS). Optimising illumination conditions to balance growth and protein expression can thus significantly enhance overall recombinant protein production in C. reinhardtii cultures.

Keywords: chlamydomonas reinhardtii, light, mixotrophic, recombinant protein

Procedia PDF Downloads 255
7710 Production of Nanocrystalline Cellulose (NCC) from Rice Husk Biomass by Chemical Extraction Process

Authors: Md. Sakinul Islam, Nhol Kao, Sati Bhattacharya, Rahul Gupta

Abstract:

The objective of the study is to produce naocrystalline cellulose (NCC) from rice husk by chemical extraction process. The chemical extraction processes of this production are delignification, bleaching and hydrolysis. In order to produce NCC, raw rice husk (RRH) was grinded and converted to powder form. Powder rice husk was obtained by sieving and the particles in the 75-710 μm size range was used for experimental work. The production of NCC was conducted into the jacketed glass reactor at 80 ˚C temperature under predetermined experimental conditions. In this work NaOH (4M) solution was used for delignification process. After certain experimental time delignified powder RH was collected from the reactor then washed, bleached and finally hydrolyzed in order to degrade cellulose to nanocrystalline cellulose (NCC). For bleaching and hydrolysis processes NaOCl (20%) and H2SO4 (4M) solutions were used, respectively. The resultant products from hydrolysis was neutralized by buffer solution and analyzed by FTIR, XRD, SEM, AFM and TEM. From the analysis, NCC has been identified successfully and the particle dimension has been confirmed to be in the range of 20-50 nm. From XRD results, the crystallinity of NCC was found to be approximately 45%.

Keywords: nanocrystalline cellulose, NCC, rice husk, biomass, chemical extraction

Procedia PDF Downloads 401
7709 From the “Movement Language” to Communication Language

Authors: Mahmudjon Kuchkarov, Marufjon Kuchkarov

Abstract:

The origin of ‘Human Language’ is still a secret and the most interesting subject of historical linguistics. The core element is the nature of labeling or coding the things or processes with symbols and sounds. In this paper, we investigate human’s involuntary Paired Sounds and Shape Production (PSSP) and its contribution to the development of early human communication. Aimed at twenty-six volunteers who provided many physical movements with various difficulties, the research team investigated the natural, repeatable, and paired sounds and shape productions during human activities. The paper claims the involvement of Paired Sounds and Shape Production (PSSP) in the phonetic origin of some modern words and the existence of similarities between elements of PSSP with characters of the classic Latin alphabet. The results may be used not only as a supporting idea for existing theories but to create a closer look at some fundamental nature of the origin of the languages as well.

Keywords: body shape, body language, coding, Latin alphabet, merging method, movement language, movement sound, natural sound, origin of language, pairing, phonetics, sound and shape production, word origin, word semantic

Procedia PDF Downloads 250
7708 Place and Importance of Goats in the Milk Sector in Algeria

Authors: Tennah Safia, Azzag Naouelle, Derdour Salima, Hafsi Fella, Laouadi Mourad, Laamari Abdalouahab, Ghalmi Farida, Kafidi Nacerredine

Abstract:

Currently, goat farming is widely practiced among the rural population of Algeria. Although milk yield of goats is low (110 liters per goat and per year on average), this milk partly ensures the feeding of small children and provides raw milk, curd, and fermented milk to the whole family. In addition, given its investment cost, which is ten times lower than that of a cow, this level of production is still of interest. This interest is reinforced by the qualities of goat's milk, highly sought after for its nutritional value superior to that of cow's milk. In the same way, its aptitude for the transformation, in particular in quality cheeses, is very sought after. The objective of this study is to give the situation of goat milk production in rural areas of Algeria and to establish a classification of goat breeds according to their production potential. For this, a survey was carried out with goat farmers in Algerian steppe. Three indigenous breeds were encountered in this study: the breed Arabia, Mozabite, and Mekatia; Arabia being the most dominant. The Mekatia breed and the Mozabite breed appear to have higher production and milking abilities than other local breeds. They are therefore indicated to play the role of local dairy breeds par excellence. The other breed that could be improved milk performance is the Arabia breed. There, however, the milk performance of this breed is low. However, in order to increase milk production, uncontrolled crosses with imported breeds (mainly Saanen and Alpine) were carried out. The third population that can be included in the category for dairy production is the dairy breed group of imported origin. There are farms in Algeria composed of Alpine and Saanen breeds born locally. Improved milk performance of local goats, Crusader population, and dairy breeds of imported origin could be done by selection. For this, it is necessary to set up a milk control to detect the best animals. This control could be carried out among interested farmers in each large goat breeding area. In conclusion, sustained efforts must be made to enable the sustainable development of the goat sector in Algeria. It will, therefore, be necessary to deepen the reflection on a national strategy to valorize goat's milk, taking into account the specificities of the environment, the genetic biodiversity, and the eating habits of the Algerian consumer.

Keywords: goat, milk, Algeria, biodiversity

Procedia PDF Downloads 185
7707 Role of Functional Divergence in Specific Inhibitor Design: Using γ-Glutamyltranspeptidase (GGT) as a Model Protein

Authors: Ved Vrat Verma, Rani Gupta, Manisha Goel

Abstract:

γ-glutamyltranspeptidase (GGT: EC 2.3.2.2) is an N-terminal nucleophile hydrolase conserved in all three domains of life. GGT plays a key role in glutathione metabolism where it catalyzes the breakage of the γ-glutamyl bonds and transfer of γ-glutamyl group to water (hydrolytic activity) or amino acids or short peptides (transpeptidase activity). GGTs from bacteria, archaea, and eukaryotes (human, rat and mouse) are homologous proteins sharing >50% sequence similarity and conserved four layered αββα sandwich like three dimensional structural fold. These proteins though similar in their structure to each other, are quite diverse in their enzyme activity: some GGTs are better at hydrolysis reactions but poor in transpeptidase activity, whereas many others may show opposite behaviour. GGT is known to be involved in various diseases like asthma, parkinson, arthritis, and gastric cancer. Its inhibition prior to chemotherapy treatments has been shown to sensitize tumours to the treatment. Microbial GGT is known to be a virulence factor too, important for the colonization of bacteria in host. However, all known inhibitors (mimics of its native substrate, glutamate) are highly toxic because they interfere with other enzyme pathways. However, a few successful efforts have been reported previously in designing species specific inhibitors. We aim to leverage the diversity seen in GGT family (pathogen vs. eukaryotes) for designing specific inhibitors. Thus, in the present study, we have used DIVERGE software to identify sites in GGT proteins, which are crucial for the functional and structural divergence of these proteins. Since, type II divergence sites vary in clade specific manner, so type II divergent sites were our focus of interest throughout the study. Type II divergent sites were identified for pathogen vs. eukaryotes clusters and sites were marked on clade specific representative structures HpGGT (2QM6) and HmGGT (4ZCG) of pathogen and eukaryotes clade respectively. The crucial divergent sites within 15 A radii of the binding cavity were highlighted, and in-silico mutations were performed on these sites to delineate the role of these sites on the mechanism of catalysis and protein folding. Further, the amino acid network (AAN) analysis was also performed by Cytoscape to delineate assortative mixing for cavity divergent sites which could strengthen our hypothesis. Additionally, molecular dynamics simulations were performed for wild complexes and mutant complexes close to physiological conditions (pH 7.0, 0.1 M ionic strength and 1 atm pressure) and the role of putative divergence sites and structural integrities of the homologous proteins have been analysed. The dynamics data were scrutinized in terms of RMSD, RMSF, non-native H-bonds and salt bridges. The RMSD, RMSF fluctuations of proteins complexes are compared, and the changes at protein ligand binding sites were highlighted. The outcomes of our study highlighted some crucial divergent sites which could be used for novel inhibitors designing in a species-specific manner. Since, for drug development, it is challenging to design novel drug by targeting similar protein which exists in eukaryotes, so this study could set up an initial platform to overcome this challenge and help to deduce the more effective targets for novel drug discovery.

Keywords: γ-glutamyltranspeptidase, divergence, species-specific, drug design

Procedia PDF Downloads 268