**MILK PRODUCTION – AN UP-TO-DATE OVERVIEW OF ANIMAL NUTRITION, MANAGEMENT AND HEALTH**

Edited by **Narongsak Chaiyabutr**

http://dx.doi.org/10.5772/1525 Edited by Narongsak Chaiyabutr

#### **Contributors**

Naceur M'Hamdi, Leonel Avendano-Reyes, Drago Kompan, Andreja Komprej, Cazim Crnkic, Aida Hodzic, Jan Olechnowicz, Luciano Pinotti, Alejandro Salvador, Rolando Hernández, Thais Diaz, Ricardo Betancourt, Stephen C. Nickerson, Silvia E. Valtorta, Miriam R. Gallardo, Pouya Zamani, Thomas McFadden, Emma Wall, Rosa Elena Miranda-Morales, Erika Margarita Carrillo-Casas, Araceli Pinelli-Saavedra, Alfonso Martinez-Borraz, Silvia Yolanda Moya-Camarena, Humberto Gonzalez-Rios, Jesus Hernandez, Siriwat Suadsong, Pascal Drouin, Carole Lafrenière, Ghader Manafiazar

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**1. Introduction**

Aerobic life inherently depends on oxygen, which is essential for a controlled oxidation of molecules containing carbon, subsequently leading to the release of energy. Nevertheless, aerobic cells, including spermatozoa, are persistently counteracting the so-called Oxygen Paradox: while oxygen is crucial to sustain aerobic life, it is simultaneously toxic to the cell survival [1]. Normal aerobic metabolism leads to the generation of by-products called free

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

radicals (FR) [2, 3], which, under physiological conditions, are necessary for a normal cell function [4]. On the other hand, if FR concentrations become too high, either because of their overgeneration or due to low levels of antioxidant defense mechanisms, oxidative stress (OS) emerges with unpredictable consequences on the cell behavior and survival [5].

Oxidative stress has been implicated in the pathogenesis of a variety of human diseases such as atherosclerosis, cancer, diabetes, liver damage, AIDS, Parkinson's disease and health complications associated with premature birth [6]. In the meantime, seminal OS is believed to be one of the main factors in the pathogenesis of sperm dysfunction in male sub- or infertility [7–9]. Several intrinsic and extrinsic factors have the ability to promote reactive oxygen species (ROS) generation in the testicular as well as post-testicular (e.g. epididymal) environment, resulting in defective spermatogenesis and altered sperm function [9]. As expected, approximately 25% of infertile patients exhibit higher ROS levels in semen as opposed to fertile men [7, 10–12].

Although the origin of ROS generation in semen and their roles in male reproduction have only recently been uncovered, numerous questions still remain unanswered, thus offering multiple strategies for future research. As such, the role of free radicals and oxidative stress in fertility and subfertility is an area requiring continuous scientific attention.


**5. The tumor microenvironment and gastric carcinogenesis**

More and more evidence supported the idea that not only malignant GC cells, but also those nonmalignant cells involved in the tumor microenvironment play indispensable roles throughout GC pathogenesis. Generally, nonmalignant cells participate in various mechanisms related to GC development, such as stromal interactions, angiogenesis, and some immune responses.

Stromal components, including fibroblasts and extracellular matrix (ECM) adjacent to cancer cells, create a suitable environment for GC development. Stromal fibroblasts are known to play a central role in tumor microenvironment by interacting with cancer cells [59, 60]. However, other than ordinary fibroblasts, cancer-associated fibroblasts (CAFs) undergo a phenotypic change into myofibroblasts. Also, CAFs exhibit distinct gene expression patents that pertain to aberrant cell growth, focal adhesion, and ECM remodeling [61]. The remodeling ECM promotes the survival ability and distant colonization cancer cells by synthesizing components, such as type I and type III collagens, fibronectins, tenascin, and versican [62–64], as well as proteases like urokinase, plasminogen activator, fibroblast activation protein (FAP), and matrix metalloproteinases (MMPs) [65–67]. These characteristics are usually associated with poor prognostics. Moreover, tumor-related stromal fibroblasts secrete small molecules, such as IL-6 to stimulate cell growth, as well as factors associated with TGF-β signaling, triggering epithelial-mesenchymal transition (EMT) [68–70].

Angiogenesis is also a pivotal process contributes to tumor progression. Cell population in GC tumor microenvironment regulates the density and architecture of new blood vessels by stimulating the proliferation and differentiation of myofibroblasts and vascular endothelial cells [71, 72]. The growing number of new vessels was reported to facilitate GC metastasis [73, 74]. To promote angiogenesis, GC cells provide numerous angiogenic factors, including VEGF, FGF-2, CXCL1, and Ang-2, to microenvironment [75–78]. It has been noted that high level of VEGF-A contributed to endothelium-dependent angiogenesis. VEGF-A signaling increased both the new blood vessel number and permeability in GC [79]. VEGF-A strongly promotes the angiogenesis and aggressive phenotype of human intestinal-type GC [80]. Bevacizumab is a specific antibody against VEGF-A, and dominantly regulates normal and pathological angiogenesis. Clinical trials of bevacizumab in phase II advanced GC suggested a satisfied curative effect [81]. Unfortunately, in the randomized phase III Avastin in Gastric Cancer (AVAGAST) study, the combination of chemotherapy and bevacizumab did not show a better overall survival extension in the first-line treatment when compared to advanced GC patients, who only subjected chemotherapy [82]. Intriguingly, REGARD and RAINBOW trials using VEGFR2 targeting antibody ramucirumab have also shown a significant increase in the overall survival of patients with advanced GC [83]. It can be partially explained by the geographical differences of GC patients.

Immune reactivity in GC development is based on various types of immune cells in different stages [84]. First, in eliminating stage, macrophages and dendritic cells recruit to secrete chemokines and cytokines, such as IL-12 and IFN-γ, to phagocytize and remove apoptotic cancer cells [85]. Cancer cells survived from elimination subsequently under equilibrium stage and adapted to immune-suppression. The number of tumor-infiltrating lymphocytes (TILs) was noted as independent predictors to evaluate lymph node metastasis and GC patient survival in this stage. Interestingly, TILs exert either oncogenic or tumor-suppressive influence in GC cells, attributing to their unique functions. In a recent report, tumor-associated macrophages with high levels of CD163 expression exhibited aggressive characteristics and expression of cancer stem cell markers in recurrent GC cases. CD163+ macrophages might, therefore, related to independent worse prognosis [86]. T-lymphocyte subsets are also significant cell types associated with both early onset of tumor and tumor progression. It has been reported that the high ratio of CD8+ cytotoxic TILs/FOXP3+ regulatory T cells (Treg) correlated with high overall survival rate and good prognosis, especially in MSI gastric cancer [87, 88]. Eventually, cancer cells escape from immune responses.

Immunogenicity could be blunted by releasing cytokines including TGF-β, TNF-α, and IL-10. Therefore, cancer cells can evade the detection by immune effectors in the tumor microenvironment [89]. PD-1 is one of the most important receptors expressed by T cells and monocytes. PD-1 negatively regulates the effectors by binding to its ligands PD-L1 and PD-L2. Blocking PD-1/PD-L1 has been suggested as a promising immune-therapeutic option [90, 91]. The relationship between PD-L1 level and prognosis remains under debate, however, a recent meta-analysis pooled all present data and suggested PD-L1 to be a valuable prognostic indicator of GC patients by dividing patients into different groups [92].

Collectively, tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development.

## **6. Conclusion**

and miR-16-1, which target a member of Hippo pathway called YAP1, are downregulated in GC) [50]. Thus, identifying the target genes of these miRNAs is crucial and it may lead us to

For example, miR-21 was the first miRNA which was influenced by *H. pylori*. In tissues of both GC and *H. Pylori* infection, it was highly detected [51, 52]. Several data have reported that this miRNA can be used as a biomarker in GC diagnosis in the clinic [53–55]. And most recently, a research conducted in China suggested this miR-21 to be a GC biomarker in both diagnosis and prognosis, for the reason that, besides the high levels found in tumor tissues compared with the normal ones, miR-21 was revealed to be associated with poor survivals in clinical patients [56]. Behind the phenomena, the molecular mechanism is still unclear in GC. In other types of cancer, however, such as colorectal cancer, miR-21 decreased the tumor suppressor protein programmed cell death 4 (PDCD4) and exhibited an oncogenic function [57]. Additionally, in nonsmall cell lung carcinoma, miR-21 was found to deregulate PTEN, a

More and more evidence supported the idea that not only malignant GC cells, but also those nonmalignant cells involved in the tumor microenvironment play indispensable roles throughout GC pathogenesis. Generally, nonmalignant cells participate in various mechanisms related to GC development, such as stromal interactions, angiogenesis, and some immune responses. Stromal components, including fibroblasts and extracellular matrix (ECM) adjacent to cancer cells, create a suitable environment for GC development. Stromal fibroblasts are known to play a central role in tumor microenvironment by interacting with cancer cells [59, 60]. However, other than ordinary fibroblasts, cancer-associated fibroblasts (CAFs) undergo a phenotypic change into myofibroblasts. Also, CAFs exhibit distinct gene expression patents that pertain to aberrant cell growth, focal adhesion, and ECM remodeling [61]. The remodeling ECM promotes the survival ability and distant colonization cancer cells by synthesizing components, such as type I and type III collagens, fibronectins, tenascin, and versican [62–64], as well as proteases like urokinase, plasminogen activator, fibroblast activation protein (FAP), and matrix metalloproteinases (MMPs) [65–67]. These characteristics are usually associated with poor prognostics. Moreover, tumor-related stromal fibroblasts secrete small molecules, such as IL-6 to stimulate cell growth, as well as factors associated with TGF-β signaling, trig-

Angiogenesis is also a pivotal process contributes to tumor progression. Cell population in GC tumor microenvironment regulates the density and architecture of new blood vessels by stimulating the proliferation and differentiation of myofibroblasts and vascular endothelial cells [71, 72]. The growing number of new vessels was reported to facilitate GC metastasis [73, 74]. To promote angiogenesis, GC cells provide numerous angiogenic factors, including VEGF, FGF-2, CXCL1, and Ang-2, to microenvironment [75–78]. It has been noted that high level of VEGF-A contributed to endothelium-dependent angiogenesis. VEGF-A signaling increased both the new blood vessel number and permeability in GC [79]. VEGF-A strongly

a better understanding of the miRNAs themselves.

12 Stomach Disorders

tumor suppressor, to promote carcinogenesis [58].

gering epithelial-mesenchymal transition (EMT) [68–70].

**5. The tumor microenvironment and gastric carcinogenesis**

There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years. Epigenetically, we are seeking to unravel the mechanisms of gastric tumorigenesis affected by chromatin remodeling. Besides, there are miRNAs, lncRNAs, and some other classic molecules that are involved in GC development, which requires a more detailed investigation regarding these aspects. The most crucially and urgently, we are struggling to explore specific and precise therapies for patients who are suffering or likely to suffer from GC, especially genomically stable GC (a type of GC with a high mortality).

When it comes to the novel small entities, there are even more issues waiting to be addressed, such as how lncRNAs interact with chromatin alterations during gastric carcinogenesis. Moreover, in addition to *H. pylori* and EBV, scientists have identified a wild variety of bacteria in the stomach through DNA sequencing. These uncultivatable bacteria have formed a complicated community and there are few clues about how they interact with *H. pylori* and host immunity during GC initiation and progression. In the early detection field, molecular findings may facilitate new approaches for diagnosing GC early, by identifying high-risk potential sufferers via the molecular features of precancerous lesions. Finally, therapeutic strategies need to be designed precisely for each GC subtypes, according to their somatic driver change of genome or tumor-associated cell compartments, such as stromal cells and tumor-infiltrating immune cells.


**Abstract**

Carbon nanofibers are promising to revolutionize several fields in material science and are suggested to open the way into nanotechnology. Carbon fiber has become an important reinforcement material in composite materials and battery technology because of its low density, high strength, and tensile modulus. Furthermore, high electrical conductivity, thermal conductivity, and mechanical properties of carbon fiber make it useful in a wide variety of products. This chapter highlighting the synthesis and growth pattern of vapor grown carbon fiber (VGCFs). This chapter work reported here includes the application of VGCFs in composite and battery technology.

**Keywords:** VGCFs, composites, PAN, epoxy, polycarbonate, floating reactor


**1. Introduction**

Within last decade the utilization of autonomous vehicles during waged military operations significantly increased in importance. The main factor of their utilization was protection and safe lives of own soldiers or contributors. This trend will surely continue and become relevant in the future as well.

In military operations the decision support systems for utilization of autonomous vehicles have become an integral part of the commander's decision-making process [1]. One of the models of autonomous vehicles are Unmanned Aerial Systems (UAS) mainly utilize for reconnaissance which is the part of the Tactical Decision Support Systems (TDSS) developed at University of Defence, Czech Republic [2]. This system aims at supporting commanders of the Czech Army with their Military Decision-Making Process (MDMP). More detailed information about the integration of TDSS into commander's Troop Leading Procedures (TLP) can be found in [3]. Reconnaissance is one of the crucial parts of intelligence support. Intelligence support is the one of the essential part of MDMP to find a solution for a specific problem allowing to fulfil the assigned mission. It consists of models of military tactics. Each model can solve the corresponding task.

One of many important models in military tactics is the optimal cooperative reconnaissance which is a problem when an area of interest needs to be searched (observed) by multiple military elements (scouts, UAVs, UGVs) as quickly as possible [4].

*Path Planning for Autonomous Vehicles - Ensuring Reliable Driverless Navigation...*

**Figure 1.**

*Military domains in operational environment.*

#### **Figure 2.**

*Categories of factors-steps for consideration and planning.*

The operational environment1 generally consists of factors and conditions that must be understood to successfully apply military capabilities protect the force and complete the mission. It influences the completion of a single mission as well as an entire campaign and its constituent elements [5]. The operational environment includes the sea, land, air and space, the enemy, neutral, friendly and other actors, facilities, weather, terrain, electromagnetic spectrum (EMS) CBRN threats and hazards, and the information environment (e.g., **Figure 1**).

The operational environment of the armed conflicts was, is and will be very diverse and it is involving many aspects. The armed forces must be able to perform a wide range of tactical activities in different domains as Land, Air, Sea, Cosmic and Cyber [5].

Both (all) fighting parties will strive to achieve their goals in the most effective way, including minimizing their loss of life and deployed resources. One of the ways to minimize the loss of lives is the utilization of modern technical means-as autonomous vehicles could be.

Nowadays the predominant domain where fighting parties operate by soldiers is Land. But the most significant domain to gain domination by forces is Air. The multiplier of requested armed forces capabilities to effectively operate in each domain is electromagnetic spectrum.

Focusing on solving issues the Land domain is the most demanding for autonomous vehicles path planning. For ground autonomous vehicles path planning

**11**

*Military Factors Influencing Path Planning DOI: http://dx.doi.org/10.5772/intechopen.86421*

planned activities after the move is over.

(terrain, weather, temperature, visibility, etc.).

**2. Capability of autonomous vehicles**

capability, evaluate four basic parameters:

1. combat power/special purpose ability,

2.protection (if applicable) of the crew (subsystems),

appropriate sensors and devices for special sub-tasks.

control selected functions and their interdependence.

planning.

3.mobility,

4. signal and command.

influencing its movement.

is possible to apply the analogical approaches as for military units movement

to point in order to create conditions for and to be capable carry out particular

Movement can be understood in broad terms as relocating someone from point

There has to be considered amount of factors that affect the move and the goals set for it (e.g., **Figure 2**). The first step in movement consideration is capability (parameters, technical data) of the autonomous vehicle itself, the second step is the autonomous vehicles mission (recce, destroy, cooperate, transport, refuel, etc.), the third step is opposite acting force and the last step is complexity of environment

Most modern armies, assessing, in particular, combat vehicles and its combat

The utilization of autonomous vehicles for military purposes can be considered in two basic missions, as lethal or non-lethal assets. Within both types of mission the opposite side tries to eliminate autonomous vehicle or to capture it. For development of autonomous vehicle to be used by military purpose should be considered the same approach as for development of the combat vehicles operated by soldiers. The parameters of autonomous vehicles have to meet maximum of factors which are

According to author's long-life military experiences and deep and comprehensive analysis of the facts in the Army of the Czech Republic Lessons Learned Databases [6] the capabilities of autonomous vehicles can be considered in following ways.

**The combat power** of the autonomous vehicle will consist of the ability to meet the desired goal. This goal can be "only" to carry out monitoring and to find out the required information about the enemy, the task environment and their transfer to appropriate locations, detect the presence of undesirable substances in the area of operation, and warn troops about the presence of such substances until possible destruction of the enemy and its objects. Autonomous vehicle will be equipped with

It is necessary to consider the degree of autonomy of the resource for the **issue of protecting** the crew of an autonomous vehicle. Fully autonomous vehicle will be equipped with an artificial intelligence that will enable him to perform the task without any human intervention (collaboration), from his deployment to the fulfilment of the task, including eventual return to assigned assembly area. Partial autonomy may consist in the necessity or only the possibility of intervening in the selected phases of the autonomous vehicle implementation by the operator. The operator may, depending on the specific conditions on the battlefield and their change over the autonomous vehicle deployment planning phase, correct and

1 According to Allied Administrative Publication 6 (AAP-6) the operational environment is defined as: *A composite of the conditions, circumstances and influences that affect the employment of capabilities and bear on the decisions of the commander.*

*Military Factors Influencing Path Planning DOI: http://dx.doi.org/10.5772/intechopen.86421*

*Path Planning for Autonomous Vehicles - Ensuring Reliable Driverless Navigation...*

**10**

**Figure 2.**

**Figure 1.**

Cyber [5].

mous vehicles could be.

electromagnetic spectrum.

*the decisions of the commander.*

*Categories of factors-steps for consideration and planning.*

hazards, and the information environment (e.g., **Figure 1**).

generally consists of factors and conditions that

must be understood to successfully apply military capabilities protect the force and complete the mission. It influences the completion of a single mission as well as an entire campaign and its constituent elements [5]. The operational environment includes the sea, land, air and space, the enemy, neutral, friendly and other actors, facilities, weather, terrain, electromagnetic spectrum (EMS) CBRN threats and

The operational environment of the armed conflicts was, is and will be very diverse and it is involving many aspects. The armed forces must be able to perform a wide range of tactical activities in different domains as Land, Air, Sea, Cosmic and

Both (all) fighting parties will strive to achieve their goals in the most effective way, including minimizing their loss of life and deployed resources. One of the ways to minimize the loss of lives is the utilization of modern technical means-as autono-

Nowadays the predominant domain where fighting parties operate by soldiers is Land. But the most significant domain to gain domination by forces is Air. The multiplier of requested armed forces capabilities to effectively operate in each domain is

Focusing on solving issues the Land domain is the most demanding for autono-

1 According to Allied Administrative Publication 6 (AAP-6) the operational environment is defined as: *A composite of the conditions, circumstances and influences that affect the employment of capabilities and bear on*

mous vehicles path planning. For ground autonomous vehicles path planning

The operational environment1

*Military domains in operational environment.*

is possible to apply the analogical approaches as for military units movement planning.

Movement can be understood in broad terms as relocating someone from point to point in order to create conditions for and to be capable carry out particular planned activities after the move is over.

There has to be considered amount of factors that affect the move and the goals set for it (e.g., **Figure 2**). The first step in movement consideration is capability (parameters, technical data) of the autonomous vehicle itself, the second step is the autonomous vehicles mission (recce, destroy, cooperate, transport, refuel, etc.), the third step is opposite acting force and the last step is complexity of environment (terrain, weather, temperature, visibility, etc.).


**Abstract**

Daily supplementation of maternal diet during pregnancy and lactation with a fish oil-enriched dairy product increases the percentage of DHA and other omega-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) in mothers (placenta, plasma, erythrocyte membranes, and breast milk) and children (plasma and erythrocyte membranes). This supplementation during critical periods such as pregnancy, lactation, and early development of a newborn may influence the levels of certain inflammatory cytokines, reducing pro-inflammatory cytokines and promoting an anti-inflammatory "environment". In pregnant women who have not received any supplement of omega-3 LCPUFAs, IL-6 plasma levels are higher, while TNF-alpha plasma levels are also higher in their breastfed infant at birth and 2 months thereafter. There could be a relationship between docosahexaenoic acid (DHA) and the concentrations of different cytokines.

**Keywords:** docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), omega-3 LCPUFAs, pregnancy, lactation, cytokines, fatty acids

#### **1. Introduction**

Interest in the therapeutic effects of omega-3 (ω-3) fatty acids has grown over the last 30 years, particularly in regard to visual and neurological development in newborns, the immune system, and inflammatory and cardiovascular diseases [1–9].

Inflammation is one of the principal causes of complications during pregnancy and of prematurity and neonatal morbidity [10–15].

Docosahexaenoic acid (DHA) has anti-inflammatory effects and can alter the production of inflammatory cytokines in animal models, cell culture, and in humans [16–26]. A high intake of omega-3 fatty acids has been associated with a reduction in arachidonic acid-derived inflammatory eicosanoids, cytokine production, reactive oxygen species, and expression of adhesion molecules [27]. It is also associated with the production of lipid mediators [28] that have anti-inflammatory [29–31] and immunomodulatory effects [27]. Both eicosapentaenoic acid (EPA) and DHA affect the function of many immune cells and can have a beneficial effect in preventing inflammatory or immune-mediated diseases, but their effects and mechanisms of action can differ [32]. They can inhibit the production of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin (IL)-1 and IL-6 [33]. In animal models their intake during pregnancy appears to exert an anti-inflammatory effect on damaged tissue in the young [34–36], while in humans it produces a decrease in Th1 cytokines such as interferon-gamma (IFN-γ)

and IL-1 in infants' plasma and a decrease in the Th2 cytokines IL-14 and IL-13 in the umbilical cord blood [32, 37].


**5. Conclusions**

In this study, we examined the spatial and temporal variation of ambient air quality in northwest China (NWC) for a period of four years (2015–2018). During the study period, the average concentration of PM2.5, PM10, SO2, NO2, CO, and O3 decreased in 92.5%, 96.2%, 92.5%, 64.5%, 88.7%, and 11.3% of the cities in NWC. The annual average concentration of particulate matter (PM2.5 and PM10) exceeded the CAAQS Grade II standards and WHO recommended air quality guidelines in NWC, while the annual average concentration of SO2 and NO2 complied with the CAAQS Grade II standards in NWC. In the case of seasonality, the highest pollution level occurred in winter except for ozone, with varying degrees of spatial distribution. The AQI, the proportion of AQI Class I, and the number of pollution days improved by 21.3%, 114.1%, and 61.8%, respectively, in NWC. The AQI improved in all the seasons, with the maximum improvement in spring followed by summer, winter, and autumn. In NWC, PM10 was a major pollutant for most of the days, followed by O3, PM2.5, NO2, CO, and SO2 with different spatial and temporal variations. A strong correlation occurred between AQI and all the pollutants except O3. Stricter regulations, e.g., a three-year action plan to win the blue sky defense war, sector-specific guidelines, and strict enforcement of environmental legislation, are the keys to pollution-free and breathable air. This paper comprehensively discussed the spatio-temporal characteristics of the ambient air quality in NWC and calls for future detailed assessment focusing on source apportionment, health risk assessment, the impact of meteorology, dispersion modeling, and impact of the chemical processes that influence the air quality.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/atmos13030375/s1, Figure S1: The locations of 53 cities in five provinces (Shaanxi (SN), Xinjiang (XJ), Gansu (GS), Ningxia (NX), and Qinghai (QH)) northwest China (NWC). Color represents the different classes of air quality index, e.g., green (0–50, good), yellow (51–100, moderate), orange (101–150, unhealthy for a sensitive group), red (151–200, unhealthy for all), purple (201–300, very unhealthy), and maroon (300+, hazardous); Figure S2: The seasonal (spring (light blue line), summer (orange line), autumn (grey line), and winter (yellow line)) spatial distribution of PM2.5 (a), PM10 (b), SO2 (c), NO2 (d), CO (e), and O3 (f) in 53 cities of northwest China between 2015 and 2018. Descriptions are as follows: light blue line with dots (spring), orange line with dots (summer), grey line with dots (autumn), yellow line with dots (winter), and the blue line (CAAQS, daily mean). The abbreviations are as follows: PM2.5 (fine particulate matter), PM10 (coarse particulate matter), SO2. (sulfur dioxide), NO2 (nitrogen dioxide), CO (carbon monoxide), and O3 (ozone); Figure S3: Annual

(a) and seasonal (spring (b), summer (c), autumn (d), winter (e)) relationship between air quality index (AQI) and criteria pollutants (PM2.5, PM10, SO2, NO2, CO, and O3). The abbreviations are as follows: AQI (air quality index), PM2.5 (fine particulate matter), PM10 (coarse particulate matter), SO2 (sulfur dioxide), NO2 (nitrogen dioxide), CO (carbon monoxide), and O3 (ozone); Table S1: Lists of cities, their rankings in five provinces (Shaanxi (SN), Xinjiang (XJ), Gansu (GS), Ningxia (NX), and Qinghai (QH)) of northwest China (NWC) between 2015 and 2018; Table S2: Pearson correlation between AQI and six criteria pollutants (PM2.5, PM10, SO2, NO2, CO, and O3) in northwest China (NWC) between 2015 and 2018. The abbreviations are as follows: AQI (air quality index), PM2.5 (fine particulate matter), PM10 (coarse particulate matter), SO2 (sulfur dioxide), NO2 (nitrogen dioxide), CO (carbon monoxide), and O3 (ozone).

**Author Contributions:** Conceptualization, S.Z.; data curation/accumulation, S.Z.; investigation and data validation, J.L. and M.B.; methodology, S.Z.; data modelling, S.Z.; GIS mapping, S.Z.; writing—original draft preparation, S.Z.; review and editing, J.L. and M.B.; supervision, J.L.; funding acquisition, J.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research work is supported by the National Natural Science Foundation of China (No. 21667026), the Social Science Foundation of Xinjiang Production and Construction Corps (No. 18YB13), and the Startup Foundation for Introduction Talent of NUIST (2017r107).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available upon request from the corresponding author.

**Acknowledgments:** I would like to acknowledge the China National Environmental Monitoring Center (CNEMC) for the provision of air quality data. I am also very thankful to Jianjiang Lu and research scholar Anam Arshad from the School of Chemistry and Chemical Engineering, Shihezi University for helping and guiding me throughout the preparation of this paper.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

**Xing Xiang 1, Guangming Shi 1,2,\* , Xiaodong Wu 1 and Fumo Yang 1,2**

1 Department of Environmental Science and Engineering, Sichuan University, Chengdu 610065, China<EMAIL_ADDRESS>(X.X<EMAIL_ADDRESS>(X.W<EMAIL_ADDRESS>(F.Y.)

**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** Sichuan Basin is an area with some of the most serious PM2.5 pollution, and it is also a key area for joint prevention and control of air pollution in China. Therefore, it is necessary to clarify the temporal and spatial distribution characteristics of PM2.5 concentration in Sichuan Basin (SCB) and study the influence of meteorological conditions. In this study, the spatial disparity of PM2.5 concentration in SCB and its variation trend from 1 December 2015 to 30 November 2019 were analyzed. The results showed that the spatial disparity of SCB was decreasing and distinct variation trends of PM2.5 concentration were observed in different areas. The PM2.5 concentrations declined rapidly in the western and southern basin (most severely polluted areas), decreased at a slower rate in the central and eastern basin, but unexpectedly increased slightly in the northern and northeastern basin. From the perspective of relative spatial anomalies (RAs), the decreasing (increasing) trend of RAs of PM2.5 concentrations in the western and southern (northern and northeastern) parts of SCB were also prominent. The reduction in spatial disparity and the regionally extraordinary increasing trend could be partly explained by the variations in synoptic circulations. Specifically, the reasons for the decrease in wintertime spatial disparity and the increase in RAs in the northern basin were the reduction in synoptic pattern Type 2 (weak high-pressure system and uniform pressure fields) and Type 3 (high-pressure system to the north) and the growth of Type 6 (weak low-pressure system with high-pressure system to the north). In spring, the reasons were the reduction in Type 1 (weak low-pressure system) and Type 5 (weak low-pressure system to the southwest) and the growth of Type 2. The reduction in Type 2 and the growth in Type 4 (weak high-pressure system to the east) could explain the variation in PM2.5 distribution in autumn. This study showed the importance of implementing more precise and effective emission control measures, especially in relatively cleaner areas, in which the impacts of meteorological conditions might cause fluctuation (even rebounding) in the PM2.5 concentration.

**Keywords:** PM2.5; Sichuan Basin; spatial distribution; spatial disparity; synoptic patterns; meteorological conditions


**3. Materials and Methods**

A systematic literature review was conducted to provide an overview of the research to date related to influences of Industry 4.0 revolution on the human capital development and consumer behavior. This systematic literature review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (http://prisma-statement.org/), being prepared following the points in the report for systematic reviews and meta-analyses [41,42].

Systematic Literature Review (SLR) is a method used to identify, evaluate, and synthesize the current situation of specific research topics in the specialized literature. This technique involves localization, restrictive collection, rigorous scientific methodological analysis, and eliminating the subjective element. The purpose of SLR is building an overview, adequately documented on a specific topic and providing a correct summary of the literature, resulting in an estimate of the overall effect for a study population [43]. The systematic review is becoming increasingly important in social science research. The scientific importance of SLR comes from its emphasis on systematically identifying and collecting all available information on a specific topic. Based on this information, it is possible to determine a certain tendency specific to the theme or domain studied. In a SLR targeting research in the field of social sciences, according to [44], the high degree of variability in the studies related to the social sciences area must be considered.

Our approach to conducting this review was based on Snyder's approach [45] and consisted of four stages: (1) designing the review, (2) conducting the review, (3) analysis, and (4) writing up the review.

#### *3.1. Information Source Search Strategy, and Identification*

A detailed strategy was developed for using the Web of Science database. A search for publications addressing Industry 4.0-related concepts, as well as human capital and consumer behavior, was conducted in February-March of 2020. The Web of Science database was selected due to its broad coverage. In addition, we performed a partial search of gray literature in Google Scholar. The last search in all databases was performed on March 2, 2020.

Regarding the search for information in articles, we have included only the open access sources because of budgetary constraints. In the first search, including articles that are not open access, 2204 titles were provided. Only 762 were maintained in the analysis, satisfying the open-access condition. This could be a limitation of the research.

Figure 1 shows the initial search yielded a total of 762 records; however, 355 records were excluded due to their document type and language. We excluded conference proceedings, book series, books, and other publications. Only journal articles were included in the systematic literature review, aiming at high-quality studies ensured by the peer-review process undertaken by academic journals. Additionally, we excluded articles written in other languages than English, thus eliminating 27 records in various other languages. Besides that, we considered only open access articles, considering the necessity of studying the entire articles. The excluded publications were organized by criterion of exclusion.

The reasons for exclusion were:

**Figure 1.** Flowchart of search and selection criteria. Source: Authors own design based on PRISMA.

#### *3.2. Inclusion and Exclusion Criteria*

The following combination of terms used to search references using Boolean operators was performed:

TI = (Industry 4.0\* OR Industry 4.0 Revolution\* OR Industrial Internet of Things\* OR Internet of Things\* OR Digitalization\* OR Cyber-Physical Production Systems\* OR Automation\* OR Information Technology\* OR Artificial Intelligence\* OR Communication Technology\*)

TS = (Human Capital Development\* OR Human Resources\* OR Labor market\* OR Labor market\* OR Consumer Behavior\* OR Consumer Behavior\*).

Figure 1 shows in detail the inclusion and exclusion criteria. The inclusion and exclusion process were prepared in accordance with the items of the PRISMA flow diagram and the Checklist. In the qualitative analysis, first, we screened the abstracts; 49 records were excluded because they provided no approach of the related to Influences of Industry 4.0 Revolution on the Human Capital Development and Consumer Behavior. Posteriorly, we proceeded to read the articles.


*4.3. Dermal Exposure*

Health and beauty products are another key source of nanoplastics, particularly in the body and facial scrubs that are used topically on the skin [11]. Nanocarriers for drug delivery via dermal application is another important exposure route. Although there are no conclusive data showing the effects of nanocarriers, small particle size and stressed skin conditions are critical factors to skin penetration [51]. There is no current research that has specifically looked at the ability of nanoplastics to penetrate the surface of the skin. Only one study reported the likelihood of engineered nanoparticles from textiles in permeating the skin barrier at very minute quantity [80].

The skin is protected by the stratum corneum, the outermost layer, which forms a barrier against injuries, chemicals and microbial agents. The stratum corneum consists of corneocytes that are surrounded by lamellae of hydrophilic lipids including ceramide, longchain free fatty acids and cholesterol [81]. Plastic particles may be introduced on the skin through health and beauty products, or through contact with nanoplastic-contaminated water. As micro- and nanoplastics are hydrophobic, it is predicted that absorption through the stratum corneum through contaminated water is unlikely, though plastic particles could enter the body via sweat glands, skin wounds or hair follicles [51].

Alvarez-Roman et al. looked at how plastic particles enter the body and how they are then distributed throughout the skin tissue. They used fluorescent polystyrene particles between 20 and 200 nm in diameter and skin tissue from a pig to conduct their experiment [82]. A confocal laser scanning micrograph of the skin revealed that a greater number of 20 nm polystyrene nanoplastics concentrated in the hair follicles than those of 200 nm nanoplastics. However, neither particles were able to permeate the stratum corneum in order to embed themselves into the deeper skin tissue. Campbell et al. supported these findings and established that polystyrene particles with diameters of 20–200 nm can infiltrate only the top layers of the skin at a depth of 2–3 μm [83]. Vogt et al. were able to

distinguish 40 nm-diameter fluorescent polystyrene nanoparticles in the perifollicular tissue of skin explants that had been treated with cyanoacrylate follicular stripping. This work ascertained that when particles were applied transcutaneously, they were then absorbed by the Langerhans cells [84].

The mechanical production method used to manufacture the microbeads of the health and beauty products, including facial and body scrubs, increases the likelihood of the breakdown of microbeads into even more harmful nanoplastics. Hernandez et al. investigated the amount of nanoplastics present in facial scrubs containing 200 μm polyethene microbeads. The results from scanning electron microscopy confirmed that nanoparticles were observed at sizes between 24 ± 6 nm and 52 ± 14 nm. Then, they examined the chemical composition of these nanoparticles by using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy and established that they consisted of polyethylene [11].

Data from these previous studies can be used to determine the likelihood of nanoplastics penetrating the stratum corneum. Exposure to UV rays causes skin damage, which means that the skin barrier becomes weaker [85]. A study on the effects of UV irradiation on murine skin found an increase in the skin permeation by carboxylated quantum dots. The intercellular adhesion in the irradiated skin was compromised by the perturbed expression of tight-junction-related proteins: Zonula occludens-1, claudin-1, and occludin [86]. There are a number of compounds, e.g., short chain- and long chain-alcohols, cyclic amides, esters, fatty acids, glycols, pyrrolidones, sulphoxides, surfactants and terpenes, that are used to enhance the chemical permeation of drugs and formulations through the skin barrier [87]. Widely used ingredients in body lotions, such as urea, glycerol and α-hydroxyl acids also enhanced the ability of nanoparticles to permeate the skin barrier [88].

Kuo et al. highlighted how oleic acid, ethanol and oleic acid-ethanol enhancers impact the transdermal delivery of 10 nm zinc oxide nanoparticles. They determined that each chemical had the potential to improve the effectiveness of zinc oxide nanoparticles in penetrating the skin barrier, through the multilamellar lipid regions between corneocytes [89]. Through crystalline structure analysis of various compositions of lipid lamellae in stratum corneum samples taken from human and porcine sources, Bouwstra et al. presented a three-layer "sandwich model", which likely prevents large nanoparticles from permeating undamaged skin [81].

To summarize, both in vitro and in vivo studies, discussed above, have established that micro- and nanoplastics can be absorbed into the human body through the skin barrier. That being said, these studies all rely on polystyrene particle models. Further studies conducted with samples collected from the environment would be helpful to fully understand the permeation qualities of micro- and nanoplastics. Such samples would include a variety of plastic particles with wide-ranging characteristics.

### **5. Cellular Uptake and Intracellular Fate of Microplastic and Nanoplastic Particles**

After permeating into the stratum corneum and absorbed into the human body, microplastics and nanoplastics are then able to interact with numerous target cells. The quantity of nanoparticles that are absorbed and subsequently react with cells depends on a number of factors, such as their size, surface chemistry or charge of the biological elements they encounter, including proteins, phospholipids and carbohydrates [90]. As nanoparticles absorb proteins from the human body, they create 'protein coronas' around themselves [91]. This means that nanoparticles that interact with organs or skin cells will usually already be surrounded with protein corona as opposed to an exposed nanoparticle. The protein coating will lead to modified characteristics of the nanoparticle. Previous in vitro experiments have determined that protein coronas will surround polystyrene nanoparticles and that this enables the nanoparticles to translocate at greater rates [62]. These studies also showed that the protein coronas would alter their form according to their environment [67] and that there were more occurences of cell interactions and

increased toxicity [92]. Finally, it was shown that protein coronas around the polystyrene nanoparticles led to them being accumulated in the gut.

Microplastics and nanoplastics can be absorbed by cells via a number of routes [93]. The primary route is via endocytotic nanoparticle uptake where adhesive interaction of nanoparticles (or inactive permeation of the cell membrane) with channel- or transportprotein occurs. Several endocytotic pathways have been identified, such as phagocytosis and macropinocytosis, along with clathrin- and caveolae-mediated endocytosis (Figure 3) [94–96].

**Figure 3.** Routes of cellular uptake of plastic particles. Phagocytosis, macropinocytosis, clathrin- and caveolae-mediated endocytosis are the common endocytotic pathways that have been identified for cellular uptake of plastic particles. Microand nanoplastics can be absorbed by cells through different routes, of which endocytotic nanoparticle uptake is the primary route where adhesive interaction of nanoparticles (or inactive permeation of the cell membrane) with channel- or transport-protein occurs.

> The initial barrier to nanoparticle incursion into the skin is the outer cell membrane. Coarse-grained molecular simulations of polystyrene (PS) particles in interacting with biological membranes revealed that polystyrene nanoparticles effortlessly penetrated the lipid bilayer membranes, causing changes to the structure of the cell membrane, ultimately disrupting the cell function [97]. Uptake inhibition studies on the absorption rate of 44 nm polystyrene particles to human colon fibroblasts and bovine oviductal epithelial cells indicated that polystyrene nanoparticles were primarily absorbed through a clathrinindependent uptake mechanism [98].

> The cellular absorption of carboxylated polystyrene nanoparticles of 40 nm and 200 nm was studied using several tumor cell lines, including human cervical HeLa cells, human glial astrocytoma 1321N1, and adenocarcinomic human alveolar basal epithelial A549 in the presence of various transport inhibitors [99]. The results indicated that the nanoparticles were always absorbed by cells through an active and energy-dependent method, suggesting that the nanoparticle uptake for different cell types utilized different pathways. Actin depolymerization significantly influenced the nanoparticle uptake in HeLa and 1321N1 cell lines, while clathrin-mediated endocytosis of the nanoparticles in 1321N1 was significantly

reduced by the inhibitor chlorpromazine. Nanoparticle uptake in A549 cell line via caveolaemediated endocytosis was notably diminished due to disruption of microtubule formation by the inhibitor genistein [99].

The routes of nanoparticle absorption in human cells are dependent on the size and surface chemistry of the particles, but also vary according to the type of cell penetrated. This is seen when 120 nm polystyrene nanoparticles altered with amidine groups were seen to permeate rat alveolar epithelial monolayers using non-endocytic pathways, whilst MDCK-II cells use energy-dependent processes to absorb nanoparticles [76,100]. Macrophages and epithelial cells were found to use various combinations of endocytotic uptake mechanisms to absorb 40 nm carboxylated polystyrene nanoparticles.

Using several endocytotic pathway inhibitors, J774A.1 macrophages were shown to absorb nanoplastics via macropinocytosis, phagocytosis, and clathrin-mediated endocytosis pathways, whilst absorption in A549 cells relied on caveolae- and clathrin-mediated endocytosis pathways [101]. If nanoplastic particles are entering the human body via non-vesicular pathways, then they may be able to interact with intracellular molecules or discharge persistent organic pollutants (POPs) straight into the cytoplasm. This, in turn, implies that POPs may be stored in human cells which could have a negative toxicological impact [102].

Plastic particles enter cells via the intracellular endocytotic pathway engaging with early and late endosomes before combining with lysosomes. Polystyrene nanoparticles have been reported to accumulate in the lysosome [103], including the observance of intracellular localization of 40–50 nm polystyrene nanoparticles in A549 cells [77]. No lysosomal leakage or any fragmentation of the nanoparticles were reported when acidic conditions were applied [104].

A comparison of two types of nanoparticles made of polystyrene and mesoporous silica demonstrated clear differences in cellular uptake mechanisms in ovarian cancer cells. Data gathered demonstrated that ovarian cancer cells absorbed both types of nanoparticles with different endocytotic pathways [105]. Caveola-mediated endocytosis was the pathway used by mesoporous silica particles to permeate the cells and these then, according to the size of the particle, either remained in the lysosome (50 nm) or translocated into the cytoplasm (10 nm). On the other hand, polystyrene nanoparticles were absorbed through a caveola-independent pathway. Localized amine-modified 50 nm polystyrene particles showed toxicity to the lysosome after 4–8 h, whereas 30 nm carboxyl-modified polystyrene particles showed no signs of toxicity and did not enter cells via the standard acidic endocytotic route.

Previous research has also determined that cytotoxicity is greater with a positive surface charge and this also leads to increased absorption of nanoparticles via non-specific binding, where they end up on the negatively charged sugar moieties on cell surfaces. In contrast, the repellent interactions of negatively charged particles will impede endocytosis [103,106]. Studies have determined that there are several cellular absorption pathways and intracellular localization of polystyrene nanoparticles depending on their physicochemical characteristics. Despite this, there is little quantitative data concerning how nanoplastics enter cells and their eventual fates.

The size of plastic particles also affects their interaction with human cells [107]. Due to their high specific surface areas, the nanoparticle-cell interaction is vastly different compared to larger particles. Furthermore, the charge of the particle can also affect its interaction with the cell and its structure [107]. Since most of the in vitro studies described here have used polystyrene particles, it is difficult to extrapolate the results to other kinds of plastic particles. It is important that future research looks at cellular uptake and behaviours of other types of plastic particles.

### **6. Potential Toxic Effects of Microplastics and Nanoplastics on Human Health**

Several in vitro and in vivo studies have shown that micro- and nanoplastics were able to cause serious impacts on the human body, including physical stress and damage, apoptosis, necrosis, inflammation, oxidative stress and immune responses (Table 1) [108–111].