**1. Introduction**

Deficiency of growth and development in the midfacial complex is a major drawback of primary CLP repair in the neonatal period of growth, well documented in the literature [1–3]. Causes are thought to be formation of scar tissue in the growth centers of the maxilla [4], mouth breathing due to obstruction of the nasal passage [5], deficiency of the alveolar process due to missing teeth [6], and a tense upper lip [7, 8]. Unrepaired bone defects on the other hand result in closer to normal maxillo-facial development [7, 8]. Because of midfacial deficiency, orthognathic surgery becomes often indispensable at the adult ages in CLP management. Treatment of CLP with orthognathic surgery involves maxillary advancement, distraction osteogenesis, and mandibular setback, combined with orthodontic treatment [9].


**3. Big data and geographic information system**

Big data and GIS are able to share several aspects together because they are similar in elements of data processing. In **Figure 5**, I show GIS data processing with its elements. There are popular open source or commercialized software and webbased online GIS systems, which play an important role in processing and analyzing GIS data.

First, GIS uses data that contains a location or space, therefore it is displayed in a map or picture form. Recently, aerial or satellite data becomes more and more important as new technologies are introduced. As a location based data, GIS data is usually large-sized as is big data.

Second, GIS collects field data such as street information, Closed Circuit TV (CCTV), or other location-based datasets. If the datasets do not provide location information, GIS technicians should perform a geo-coding process to convert into GIS datasets. People's participation is also an important way to get GIS data; so the participatory GIS system becomes a significant field of GIS. Crawling with search engine robot is also useful tool for obtaining data in GIS.

Third, GIS has web server, geospatial data server, or cloud server for its data storage. These servers can be overlapped one another sometimes, but they have their own territories that cannot be shared. In **Figure 6**, I introduce a basic principle of geo-database for single-user and multi-users with the ESRI's official website information. Geo-database system is crucial to manage complicated structured GIS datasets and their attributes.

Fourth, GIS desktop and online software plays a pivotal role in the rest of process including data processing (building), analysis, and visualization. In the GIS data processing (building), efficient systems included are ArcGIS Online, Google Maps JavaScript API, Here Maps JavaScript API, Microsoft Bing Geocode Dataflow API, and US Census Geocoder. They are helpful for building up geo-coding and mapping coordinates in the database.

Fifth, GIS data analysis contains several functions as **Table 1** briefly shows with ArcGIS analysis toolbox summary. Similar analyses are conducted with other software such as ArcGIS, QGIS, GRASS GIS, GeoDa, CartoDB, Mapbox, and the other desktop or online GIS systems.

#### **Figure 5.**

*GIS data processing and its elements.*

**125**

**Figure 7.**

**Table 1.**

*GIS and Big Data Visualization*

*DOI: http://dx.doi.org/10.5772/intechopen.82052*

*GIS data analysis toolbox example with ArcGIS [11].*

*GeoDa desktop software's visualization windows with crime data.*

**Toolsets Description**

Sixth, GIS data visualization intends to display spatial patterns or relationship between or among locations. Popular open source software included here are ArcGIS, Tableau, InstantAtlas, QGIS, SAGA GIS, GeoDa, and MapWindow. These tools are

Extract GIS datasets often contain more data than you need. The Extract

feature class or table. Overlay The Overlay toolset contains tools to overlay multiple feature

Pairwise Overlay The Pairwise Overlay toolset provides an alternative to some of

Proximity The Proximity toolset contains tools that are used to determine

or around them. Statistics The Statistics toolset contains tools that perform standard

tools let you select features and attributes in a feature class or table based on a query (SQL expression) or spatial and attribute extraction. The output features and attributes are stored in a

classes to combine, erase, modify, or update spatial features, resulting in a new feature class. New information is created when overlaying one set of features with another. There are six types of overlay operations; all involve joining two existing sets of features into a single set of features to identify spatial

the proximity of features within one or more feature classes or between two feature classes. These tools can identify features that are closest to one another or calculate the distances between

statistical analysis (such as mean, minimum, maximum, and standard deviation) on attribute data as well as tools that calculate area, length, and count statistics for overlapping and neighboring features. The toolset also includes the Enrich tool that adds demographic facts like population or landscape facts

relationships between the input features.

the tools in the Overlay toolset.

like percent forested to your data.

**124 Figure 6.** *GIS data in the geo-database (GDB) [10].*

*Geographic Information Systems and Science*

**124**

**Figure 6.**

**Figure 5.**

*GIS data processing and its elements.*

*GIS data in the geo-database (GDB) [10].*

#### **Table 1.** *GIS data analysis toolbox example with ArcGIS [11].*

Sixth, GIS data visualization intends to display spatial patterns or relationship between or among locations. Popular open source software included here are ArcGIS, Tableau, InstantAtlas, QGIS, SAGA GIS, GeoDa, and MapWindow. These tools are

actively adapted to big data based software or systems to build up location oriented systems as well as more persuasive graphic works. **Figure 7** shows visualization windows with GeoDa desktop software.


*2.1. Hapten Design and Synthesis*

The generation of antibodies to AOH has so far been based on the preparation of the required immunogens from AOH itself, which does not allow fine control over the specific position of the mycotoxin framework where the functionalized linker is introduced. In this study, we have synthesized two regioisomeric haptens of AOH from scratch. One of them, hapten **AL***a*, incorporates a five-atom carboxylated aliphatic spacer arm through the hydroxyl group at C-9, whereas the other one, hapten **AL***b*, incorporates the same linker via the hydroxyl group at C-3 (Figure 1). In contrast to previous strategies, these two haptens allowed the preparation of bioconjugates with well-defined compositions.

**Figure 1.** Chemical structures of alternariol, alternariol monomethyl ether, and the synthetic haptens.

The synthetic strategy for preparing hapten **AL***a* was based on a convergent methodology previously used by several research groups to synthesize AOH and other structurally related molecules [17–20]. A key step in this synthesis is a Pd(0)-catalyzed cross-coupling reaction between an aryl triflate (**4**), which already contained the spacer arm, and an appropriately functionalized arylboronic acid (**6**) (Scheme 1). The aryl triflate **4** was prepared in two steps from the readily available 1,3-benzodioxinone **1** [21,22]. First, an *O*-alkylation reaction with methyl 5-bromovalerate was performed under standard Williamson ether synthesis conditions. The alkylation process produced a 6:1 mixture of di- and mono-*O*-alkylation products, **2** and **3**, respectively, which were easily separated by column chromatography to provide the product resulting from the selective *O*-alkylation of the less hindered hydroxyl group, i.e., **3**, with a 75% yield. The free hydroxyl group of **3** was then converted to the required triflate group by reaction with triflic anhydride in pyridine, giving the triflate **4** in 91% yield. The additional required coupling reactant, aryl boronic acid **6**, was prepared from the orcinol-derived bromide **5** [23] by halogen-metal exchange using butyllithium and reaction of the resulting lithiated derivative with triisopropyl borate.

The subsequent palladium-catalyzed Suzuki-Miyaura coupling between the aryl triflate **4** and the labile boronic acid **6** gave the biaryl **7** in 75% yield. Hydrolysis of the methoxymethyl ether (MOM) groups by treatment with methanolic HCl, followed by intramolecular transesterification promoted by trifluoroacetic acid, completed the synthesis of the tricyclic benzochromenone backbone and afforded the methyl ester of hapten **AL***a*, compound **8**, in 97% yield. To complete the synthesis of hapten **AL***a*, only the hydrolysis of the methyl ester moiety of **8** was required, which was initially carried out under basic conditions (LiOH in THF-H2O at room temperature, rt). However, under these conditions, the central lactone group of the benzochromenone core was partially opened, requiring acid treatment of the reaction crude to reconstruct the tricyclic ring system. It proved more convenient to carry out this transformation using enzymatic hydrolysis, so a lipase from *Candida antarctica* immobilized on an acrylic resin was used to hydrolyze the methyl ester group, providing hapten **AL***a* in practically quantitative yield.

**Scheme 1.** Synthesis of **AL***a***-NHS** ester. Reagents and conditions: (a) Br(CH2)4CO2CH3, K2CO3, KI, Bu4NBr, acetone, reflux, 16 h, 75% of **3**. (b) Tf2O, pyridine, 0 ◦C to rt, 20 h, 91%. (c) i. n-BuLi, THF, −78 ◦C, 40 min; ii. B(Oi Pr)3, −78 ◦C to 0 ◦C, 1.5 h, 93%. (d) Pd(PPh3)4, K2CO3, DMF, 93 ◦C, 24 h, 75%. (e) i. HCl, MeOH, rt, 22 h; ii. TFA, CH2Cl2, rt, 20 h, 97%. (f) Lipase acrylic resin, THF-PB 100 mM, rt, 20 h, 93%. (g) EDC·HCl, NHS, DMF, rt, overnight, 99% of crude product.

Upon completion of the synthesis of hapten **AL***a*, its carboxylic group was activated by forming the corresponding *N*-hydroxysuccinimidyl ester. This transformation was carried out under conventional activation conditions, with *N*-(3-dimethylaminopropyl)-*N* ethylcarbodiimide hydrochloride (EDC·HCl) and *N*-hydroxisuccinimide (NHS) in *N*,*N*dimethylformamide (DMF) at rt, yielding the corresponding *N*-hydroxysuccinimidyl ester, **AL***a***-NHS**, in good yield. The activated hapten was extracted essentially pure from the reaction as judged by 1H NMR, so it was further used without additional purification by column chromatography. NMR spectra of all of the intermediates and the hapten can be found in the Supplementary Materials file.

Hapten **AL***b* was synthesized following a similar procedure as hapten **AL***a*, except that in this case the tricyclic benzochromenone core was built first, with the hydroxyl groups appropriately protected to allow subsequent incorporation of the spacer arm at the required C-3 position. As shown in Scheme 2, the synthesis of the benzochromenone ring system began with the palladium-catalyzed cross-coupling reaction between the aryl boronic acid **6** and the previously reported bromobenzaldehyde **9** [24,25]. This coupling was carried out under conditions similar to those previously used for the conversion of **4** and **6** into **7**, obtaining the biphenyl-2-carbaldehyde **10** in 77% yield. The formyl group was further oxidized to the carboxylic group under Pinnick oxidation conditions to afford the biphenyl-2-carboxylic acid **11**, which was then treated with methanolic HCl at 55 ◦C to promote deprotection of the MOM groups and further intramolecular esterification, thus completing the formation of the tricyclic benzochromenone system. Under these conditions, both sequential processes worked extremely well, affording **12** in practically quantitative yield. *O*-alkylation of the phenol-like hydroxyl group at the C-3 position of **12** with methyl 5-bromovalerate, using Cs2CO3 in DMF as base, gave the *O*-alkylated derivative **13** in 94% yield. The methyl ester of **13** was further converted to the corresponding carboxylic group under enzymatic hydrolytic conditions, yielding **14** also in high yield. The hapten **AL***b* was first obtained by hydrogenolysis of both benzyl ether groups of **14** using 5% Pd on activated carbon as catalyst. With hapten **AL***b* in hand, we activated the carboxylic

group using the carbodiimide-NHS procedure as was done for hapten **AL***a*. However, the overall yield from these two processes was low, most likely motivated by an intermolecular esterification reaction between a hydroxyl group and the aliphatic active ester that resulted in the spontaneous formation of a transparent thin film, a polyester polymer, on the flask walls. By reversing the order of these steps, i.e., by activating the carboxylic group first and then releasing the hydroxyl groups, a much better result was obtained. Thus, treatment of carboxylic acid **14** with EDC and NHS as before, followed by hydrogenolysis of the benzyl ether moieties of the resulting *N*-hydroxysuccinimidyl ester **15** with 5% Pd on activated carbon in acetone, gave the desired *N*-hydroxysuccinimidyl ester of hapten **AL***b*, **AL***b***-NHS** ester, with a very high overall yield. As in the case of the active ester of hapten **AL***a*, the **AL***b***-NHS** ester was extracted essentially pure from the reaction as judged by 1H NMR, so it was further used without additional purification by column chromatography. NMR spectra of all of the intermediates and the hapten can be found in the Supplementary Materials file.

**Scheme 2.** Synthesis of **AL***b***-NHS** ester. Reagents and conditions: (a) Pd(PPh3)4, K2CO3, DMF, 95 ◦C, 19 h, 77%. (b) NaH2PO4·H2O, NaClO2, t BuOH-H2O (5:1), rt, 5 h, 96%. (c) i PrOH, THF, conc HCl, 55 ◦C, 24 h, 98%. (d) Br(CH2)4CO2CH3, Cs2CO3, DMF, 94%. (e) Lipase acrylic resin, THF-PB 100 mM, rt, 20 h, 99%. (f) EDC·HCl, NHS, DMF, rt, overnight. (g) 5% Pd/C, acetone, H2 (1.5 atm), rt, 19 h, 95% of crude product from **14**.


*4.5. QGroundControl*

QGC (QGroundControl, more info at: http://qgroundcontrol.com/, last access: 30 March 2022) is software providing a graphical interface useful for monitoring a quadrotor's status, full flight control, mission planning, and tuning of an autopilot system's parameters.