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Wars2^V117L/V117L Mice Failed to Gain Fat Mass

To refine the reduced body weight phenotype, we analyzed body composition at monthly intervals and found reduced total body weight from 2 months of age, reduced fat mass from 2 months (female) or 3 months (male) of age, and lean mass from 3 months (male) or 5 months (female, in cohort 1 only) of age (Figures 2A–2C, male; Figures 2D–2F, female cohort 1; Figures S4A–S4C, male; Figures S4D–S4F, female cohort 2). Thus, demonstration of the reduction in total mass was primarily due to decreased adiposity and a failure to increase fat mass. We further investigated whether these differences were the result of specific organ weight changes in Wars2^V117L/V117L mice dissected at 6 months of age. Visceral gonadal white adipose tissue (gWAT), subcutaneous inguinal WAT (iWAT), and brown adipose tissue (BAT) normalized to body weight were all significantly reduced in Wars2^V117L/V117L mice compared to wild-type colony mates (Figure 3A), consistent with reduced adiposity. Strikingly, heart weight was increased in Wars2^V117L/V117L mice (Figure 3A). No significant differences in liver or kidney weight (Figure 3A) were observed, demonstrating organ specificity and that the changes in adipose tissues and heart weight were not because of global growth or development impairment.

Wars2^V117L/V117L Mice Have Reduced Body Weight due to Reduced Adiposity

Male and female cohort 1 mice: (A and D) body weight, (B and E) fat mass, and (C and F) lean mass, respectively. Wars2^V117L/V117L, Wars2^V117L/+, and Wars2^+/+ littermate numbers were 7 and 8, 13 and 17–21, and 11 and 3 male and female, respectively; mean ± SD. Areas under the curve (AUCs) were compared for males using an ordinary one-way ANOVA with Tukey’s multiple comparison test and for females using a one-way ANOVA non-parametric Kruskal-Wallis test and Dunn’s multiple comparison test. For AUC for Wars2^+/+ and Wars2^V117L/V117L, Wars2^+/V117L and Wars2^V117L/V117L, and Wars2^+/+ and Wars2^V117L/+, male body weight was p < 0.0001, p = 0.0002, and p > 0.5057; fat mass was p < 0.0001, p < 0.0001, and p = 0.6505; and lean mass was p = 0.0063, p = 0.0008, and p = 0.5314. Female body weight for Wars2^+/V117L and Wars2^V117L/V117L was p < 0.0001, fat mass was p = 0.0001, and lean mass was p = 0.0055 (wild-type [WT] comparisons not shown, because n = 3). Significance at specific time points was calculated with a one-way ANOVA non-parametric Kruskal-Wallis test and Dunn’s multiple comparison test. Significance between Wars2^+/+ and Wars2^V117L/V117L and between Wars2^+/V117L and Wars2^V117L/V117L is shown as  and #p < 0.05, and ##p < 0.01, and and ###p < 0.001, respectively. Wars2^V117L/V117L mice are blue squares, Wars2^V117L/+ mice are red circles, and Wars2^+/+ mice are black triangles. See also Figure S4.

The Wars2^V117L Allele Causes Hypertrophic Cardiomyopathy

(A) Organ weight divided by body weight at 6 months of age in male mice. Wars2^V117L/V117L and Wars2^+/+ animal numbers were 3 and 3, respectively; mean ± SD. Data were analyzed with multiple t tests by the Holm-Sidak method.

(B) Representative echocardiogram images of the left ventricle in male Wars2^V117L/V117L and Wars2^+/+ mice at 6 months of age.

(C) Functional analysis of images for left ventricle anterior wall (LVAW) diameter, left ventricle (LV) mass, stroke volume (SV), and cardiac output (CO). Wars2

Abstract

Container multimodal transport system was an important promoter of postwar globalization. But in the future, part of global manufacturing may change from centralized to distributed due to 3D printing. To evaluate its impact, this research established a system dynamics model of sneakers supply chain firstly. The modeling showed that the total demand of international transport would decline after the application of 3D printing. For consumer country, the return of manufacturing would increase its container business. And that of producer country would reduce correspondingly. But for resource country, its resource exports would decline, while its container business may grow for the local processing of printing filaments. Secondly, the evaluations based on the data of Guangzhou port suggest that the 3D printing of sneakers was not enough to subvert the existing system. It would be broken only after the 3D printing of electrical products. By then, more manufacturing activities would transfer to the end of supply chain. On the other hand, producer country may actively respond to maintain its advantage in incumbent industrial pattern, such as Belt and Road initiative proposed by China. Deglobalization, caused by 3D printing, and globalization strengthening, caused by trade cooperation, will affect this system simultaneously.

1. Introduction

Container was one of the most important logistics inventions in the 20th Century. Levinson (2008) reviewed that this magic box was born in the United States (US) industrial booming after World War II. It was firstly applied in domestic coastal routes by Sea Land Company and Mattson Company and then quickly changed the traditional transport mode. Since 1960s, frequent trade activity between the United States and Europe has led to acceptance of this efficient logistics tool in most of European ports. With the Japanese product marketing in the western world in 1970s and the US Defense Department on the promotion of military containers in the Vietnam War, the initial Pacific Rim route US-Vietnam-Japan is gradually shaped. On the basis of the Atlantic and Pacific routes, container logistics has spread all over the world [1]. This simple box obviously shortens the loading-unloading time of the goods and compresses the transshipment links. In order to give full play to its potential, the International Standardization Organization (IMO) has developed a global size standard for it, which improves the efficiency of container logistics system and expands the scope of application of containers.

To fill up a huge container ship, the necessary labor force is very small, and the time required is only about half of that required for a small traditional ship to be loaded in 1960s. With containers, a small number of crew members can easily manage an ocean ship which is bigger than three football pitches. A driver can put down a trailer at the dock and then hang another one and drive away. He does not have to wait for the goods unloading from the container. Qingdao, Rotterdam, and other large ports have even realized the automatic loading and unloading of containers in the yard. That can reduce the interference of human factors. Transportation has become so efficient that freight costs will largely not have much impact on multinational production decisions.

Container can not only reduce transportation costs, but also save time. After combining the computer tracking management system into container, the multinational enterprises have developed the production mode of Just in Time (JIT) in the global scale. JIT was developed by Japanese car manufacturers firstly. And before container used, JIT was implemented only within the territory of Japan. Container realized the accuracy of the global flow of goods, significantly reducing the inventory of manufacturers and transshipment links. This promoted a longer supply chain so that buyers can safely place orders to the other side of the earth. The multimodal transport system based on container has combined ships, railways, and roads together to achieve global manufacturing and sales of goods.

Container transport has developed into a global scale, highly automated, and standardized industry today. For decades, container and a series of industrial modes derived from it have profoundly changed our world. In the international industry relayout, as container reduced the threshold of international logistics, the labor-intensive industries have gradually shifted from developed countries to developing ones with lower labor costs. After being manufactured in these countries, finished products were shipped all over the world by high-speed container liners. The global industry is evolving into a “resource-producer-consumer” pattern. The geographical distance between consumption and production is longer and longer. In order to maintain the competitiveness of producer countries in the international industrial layout, they are always upgrading their ports, highways, railways, and other container infrastructures, such as China, Korea, and ASEAN. Countries that lack container infrastructure are fixed as the role of the resource countries, such as Africa and South America. The infrastructures in these countries are more designed for the export of raw resources, such as crude oil pipe and minerals convey belt, rather than goods suitable for container shipment, such as semiproducts and finished products.

Upgrading a region’s existing container infrastructure and conveyance requires a large amount of continued investment. This makes the current international industrial structure difficult to change in a short time. But that does not mean it is a permanent situation. We can review the case of digital camera that digital imaging technology rapidly and profoundly changed the way how people use camera. Some disruptive innovations, such as 3D printing (3DP), will probably break the existing supply chain mode. 3DP, or called additive manufacturing, is a digital manufacturing technology. Through a universal manufacturing machine, it can directly transform a digital file into a physical product. That means being free of customization and flexibility. It requires neither tools nor molds to produce the complex geometric structure. This also eliminates redundant assembly and reduces manual activities in the manufacturing process (Weller et al., 2015) [2]. It is drilling into the current system in some forms and gradually affecting the current container logistics. Then it may subvert the current global industrial division. The direction, velocity, and volume of global commodity flow may change dramatically.

Tien (2011) and Berman (2012) believed that 3DP and other digital technologies could combine together and let everyone participate in the manufacturing of goods through online platform [3, 4]. The main production paradigm would shift from the producer-centric mass production to the consumer-centric mass customization. Zeleny (2012) proposed that future manufacturing would not happen in the other side of the earth but around the consumers themselves. People could meet their material needs of daily work and life by using 3D printers and various printing materials, such as plastic filament and metal powder [5]. When 3DP has developed to this stage, the existing global industrial structure will be seriously impacted. While international container logistics system and globalization complement each other, globalization was derived from centralized production. Does centralized production transforming into distributed production mean that container will die out in the future?

2. Review of 3DP

3DP is a generic term for a variety of rapid prototyping technologies, such as Fused Deposition Modeling (FDM) and Stereo Lithography Apparatus (SLA) for plastic printing and Selective Laser Sintering (SLS) for metal printing. It was originally only for industrial product prototyping. In recent years, this technology has made a great breakthrough in the use of various materials. Industry began to use 3DP to make components and even finished products, but they have not formed scale yet. Now industry and academia are committed to explore its application of feasible models, both at the industrial level and at the personal level.

2.1. 3DP at Industrial and Personal Levels

In what circumstances will the factory executives choose 3DP? Scott and Harrison (2015) investigated and compared several factors in the manufacturing process, including total demand, factory operating cost, product variable cost, processing time, 3DP equipment efficiency, and printing filament cost. They found that total demand was a key factor in deciding whether to adopt 3DP, and the decline of filament cost would promote the 3DP application obviously [6]. Khajavi et al. (2015) put forward that the combination of 3DP and conventional process could greatly reduce the risk of new product sales. Firstly a batch of 3DP samples were thrown into the market. If successful, the mass production with conventional technology would follow. This proved that sometimes 3DP and conventional process would not substitute but complement each other [7]. On the other hand, 3DP is more suitable for the manufacturing of spare parts. Ruffo et al. (2007) proposed that the decision of enterprises to purchase or print small batches of spare parts depends on the cost, capacity, knowledge, response, and quality of 3DP. Integrated various factors, self-printing was better for spare parts replacement, rather than ordering out [8]. Sirichakwal and Conner (2016) summarized that the use of 3DP could achieve the virtual inventory. This helped to reduce the stock-out probability and inventory obsolescence of spare parts [9].

The above researches are more concentrated within the producers. But 3DP features will allow more consumers to participate in the manufacturing of products, called “prosumer.” Cautela et al. (2014) proposed that the current personal applications of 3DP were mainly from direct E-commerce, alliances with established distributors, and specialized retail channels. The role difference among manufacturers, distributors, and consumers was becoming blurred increasingly [10]. In recent years, with the expiration of a variety of patent and the emergence of open source application, the threshold of 3DP continues to decline. For the economic analysis of 3DP in home applications, Wittbrodt et al. (2013) carried out an experiment. In a whole year the experimenters used RepRap, a kind of open source printer, to manufacture 20 kinds of products to meet their daily needs instead of going to shop. The results showed that this behavior saved a lot of money [11]. This allowed the users of 3DP to expand from enterprises to individual hobbyists and creative customers (Laplume et al., 2016) [12]. 3DP business has allowed consumers to take over more jobs from producers. The manufacturer-consumer decoupling point would shift to upstream more than in conventional ones. It could not only meet the personal requirements but also achieve a leaner and agiler supply chain.

2.2. 3DP and Global Supply Chain

The application of 3DP has blurred the boundary between producers and consumers. The ordinary production mode is evolving from centralized to distributed one. That will gradually be transmitted from domestic to international scope, thus affecting the current layout of global industries (Gress and Kalafsky, 2015) [13]. Laplume et al. (2016) believed that if 3DP gets more applications, a considerable part of the incumbent manufacturing activities would flow out from Asia back to Europe and US. Not only was 3DP closer to the consumption location, but also it could save more human activities, so that the comparative advantage of human cost in Asia was no longer obvious. Moreover, the local use of 3DP would save a large amount of import tariffs and bypass the technical barriers in some consumer countries. This in part offsets the current high cost of printing materials [12]. And as 3DP applications continue to expand, the cost of materials would slowly decline. That in turn would promote 3DP to be further accepted by the public.

From the perspective of logistics and supply chain, the use of 3DP will greatly reduce the material consumption during the manufacturing process. Global freight volume will decrease and logistics network will face strategic contraction. Chen (2016) pointed out that relevant countries should carry out feasible measures, such as the reform of logistics facilities and the cooperation with origin country of printing materials, to face the challenge brought by 3DP [14]. In the 3DP era, no complex JIT distribution and no complicated raw material or product category management existed. Global logistics scheduling would not be difficult any more. The conventional logistics providers must get transition to enhance their core competitiveness. Dong et al. (2016) analyzed the case of UPS Company and proved that a logistics servicer was transforming to a logistics manufacturer under the 3DP circumstance. In order to respond to customer demand quickly, logistics companies needed to change their inventory structure. In addition to regular goods, their distribution centers were also required to store a variety of printing materials for immediate production of the necessary order, to avoid shortages [15].

3. Research Idea

According to the above research, 3DP, which was originally used for prototyping only, is now developing into a mainstream way of manufacturing. At the industrial level, many companies are considering the combinations of 3DP and traditional process to shorten the product lead time. At the personal level, private users are attempting to make daily necessities by 3DP. The incumbent pattern will turn from centralized production to distributed one. Since 3DP can greatly reduce the traditional processes such as turning, milling and grinding, and the use of molds, the transportation of materials during the manufacturing process will decrease significantly. Traditional distribution servicers will be required to provide real-time print service of urgent goods.

At present, the mainstream 3DP material cost is relatively high. Its printing speed is also slow. This hinders the further popularization of this technology. But RepRap’s case (Wittbrodt et al., 2013) showed that while consumers spent more on materials, they saved time and other costs to get goods [11]. In general, some niche goods with lower demand, especially personalized products and spare parts, are ideal for 3DP, which only needs to be produced of one or several unique pieces in a short time. Similarly, 3DP is also applied to some regular goods requiring to be more personalized, such as clothing, shoes, toys, and even houses. They have not become a scale yet. But their manufactures are constantly forging ahead. When 3DP matures, 3DP may be a powerful substitute of conventional process. Will the current industrial structure be affected? What about the evolution trend of global container multimodal transport system?

For different materials, the printing cost varies. For example, SLS for printing metals is quite expensive. The cost of printer and metal powder is many times that of conventional process. So it is generally used in the manufacturing of high-value components, such as aviation parts. In the short term, 3DP metal product is difficult to mass spread. Therefore, this research is more inclined to study the plastic resin product, which is cheaper and more mature.

3DP is more suitable to manufacturing the goods made of a single material. In recent years, with consumer demand for personalized products, they have become less satisfied with the regular styles of sneakers. Nike, Adidas, New Balance, and other transnational sports giants have been committed to the development of 3DP sneakers. These products are usually made of one or a few types of artificial plastics and their printing technology is FDM or SLA. Customers provided their foot size to the sneaker manufacturer and finally received their orders by real-time 3DP through the distributors. Because it was customized, the price was relatively high. And these orders have not been commissioned to the oversea foundry but the local 3DP workshop. The 3DP sneakers’ accuracy is OK, but the speed and cost cannot match the requirements of mass production yet. This model is more like concept marketing and not so popular among the ordinary people.

In 2017, Carbon, which was a start-up company in Silicon Valley, cooperated with Adidas Company and developed the Continuous Liquid Interface Production (CLIP) technology to optimize the process of sneakers in collaboration with sports manufacturers. It could reduce the printing time of sneakers from 1.5 hours to 20 minutes. This greatly improved the productivity of 3DP sneakers. Adidas hoped to sell 5,000 pairs in 2017. And the annual sales volume could expand to 100,000 pairs in the future when the production times were shortened (Vincent, 2017) [16]. This is only a small amount compared to Adidas’s annual sales of 100,000,000 pairs, but with the further development of 3DP technology and the promotion of consumer personalized requirement, sneakers may be the first product which are 3DP mass-customized in the foreseeable future. Therefore, this research focuses on the supply chain of 3DP sneakers.

3DP has not been large scale applied. The relevant data is lacking. Moreover, most of the existing achievements have focused on domestic scope. There is less quantitative research on the worldwide range. In order to evaluate the impact of 3DP on container multimodal transport system, it is necessary to analyze the evolution of transnational supply chain. Based on the case of 3DP sneakers, this research intends to establish a system dynamics model and then simulate possible scenarios and discuss the evolution of supply chain under these circumstances. Finally, the impacts of 3DP on the system are discussed based on the throughput data from a typical port in producer country.

System dynamics is a systematic simulation method to analyze the problems of production and inventory management. It is common in supply chain construction. Under the premise of insufficient data, the method can still predict conditional target variables by using flow diagrams which containing causal loops. Moreover, the flow diagram structure can intuitively reflect the operation process of the chain. Currently, 3DP related data is lacking. Therefore, system dynamics is viable to quantify the impact of 3DP on container multimodal transport system.

4. Modeling of the Sneakers Supply Chain

4.1. Traditional Supply Chain Model

The first step is to model the transnational supply chain of traditional sneakers. According to recent years’ public data from Nike Company, it has 25% of employees and 10% of sales in China. In North America, it has about 1% of employees, but sales account for 50%. In the Middle East, Russia, and other oil origin regions, the number of employees is 1%, and the sales are only about 5%. There is no doubt that, in the Nike sneakers industry chain, China is a producer country, US is a consumer country, and the Middle East plays the role of a resource region. Set the starting point of the chain as an oil field in the Middle East. Its production of oil is shipped to China and refined to form raw plastic and then processed into sneakers. Ultimately these finished products are shipped to US, China, and the Middle East for sale. Since the research is concerned more with the transnational changes of material transportation, the domestic distribution part is not the focus. Therefore, the local sneakers distribution centers in these three regions are set to be the supply chain terminals.

In the model setting the sneakers are made of one single plastic. The main steps of the whole supply chain are as follows.(1)The crude is exploited from the oil field in the Middle East and transported to the depot of the Persian Gulf by pipeline.(2)The crude is loaded on a tanker and goes to the Beibu Gulf in China, which is a petrochemical industry cluster. In a refinery in the Beibu Gulf, the crude is processed into raw plastic and then shipped by trailer to a plastic processing factory in the nearby Pearl River Delta, a main manufacturing cluster in China.(3)The raw plastic is transformed into plastic particles, which is the basic material for many plastic products.(4)A foundry there receives the order from Nike headquarter and purchases these required plastic particles for production. In this process, its transport vehicle is still trailer. Through the injection molding, cutting, sewing, and other processes, the sneakers are completely made.(5)The finished products for US and the Middle East will be shipped out through a port in the Pearl River Delta. The sneakers destined for US will go to one of the western coastal ports and then to the local distribution center by road. The sneakers destined for the Middle East will arrive at a port in the Persian Gulf and then also to the local distribution center by road. The sneakers for China are directly transported from the foundry to the local distribution center by domestic road.

The model is established by the VENSIM PLE software. The variable meaning in the model is shown in Table 1.

Based on the descriptions that is shown in Table 1, the system dynamics model of traditional supply chain is shown in Figure 1. The supply chain in this scenario is called Scenario T.

The focus of this research is to evaluate the impact of 3DP on the container transport system. The parameter setting is concerned more with the differences among various kinds of vehicle but does not pay much attention to storage. In addition, the shortest length of the supply chain under different circumstances needs to be determined. That means that all the goods should not stay long at any node. After the goods are ready for shipment they cannot remain in the same node for more than one day. According to the above setting, referring to actual geographical and transport data, the transportation mode and their time spent are shown in Table 2.

This is set to be a supply and demand equilibrium model. When the model runs, no excess inventory is in any node of the chain. Based on the sales data of Nike Company, 20 tons of the sneakers is sold per day in the three regions, including 15 tons sold in US, 4 tons in China, and 1 ton in the Middle East. According to field investigation data, the conversion rate of crude into raw plastic is 33.33%. The conversion rate of raw plastic into plastic particles is 95.4%. In the shoemaking process, there is some wastage such as leftover bits and pieces. And the conversion rate of plastic particles into sneakers is 87.5%. In the circumstance of balanced supply and demand, the oil field in the Middle East produces 72 tons of crude per day to manufacture sneakers. Input the above data into the model and run the model simulation for 365 days. The result is shown in Table 3.

4.2. Future Scenarios and Matching Models

If the sneakers realize the 3DP production, the incumbent process will be completely overturned. The manufacturing activity in China will shift closer to the end consumer. Some studies have shown that consumers may choose to print the personal items at home, but the factory and workshop can provide the 3DP product with higher quality. That is because 3DP requires necessary postprocesses according to current technology. Nonprofessional consumer, if not able to cope, will reduce their experience. So it became complex to determine proper 3DP locations in the supply chain (Bogers et al., 2016) [17]. Sneakers are with a certain technical content. If printed by consumer themselves, they are not as good as from professional enterprises. Zeltmann et al. (2016) found that if 3DP was performed in a decentralized environment such as being homemade, there was risk of strength and durability in the finished product due to lack of qualified inspection [18]. The case of UPS Company (Dong et al., 2016) showed that in the 3DP era distribution provider is fully capable of acting as a qualified end-manufacturer [15]. Therefore, this model assumes the printing behavior of sneakers conducted in the local distribution centers of US, China, and the Middle East. The distribution centers get authorized and technical support from Nike Company. When they receive orders, they will print and deliver the product immediately. On the other hand, as a result of the shale gas revolution in recent years, US is likely to achieve self-sufficiency in the supply of crude. This means that the origin of crude is no more limited to the Middle East. Taking account of these possibilities, this research designed three extreme scenarios, called Scenario , Scenario , and Scenario . Among them, the origin of crude, the processing location of printing materials, and the region where sneakers are manufactured will change. The actual supply chain evolution may occur in the range among the three scenarios.

4.2.1. Simulation of Scenario 1

In Scenario , the origin of crude is still the Middle East. The materials used to make sneakers are no longer plastic particles, but special filaments for 3DP. Its production process is similar to plastic particles, which are manufactured by raw material in a processing factory. Since US and China have conducted a lot of investments in the research and development of 3DP for many years, such as “National Strategic Plan for Advanced Manufacturing” (2012) and “National Network for Manufacturing Innovation” (2012) in US and “Made in China 2025” (2015) and “National promoting plan of additive manufacturing” (2015) in China, this scenario sets that the locations of filament production are in US and China, respectively. The filaments made in US are for the sneakers of US consumers. And the filaments made in China are for the sneakers of China and the Middle East consumers. The crude for filament production is all from the Middle East. In Scenario , US is not only a consumer country, but also a filament producer. And its major crude unloading port and refinery cluster are around the Gulf of Mexico. Thus three new nodes are added. Their symbols are shown in Table 4.

In Scenario , the main steps of the whole supply chain have changed as follows.(1)The crude is exploited from the oil field in the Middle East and transported by pipeline to the depot in the Persian Gulf.(2)Different from Scenario T, the crude traffic is divided into two parts. One part is shipped to a port in the Gulf of Mexico and then refined to raw plastic and shipped by trailer to a plastic processing factory in US. The other is shipped to a port in the Beibu Gulf, also refined to raw plastic, and shipped by trailer to a plastic processing factory in the Pearl River Delta.(3)The raw plastic is transformed into plastic filaments, which is the basic material for the 3DP of plastic. The model sets that the shipping way of filaments is container, no matter the container trailer by road or the container vessel by sea.(4)Filaments made in US are shipped by trailer to a US distribution center. Filaments made in China are shipped to the distribution center in China by trailer and to the distribution center in the Middle East by container vessel, respectively.(5)Nike headquarter informs the distribution centers to print and sends the sneakers in real time to the customers.

According to the above settings, the model is modified as shown in Figure 2.

Sneakers are not made in a shoe factory but printed directly in a distribution center. So the goods stay for 2 days at the distribution center, including printing and sorting, 1 day longer than that of Scenario T. The time spent in the newly added nodes is adjusted according to the actual investigated data. The remaining parameters of Scenario are the same as those of Scenario T. Therefore, the transportation mode and their time spent are modified and shown in Table 5.

The sales per day of Scenario are set the same as the one of Scenario T, 15 tons in US, 4 tons in China, and 1 ton in the Middle East. All kinds of materials have the same conversion rate in US and China. The conversion rate of crude into raw plastic is 33.33%. The conversion rate of raw plastic into plastic filaments is 93.8%. As the sneakers are made by 3DP, the loss is greatly reduced to negligible extent. The model sets that the conversion rate of filaments into sneakers is 100%. According to the setting, the crude shipped to US is 48 tons per day and generates 15 tons of filaments to the US distribution center. The crude shipped to China is 16 tons per day and generates 5 tons of filaments, in which 4 tons is shipped to China distribution center and 1 ton is shipped to the Middle East one. Input the above data into the model and run the model simulation for 365 days. The result is shown in Table 6.

4.2.2. Simulation of Scenario 2

Unlike Europe, US has gradually shifted from a typical crude consumer to a major producer because of the shale gas revolution in recent years. In Scenario , there are 2 origins of crude, the Middle East and US. The filaments used in China and the Middle East are processed by the crude from the Middle East. The filaments made in US are processed by the crude from US. The US origin area is still set around the Gulf of Mexico. Thus, add one new node into the Scenario model, an oil field in the Gulf of Mexico. Its symbol is OfGM. The crude oil passes through the pipeline to the nearby refinery, with a time spent of 2 days. Other settings remain the same as Scenario . The model is modified as shown in Figure 3.

The sales per day of Scenario are set the same as the one of Scenario T, 15 tons in US, 4 tons in China, and 1 ton in the Middle East. The Middle East produces 16 tons of crude per day and ships it to China for manufacturing sneakers, while US produces 48 tons of crude per day locally. The other parameters of Scenario and Scenario are the same. Input the above data into the model and run the model simulation for 365 days. The result is shown in Table 7.

4.2.3. Simulation of Scenario 3

These years many regions have increased investment in the research and development of 3DP, including some countries in the Middle East. For example, Dubai, UAE, planned to build the whole nation into a global hub for 3DP by 2030. It majored in the industries of construction, medical products, and consumer goods. A market research institute, Future Market Insights, released a report (2016) predicting that from 2015 to 2025 the 3DP materials market in the Middle East will grow 16.7% per year [19]. In the foreseeable future some Middle East countries will probably get rid of the roles of resource country and be able to utilize 3DP technology to participate the international manufacturing more actively. Therefore, in Scenario the Middle East will not export crude but process it into filaments and then export. In this case, in the Middle East the crude exploited from the oil field is firstly sent to a nearby refinery to transform into raw plastic. Then the raw plastic is transport by trailer to a plastic processing factory to produce filaments. Part of the filaments is shipped to the distribution center for local sneakers printing. The rest are shipped to Pearl River Delta port through the Persian Gulf port and finally reach a distribution center of China, which is used to make sneakers for Chinese customers. Add two new nodes to the model of Scenario . The settings of US remain the same. Their symbols are shown in Table 8.

The time spent in the newly added nodes is adjusted according to the actual investigated data. The remaining parameters of Scenario are the same as those of Scenario . Therefore, the transportation mode and their time spent are modified and shown in Table 9.

According to the above, the model is modified as shown in Figure 4.

The sales per day of Scenario are set the same as the one of Scenario T, 15 tons in US, 4 tons in China, and 1 ton in the Middle East. The Middle East produces 16 tons of crude per day and ships it to China for manufacturing sneakers, while US produces 48 tons of crude per day locally. The other parameters of Scenario and Scenario are the same. Input the above data into the model and run the model simulation for 365 days. The result is shown in Table 10.

5. Simulation Result Analysis

In each scenario, there are two major transport ways in supply chain. The first one is bulk transport for crude, no matter by pipeline or tanker. The second one is container transport for semiproducts and finished plastic products, by vessel and trailer. According to Tables 3, 6, 7, and 10, Table 11 is established for comparing the simulation of four scenarios.

5.1. Flow Direction

For crude transportation, in Scenario one part of crude is exported to US for filaments processing. This has facilitated the material flow within US territory and increased its port throughput. China’s crude traffic is correspondingly reduced. But the Middle East remains the only resource exporter. In Scenario , US uses its own crude to process filaments. The oil of the Middle East is all exported to China. In Scenario , the Middle East enterprises made crude oil into filaments and then exported. The flow of crude only existed in the pipeline from oil fields to refineries. This proves that the 3DP distributed production will greatly shorten the global flow distance of primary raw materials. The unit freight turnover of primary raw materials will be significantly reduced.

For container transportation, Scenario and Scenario show that all semiproduct and finished plastic products of US circulate within the US territory. This will lead to the useless marine containers because of the non-trans-ocean transport. In the case of only domestic transport, it is likely that logistics providers are not willing to use container trailers but ordinary van to complete it, which has a more flexible demand response. In Scenario 3, the Middle East has become the exporter of filaments but not the importing region of sneakers. The container goods do not flow from China to the Middle East but in the opposite direction. On the one hand, the application of 3DP makes the countries which have both resource and consumer characteristics tend to circulate the business in domestic range. While container is more suitable for international multimodal transport, their use will decline if there is only domestic demand. On the other hand, the use of container in nonresource country can be maintained, because the transoceanic container of printing filaments is an efficient and punctual way to provide quick response to the demand of consumers in this digital era.

5.2. Flow Velocity

The faster the flow velocity, the shorter the start sales time of sneakers. In Scenario T, materials need to be transferred among multiple nodes and applied by several procedures. After 3DP application, the filaments generated by crude can be directly transported to the distribution center and printed according to the customer’s order. The part of foundry manufacturing can be omitted, and there is no need to prepare the corresponding mold. It seems that the simplification of the process reduces the response time and improves the flow velocity. Although the printing speed of a single printer was still slower than that of the conventional process, some enterprises began to solve the problem. For example, Voodoo Manufacturing Company set up a printer group called Project Skywalker. They designed software to connect several to hundreds of ordinary FDM printers and even mechanical arms or other automation equipment together, just like “robot factory.” These 3DP systems or groups could print large numbers of individual components and achieve mass production while maintaining the technical advantages of 3DP (3ders.org) [20]. The same way, of course, can also be applied to athletic footwear manufacturing. Moreover, with the application of CLIP or later the introduction of new technologies, the printing speed of sneakers can fully meet the requirements of mass production. Therefore, the shortcoming of 3DP speed will not delay start sales time any more.

Influence of crystal packing on the thermal properties of cocrystals and cocrystal solvates of olanzapine: insights from computations†

Abstract

Structure–property correlation is an important aspect in crystal engineering which has direct applications in the development of pharmaceutical solid dosage forms. In this manuscript, we present a combined structural, thermal and computational study of seven new cocrystals and cocrystal solvates of an antipsychotic drug, olanzapine, with three coformers (hydroquinone, resorcinol and catechol) and attempt to understand the effect of solid-state molecular packing on the thermal properties (desolvation and melting behaviour). The cocrystals were designed by utilizing the robust hydrogen-bonded synthons between the drug and coformers, while the cocrystal solvates were obtained by the isostructural replacement of toluene in a previously reported multicomponent structure by benzene, xylene and ethyl benzene. The positional variations of hydroxyl groups in coformer molecules had a remarkable influence on the crystal packing of cocrystals. The olanzapine–hydroquinone (OLZ–HQ) combination in 1 : 1 stoichiometry crystallized as cocrystal solvates that was attributed to the persistent formation of rectangular hydrogen-bonded grid networks with inherent hydrophobic cavities for aromatic guest molecule inclusion. In contrast, the olanzapine–resorcinol (OLZ–RES) and olanzapine–catechol (OLZ–CAT) combinations in 1 : 1 stoichiometry resulted in non-solvated cocrystals and can be classified as pharmaceutical cocrystals. The desolvation patterns of cocrystal solvates were explained based on the structural similarities and dissimilarities, host–guest interactions, void types (closed vs. open), void size (narrow and wide), packing coefficients and boiling points of the guest molecules. Solid-state DFT calculations were performed to assess the desolvation energies, stabilization energies of desolvated systems and lattice energies of all cocrystals and cocrystal solvate systems and the results were correlated with the experimental observations. The solvent molecules play an important role in the structure stabilization, rendering the crystal lattice of the OLZ–HQ structure energetically feasible and compensating for the loss of packing density rather than simply occupying the void space in the crystal structure. The large melting point differences and thermal stabilities of two anhydrous cocrystals (M.P. of OLZ–RES is 196 °C and M.P. of OLZ–CAT is 135 °C) were also explained on the basis of packing coefficients and lattice energy calculations.

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Article information

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CrystEngComm, 2020, Advance Article

Influence of crystal packing on the thermal properties of cocrystals and cocrystal solvates of olanzapine: insights from computations

A. V. S. D. Surampudi, S. Rajendrakumar, J. B. Nanubolu, S. Balasubramanian, A. O. Surov, A. P. Voronin and G. L. Perlovich, CrystEngComm, 2020, Advance Article , DOI: 10.1039/D0CE00914H

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