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Into Unscientific Chapter 638
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Into Unscientific Chapter 638

Chapter 638: Dawn has appeared

 “Xiao Xu, paclitaxel has been synthesized!”

 With the sound of this sentence.

 In the house.

Xu Yun's polite words that he was about to blurt out were stuck in his throat, and he subconsciously turned his head and looked at the entrance of the room.

 After a while.

 The door of the house was pushed hard from the outside, and Lao Guo's panting figure flashed out from behind the door:

“Xiao Xu, good news, good news! I just received the news from Comrade Zhicen that paclitaxel has been successfully synthesized!”

Xu Yun couldn't help showing a surprised look when he saw this, and asked Lao Guo:

“Guo Gong, are you telling the truth?”

Xu Yun's surprise was not fake, he was really unprepared for the news.

According to his previous estimates, Lou Zhicen and Tu Luming would be able to achieve a breakthrough in mid-November very quickly. Now it is a month and a half ahead of schedule, almost on par with the efficiency of the paper team.

Lao Guo gave a heavy hum, his lips subconsciously made a "Xiao Han" mouth shape, but he immediately corrected himself:

“Yes, Xiao Xu, that's what the message I received said—but I just learned about it a while ago, and I don't know much about the specific situation.”

 After saying that, he raised his eyes and glanced at Zhao Zhongyao opposite, and asked tentatively:

 “Xiao Xu, Lao Zhao, do you like your paper?”

Hearing this, Xu Yun raised the English manuscript in his hand towards Lao Guo. In order to avoid damage to the manuscript, he did not move too much. At the same time, he smiled and said:

“I'm pretty optimistic about it. There are basically no big problems with the paper. Only some details can be optimized.”

 “For example, the overlapping integral of the wave function here, and”

Xu Yun simply pointed out some details that could be added in the manuscript. In addition, as mentioned before, he deliberately left some small errors and omissions that were not conceptually correct but could help understand this era.

 Some concepts are proposed a few years in advance, which is called forward-thinking, and those proposed twenty or thirty years in advance are called geniuses, but those proposed sixty or seventy years in advance are pure heresies.

 After everything was settled, Xu Yun looked at Zhao Zhongyao again, considered and said:

“Director Zhao, that's it for the revision of the paper. Will you come with us next or...?”

Zhao Zhongyao thought for a few seconds, clicked his tongue, and pointed his index finger in a certain direction:

“Since this matter of paclitaxel is related to Lao Yang, I will go over with you to take a look.”

The Lao Yang that Zhao Zhongyao refers to is naturally Mr. Yang Kaiqu, Zhou Kaida's teacher and the most important treatment target for this targeted drug development.

Although Yang Kaiqu is not a big boss at the academic committee level, academic committee members are not the only channel for top scholars to get to know each other:

Yang Kaiqu and Zhao Zhongyao are both from Zhuji, Zhejiang Province. They are only a few months apart in age. They have known each other since they were in elementary school.

When they were in high school, they also joined the local National Salvation Industrial Association in Hangzhou, took to the streets together to shout slogans, and signed their names on the National Salvation Volunteer Form. It has been more than 40 years ago.

 Later, one of them invested in the agricultural field, cultivating crops and cultivating grain, and also brought out outstanding students like Zhou Kaida.

 The other devoted himself to high-energy physics, paving the way for particle theoretical physics in China. His students are all over the world, and they are all using their lives to fulfill their original promise of saving and strengthening the country, and their original enthusiasm has not yet frosted.

 So even though one of them is a member of the academic department and the other is just a professor, the relationship between them has long gone beyond the scope of professional titles.

When Yang Kaiqu had physical problems, Zhao Zhongyao also deliberately found connections and contacted several experts to conduct a physical examination on Yang Kaiqu. This was the only time in Zhao Zhongyao's life that he "went through the back door."

Later, Yang Kaiqu and the others came to Base 221, and Zhao Zhongyao also visited his good friends.

Now that he has learned that there has been some progress in the treatment of Yang Kaiqu, Zhao Zhongyao couldn't help but put down his work temporarily and wanted to see the situation even though the compilation of the paper was very important.

  Anyway, the rest of the paper is basically the accelerator experimental part. As soon as this part is short of power, the accelerator quota has been used up, and it will be difficult to start up in the short term.

 Secondly, Zhao Zhongyao is notoriously shady and has basically no room to participate in the launch of the accelerator.

 That's right, Zhao Zhongyao is a world-famous non-chief.

 When he was at MIT MOH, he was responsible for the startup of console instructions. As a result, there were no new cases in the MIT accelerator for four months.

Later, Zhao Zhongyao missed an experiment due to illness. As a result, MOH discovered the phenomenon that the Δ3 angle of neutron scattering was too large.

From then on, the MOH laboratory still allowed Zhao Zhongyao to access any data, but he was not allowed to touch the power switch and the start button.

Over time, Zhao Zhongyao got used to this, so even though he usually inspected the accelerator every day, he never pressed the start button.

 Including the previous accelerator trial operation at the base, Wang Ganchang and Cheng Kaijia were also responsible for the operation.

Hence, it can be said that the follow-up accelerator issue actually has nothing to do with Zhao Zhongyao, and it is okay for him to fish for a while.

So Zhao Zhongyao quickly recruited Wang Ganchang and temporarily handed over the situation on the scene to his favorite disciple.

 Then he, Lao Guo and Xu Yun left the house and ran straight to the

 Pharmaceutical laboratories.

 Mentioned earlier.

The pharmaceutical laboratory of the base is located in the seventh branch of the eighteen factories. It is adjacent to the chemical laboratory in charge of Liu Youcheng. It is in the same factory area as the most expensive tandem electrostatic accelerator of the base at this time.

  Half an hour later.

Lao Guo, Xu Yun, Zhao Zhongyao and Xu Yun's bodyguard Mou Fangdong stepped out of a jeep and arrived outside a small building.

Looking at the small building in front of him, Zhao Zhongyao couldn't help but raise his eyebrows, and the surprised Lao Guo said:

"Friends, this is the drug laboratory of the base? Isn't this too, well, too plain?"

To be honest, Zhao Zhongyao is not a person who pursues ostentation. He has had the experience of sleeping in Datongbu and eating cornbread, and even ate rats on his way back home.

 But when it comes to scientific research sites, especially those with certain technical content, he still has some framework understanding:

The building may not be high-floor, and the appearance may be as shabby as if it just came off Shangganling, but the building's footprint should at least not be too small.

  After all, when it comes to technology, all kinds of instruments are definitely needed. If there are instruments, there will naturally be space requirements for the venue.

 In addition, rabbits have nothing but land these days, so most of the departments with scientific research functions in the base are "short" but "fat".

 But this small building is different now.

This building is only two stories high, and its area, including fences and some vegetation, is estimated to be less than 150 square meters. It is located alone at the corner of the factory area and looks extremely inconspicuous.

Although Liu Youcheng's chemical engineering laboratory next door is only one floor higher than this building, its area is still only 300 square meters smaller. The difference is really obvious.

Upon seeing this, Lao Guo shook his head slightly, pointed to another building not far away, and explained:

“Old Zhao, you may not know much about the situation. Due to resource issues, the topic of the pharmaceutical laboratory is actually a research carried out together with the chemical laboratory led by Comrade Youcheng.”

“For example, the PCR technology is handled by Comrade Youcheng's team members. After all, some equipment is scarce in China, so it would be great if one can be given to the base.”

“The drug laboratory mainly analyzes and extracts components of terminal properties. The relevant equipment comes from Comrade Lou Zhicen and his original drug research institute, so the demand for space is naturally not high.”

Zhao Zhongyao then nodded clearly:

"I see."

Lao Guo glanced at him quickly and quickly withdrew his gaze.

 In fact, Lou Zhicen and the others chose this building for another reason that Lao Guo is not convenient to introduce, and it was because of Lou Zhicen's own request.

How do you say Lou Zhicen? In the words of later generations, he is a typical person who thinks too much, or is relatively sensitive.

He felt that his team had not achieved anything when they first arrived at the base. Buildings that were too big would easily be criticized—otherwise, although the base had limited equipment supplies, the space could still be filled up at will.

And this kind of small building located in a remote corner can just satisfy Lou Zhicen's sense of security. This mentality is somewhat similar to the way many people in later generations like to sit in corners when going to Internet cafes.

So at Lou Zhicen's request, the base assigned this building to the Institute of Drug Research.

Lao Guo then coughed lightly, ended the chat, and led Xu Yun and others up to knock on the door.

be honest.

Xu Yun was inexplicably afraid of this kind of small single-family building, because generally when such a door was knocked, a black-faced man similar to the old Zhou would appear, taking off his pants and robbing him.

 Fortunately, the specifications of the drug laboratory were not as high as those of Lu Guangda and his theory team. After a while, the door was opened directly from the inside.

The person who opened the door was an acquaintance of Xu Yun, Tu Luming, who would be famous in later generations. It was just a one-sided acquaintance with Xu Yun. Tu Luming now only knew Xu Yun a little better than the passers-by.

Xu Yun then glanced at the still young future boss, and the corners of his mouth curved slightly.

 She probably doesn't know that she has been on a certain list.

Tu Luming obviously didn't know Xu Yun's inner thoughts, but at this time there was still an obvious joy in her eyebrows, and her eyes lit up even more when she saw Lao Guo and others:

“Director Guo, Director Zhao, Consultant Xu, you are finally here, please come in quickly!”

 Xu Yun's expression was not that surprised at Tu Luming's title.

Although only four people in the base knew his true origin, after meeting with the writer in the capital that day, Xu Yun's real name was no longer a secret.

The base's external statement is that Comrade Han Li changed his name to Xu Yun due to work needs, which is somewhat similar to the situation where Wang Ganchang changed his name to Wang Jing, and various subordinate departments were quickly notified.

This kind of temporary name change is actually very common in the base. Some experts have to change their names when they are transferred from the second branch to the first branch. Today they may be called Zhang San, but tomorrow they will be called Li Si.

 Many times colleagues in the base know the other person's real name, but still have to accept the fact that the other person will change their name every few months.

Therefore, there was not much doubt within the base about Xu Yun's "name change", but only Lao Guo and the others knew that the truth was actually the opposite.

 Okay, let's return to reality.

 After saying those welcome words, Tu Luming pushed the door completely open, and at the same time made way for a few people to pass.

Lao Guo and others left Xu Yun's correspondent Mou Fangdong outside on duty, and the remaining three followed Tu Luming into the small building.

 The layout of the first floor of the small building is the same as its appearance, so simple that it can be called crude:

There is a chandelier hanging from the ceiling, and the lower room is neatly divided into two rooms on the left and right. There is a walkway in the center, and at the end of the walkway is the staircase leading to the second floor.

At the same time, there was an extremely strong smell of traditional Chinese medicine or medicinal materials, but Xu Yun couldn't smell the specific medicinal materials.

 First of all, he really has no relevant knowledge reserves, and secondly, because his nostrils have been burned into the same peripherals as Voldemort's, and it is difficult to even breathe, let alone smell.

 Subsequently under the guidance of Tu Luming.

Everyone soon arrived at the entrance of the room on the left. Tu Luming gently knocked on the ajar door:

“Teacher, Director Guo and the others are here.”

 There was some discussion in the room, but after hearing this, there was an immediate silence. A moment later, Lou Zhicen's voice rang out:

 “Please come in!”

Tu Luming opened the door of the house, and Xu Yun and three others followed.

This room is only about 40 square meters. The walls are rarely painted white, and the wooden tables are also painted white. There is a faint shadow of a laboratory in later generations.

At this time, there were also three men in the room, namely Tu Luming's teacher Lou Zhicen, doctor Lin Yu from the Workers' Hospital, and Liu Youcheng, the head of the chemical laboratory that Xu Yun was familiar with.

Lao Guo had introduced the relationship between Liu Youcheng and Lou Zhicen's laboratory before entering the house, so when he saw Liu Youcheng's appearance, Zhao Zhongyao, who was here for the first time, did not show any obvious surprise on his face.

 At the same time as the three of them followed Tu Luming into the house.

Lou Zhicen, Lin Yu, and Liu Youcheng, who were sitting and chatting, all stood up and hurried towards Lao Guo under the guidance of Lou Zhicen:

“Director Guo, Director Zhao, Consultant Xu, you are here.” “Comrade Zhicen, Comrade Youcheng, good morning.”

Lao Guo and the other two greeted Lou Zhicen and Liu Youcheng equally politely. Then Zhao Zhongyao rubbed his hands and asked impatiently:

“Comrades, I heard that paclitaxel has been synthesized?”

 Lin Yu, as one of Yang Kaiqu's attending physicians, has frequently met with Zhao Zhongyao who went to see his old friend's condition during the past period, and he has a good relationship with Zhao Zhongyao.

Hearing this, he pointed to the table next to him and said:

“That's right, Comrade Zhongyao, that's the small box on the table.”

Upon seeing this, Zhao Zhongyao quickly walked to the table and looked at the things on the table.

 I only see this moment.

 There was a small, palm-sized white plastic box on the table, which contained some transparent liquid.

The volume of the liquid is about half of the capacity of the small box. Although there is no actual contact or shaking, it can be seen at a glance that its density is definitely higher than water, and it should be a relatively viscous liquid.

 Perhaps a bit like transparent rice milk?

While Zhao Zhongyao was staring at the box, Lou Zhicen also brought Xu Yun and Lao Guo to the table, and took the initiative to explain:

“Guys, this is the paclitaxel extract we synthesized—well, to be precise, it should be called the extracted extract.”

“About a month and a half ago, we got the first batch of yew trees from Longyou, weighing seven to eight hundred kilograms.”

“After repeated research on materials, we decided to use ten-year-old young stems as materials to extract components by inducing callus and screening high-yield cell lines.”

"So Comrade Youcheng introduced malondialdehyde, observed cell growth and cell membrane permeability, and determined the two-stage policy of methyl jasmonate and ethephon as separation agents. The concentrations of the two were 103.389 μmol respectively. /L and 73.771μmol/L.”

“In the end, through manual observation and comparison that lasted for half a month, we came up with the final solution of the extraction process with a solid-liquid ratio of 1:43.5, an ultrasonic time of 50 minutes, and an added amount of FeCl3/Br2 of 1.5wt%, and it was officially announced three days ago. A sample of paclitaxel was extracted.”

 After Lou Zhicen finished speaking, Liu Youcheng on the side also nodded.

 Mentioned earlier.

 Paclitaxel. In other words, including subsequent targeted drugs, the difficulty and focus lies in which strategy to use to construct a five-membered ring.

Due to the relatively mature equipment precision in later generations, the synthesis of five-membered rings can be completed by constructing C9-C10 or C10-C11 bonds, but this period is far less developed.

 In addition, the capital writer had not arrived at the base a month and a half ago, and Xu Yun had not completely let himself go, so this part of the plan was indeed a bit difficult for Liu Youcheng and others.

 Finally, after many intense discussions, Liu Youcheng and the others finally settled on an idea:

The starting material is first treated by introducing malondialdehyde to convert it into an unstable aldehyde compound, and then converted into an unsaturated aldehyde and ketone compound through an addition reaction, and finally the young stem material is guided to isolate a five-membered ring compound.

When Xu Yun learned about this plan, he was indeed shocked for a long time.

  After all, the concept of hybrid orbitals in this era has not yet been fully established. It is obviously something that involves in-depth theory, but it can still only be dealt with at the macro level.

Not to mention that the synthesis of five-membered rings was not easy in later generations. How many readers do you think know how to make this thing?

But even in this situation where the underlying principles were vague, Liu Youcheng and the others found the right path. Why didn't this surprise Xu Yun?

 In terms of chemical nature, the idea of ​​Liu Youcheng's plan is very close to a later paper by the team of Professor Li Chuangchuang of the Southern University of Science and Technology.

Schoolmates who were yew trees in their previous life should all know this.

 From a structural point of view.

Paclitaxel has a unique [5.3.1] bridged ring system containing a bridgehead double bond, which is an anti-Bredt olefin. It also contains 11 stereochiral centers on the 6/8/6/4 high-tension four-ring skeleton and 8 oxygen-containing functional groups.

 Hence, it is actually very difficult to fully synthesize this substance, and semi-synthetic extraction is actually the most efficient method.

Liu Youcheng's plan is equivalent to "labeling" the olefin of paclitaxel first, and then sieving out irrelevant substances layer by layer like sieving beans, and finally obtains the paclitaxel compound.

Of course.

Although the whole process of this plan was directed by Liu Youcheng, Xu Yun did not do nothing.

 Among them, Tu Luming's culture medium for cultivating cell lines was a plan proposed by Xu Yun. Tu Luming originally planned to apply magnesium chloride to the young stems of yew, but at Xu Yun's suggestion, it was changed to donkey saliva.

After all, the effect of this thing has been proven in reality, that is, during the cultivation process of Yi'an bacteria, and the effect is even higher than that of apocrine secretion.

Nowadays, the apical secretions of local donkeys are used to make donkey pulp films, so Xu Yun naturally considered donkey saliva.

It is said that recently the Kampot captain of the base animal husbandry team is working hard to add sour plums to the feed of local donkeys. I don't know if this human body fluid production method is useful for local donkeys.

It is also said that the base is still considering whether there can be a use for the donkey's fluid. After all, the only renewable thing in Brother Donkey's body is this thing. If he doesn't use it, his obsessive-compulsive disorder will always feel uncomfortable. .

Looking back to reality.

After Liu Youcheng and others introduced the extraction method of the extract, Zhao Zhongyao couldn't help but touch it twice himself, and then asked:

“Comrade Zhicen, how effective are these extracts? Have there been any clinical trials?”

“It's not available clinically yet, but Director Liu has done in vitro experiments.”

Hearing this, Lou Zhicen pointed to Liu Youcheng again and introduced:

“Their laboratory has been cultivating tumor cells. Recently, the PCR technology that Xiao Xu mentioned has also made some progress. Although it is still early to lock in the specific point, there is still no problem in identifying the nature of the cells.”

“Didn't I just say that we actually extracted the paclitaxel compound three days ago. The reason why we didn't rush to report it to the base was to observe its effect.”

Xu Yun glanced at the small box in Zhao Zhongyao's hand and nodded slightly.

 Mentioned earlier.

In the PCR technology research plan designed by Xu Yun, the sample cells used were mainly based on the phenotype of the local donkey's LightPoint, that is, the MC1R gene.

This approach avoids the frequent extraction of tumor cells from Yang Kaiqu, which would cause further damage to Yang Kaiqu's body.

But on the other hand.

After all, the entire targeted drug was proposed to treat Yang Kaiqu's lung tumors, so local donkey cells can only replace tumor cells in most cases, and tumor cells must still be used when they should be used.

 Therefore, Liu Youcheng and his lab have been cultivating some of the cancer cells collected from Yang Kaiqu for use at this time.

Of course.

If it weren't for the purpose of understanding Yang Kaiqu's deterioration, collecting the cancer cells once would actually be enough. This thing's ability to proliferate in vitro is still very strong.

For example, the famous HeLa cells have been passed down for an unknown number of generations since 1951, and the number of HeLa cell lines currently cultured has exceeded 50 million tons—although this is also an exception among cancer cells.

However, the tumor cells cultured in this in vitro state will be very different from the original generation, so Liu Youcheng and others must collect them repeatedly at intervals.

 The task of collecting and cultivating cancer cells is naturally to test the effects of targeted drugs and related pre-products.

Then Lou Zhicen paused, walked to the table, picked up another document, and said to Zhao Zhongyao:

“Director Zhao, look, this is the experimental result we observed.”

"oh?"

Zhao Zhongyao took the document and glanced at it a few times, but quickly stuffed it back into Lou Zhicen's hand:

"can't read."

Lou Zhicen was stunned for two seconds, and then he realized that he and Liu Youcheng and Lin Yu had just had a lively chat, so he subconsciously regarded Zhao Zhongyao as an expert in biomedicine.

So he took back the document calmly, touched his nose twice, and said:

“According to our experimental results, within seven hours after adding paclitaxel extract for infiltration, the growth rate of tumor cells in vitro showed a certain degree of hysteresis.”

“At the same time, the cargo protein of extracellular vesicles is significantly increased. To put it bluntly, this means that cancer cells that have completed the doubling of chromosomes and protein replication cannot successfully divide into two new daughter cells.”

“Comrade Youcheng speculates that this substance may activate the suicide mechanism of cancer cells, but the phenomenon in earlier mouse experiments seems to be related to T cells.”

“Which of the above two guesses is correct cannot be determined at the moment. In short, as of this morning, the expansion of cancer cells has stopped very obviously.”

“So we immediately contacted Assistant Zhou of the main factory and asked him to relay the news to you.”

Zhao Zhongyao nodded with understanding.

Zhao Zhongyao is a very standard physicist, so he is not very familiar with terms such as extracellular vesicles mentioned by Lou Zhicen.

 However, no matter how thick the professional barrier is, he still has some knowledge about cell division.

Cancer cells are cells that reproduce indefinitely. The way to eliminate them is either to be recognized by T cells or to inhibit their division.

 Although the specific mechanism is not known, paclitaxel apparently achieves this effect.

Think of this.

Zhao Zhongyao couldn't help but have a flash of excitement in his eyes.

If even a pre-substance like paclitaxel can have a significant impact on cancer cells, what about subsequent targeted drugs?

If this is the case, maybe Yang Kaiqu really has hope of living for another five years?

 By the way, Yang Kaiqu!

Zhao Zhongyao suddenly realized something and immediately looked at Lou Zhicen:

“Comrade Zhicen, since you have extracted paclitaxel, have you notified Lao Yang?”

Lou Zhicen smiled and pointed at Lin Yu beside him, with a hint of "You are concerned but you are confused" expression on his face:

“Director Zhao, Dr. Lin is here. Do you think Comrade Kaiqu doesn't know about this?”

 Zhao Zhongyao was suddenly startled.

 A few seconds later, he slapped his forehead in annoyance:

 “Hey, look at my brain!”

 Lin Yu is currently the most skilled attending physician in the Staff Hospital and is currently responsible for four patients:

Xu Yun, U2's only living pilot Yang Shiju, 8 ahem, the man suspected of being a pilot that Xu Yun fished from Qinghai Lake, and Yang Kaiqu, a terminal cancer patient.

So if Lin Yu appears here at this time, Yang Kaiqu must also be there.

So Zhao Zhongyao patted his forehead and asked Lou Zhicen:

“Comrade Zhicen, where is Lao Yang now? Upstairs or next door?”

Lou Zhicen smiled and pointed to the left.

 It's a coincidence.

At the same time Lou Zhicen stretched out his index finger, the voice of Special Protector Qiao Caihong happened to be heard outside the house:

“Director Lin, Comrade Kaiqu has already started the infusion!”

Note:

  12,157 words will be updated every day for the next three days. Look at me, a computer, a handsome guy, three nights, a miracle! !

 (End of this chapter)

Chapter end

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Chapter 699
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Chapter 654
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Chapter 652
Chapter 651
Chapter 650
Chapter 649
Chapter 648
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Chapter 646
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Chapter 643
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Chapter 640
Chapter 639
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Chapter 637
Chapter 636
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Chapter 634
Chapter 633
Chapter 632
Chapter 631
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Chapter 628
Chapter 627
Chapter 625
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Chapter 622
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Chapter 620
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Chapter 598
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Chapter 595
Chapter 594
Chapter 593
Chapter 592
Chapter 591
Chapter 590
Chapter 589
Chapter 588
Chapter 587
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Chapter 585
Chapter 584
Chapter 583
Chapter 582
Chapter 581
Chapter 580
Chapter 579
Chapter 578
Chapter 577
Chapter 576
Chapter 575
Chapter 574
Chapter 573
Chapter 572
Chapter 571
Chapter 570
Chapter 569
Chapter 568
Chapter 567
Chapter 566
Chapter 565
Chapter 564
Chapter 563
Chapter 562
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Chapter 560
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Chapter 557
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Chapter 549
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Chapter 547
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Chapter 516
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Chapter 513
Chapter 512
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Chapter 510
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Chapter 507
Chapter 506
Chapter 505
Chapter 504
Chapter 503
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Chapter 501
Chapter 500
Chapter 499
Chapter 498
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Chapter 496
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Chapter 414
Chapter 413
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Chapter 406
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Chapter 401
Chapter 400
Chapter 399
Chapter 395
Chapter 394
Chapter 393
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Chapter 391
Chapter 390
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Chapter 387
Chapter 386
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Chapter 379
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Chapter 377
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Chapter 375
Chapter 374
Chapter 373
Chapter 372
Chapter 371
Chapter 370
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Chapter 367
Chapter 366
Chapter 365
Chapter 364
Chapter 363
Chapter 362
Chapter 361
Chapter 360
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Chapter 343
Chapter 342
Chapter 341
Chapter 340
Chapter 339
Chapter 338
Chapter 337
Chapter 336
Chapter 335
Chapter 334
Chapter 333
Chapter 332
Chapter 331
Chapter 330
Chapter 329
Chapter 328
Chapter 327
Chapter 326
Chapter 324
Chapter 322
Chapter 321
Chapter 320
Chapter 319
Chapter 318
Chapter 317
Chapter 316
Chapter 315
Chapter 314
Chapter 313
Chapter 312
Chapter 311
Chapter 310
Chapter 309
Chapter 308
Chapter 307
Chapter 306
Chapter 305
Chapter 304
Chapter 303
Chapter 302
Chapter 301
Chapter 300
Chapter 299
Chapter 298
Chapter 297
Chapter 296
Chapter 295
Chapter 294
Chapter 293
Chapter 292
Chapter 291
Chapter 290
Chapter 289
Chapter 288
Chapter 287
Chapter 286
Chapter 285
Chapter 284
Chapter 283
Chapter 282
Chapter 281
Chapter 280
Chapter 279
Chapter 278
Chapter 277
Chapter 276
Chapter 275
Chapter 274
Chapter 273
Chapter 272
Chapter 271
Chapter 270
Chapter 269
Chapter 268
Chapter 267
Chapter 266
Chapter 265
Chapter 264
Chapter 263
Chapter 262
Chapter 261
Chapter 260
Chapter 259
Chapter 258
Chapter 257
Chapter 256
Chapter 255
Chapter 254
Chapter 253
Chapter 252
Chapter 251
Chapter 250
Chapter 249
Chapter 248
Chapter 247
Chapter 246
Chapter 245
Chapter 244
Chapter 243
Chapter 242
Chapter 241
Chapter 240
Chapter 239
Chapter 238
Chapter 237
Chapter 236
Chapter 235
Chapter 234
Chapter 233
Chapter 232
Chapter 231
Chapter 230
Chapter 229
Chapter 228
Chapter 227
Chapter 226
Chapter 225
Chapter 224
Chapter 223
Chapter 222
Chapter 221
Chapter 220
Chapter 219
Chapter 218
Chapter 217
Chapter 216
Chapter 215
Chapter 214
Chapter 213
Chapter 212
Chapter 211
Chapter 210
Chapter 209
Chapter 208
Chapter 207
Chapter 206
Chapter 205
Chapter 204
Chapter 203
Chapter 202
Chapter 201
Chapter 200
Chapter 199
Chapter 198
Chapter 197
Chapter 196
Chapter 195
Chapter 194
Chapter 193
Chapter 192
Chapter 191
Chapter 190
Chapter 189
Chapter 188
Chapter 187
Chapter 186
Chapter 185
Chapter 184
Chapter 183
Chapter 182
Chapter 181
Chapter 180
Chapter 179
Chapter 178
Chapter 177
Chapter 176
Chapter 175
Chapter 174
Chapter 173
Chapter 172
Chapter 171
Chapter 170
Chapter 169
Chapter 168
Chapter 167
Chapter 166
Chapter 165
Chapter 164
Chapter 163
Chapter 162
Chapter 161
Chapter 160
Chapter 159
Chapter 158
Chapter 157
Chapter 156
Chapter 155
Chapter 154
Chapter 153
Chapter 152
Chapter 151
Chapter 150
Chapter 149
Chapter 148
Chapter 147
Chapter 146
Chapter 145
Chapter 144
Chapter 143
Chapter 142
Chapter 141
Chapter 140
Chapter 139
Chapter 138
Chapter 137
Chapter 136
Chapter 135
Chapter 134
Chapter 133
Chapter 132
Chapter 131
Chapter 130
Chapter 129
Chapter 128
Chapter 127
Chapter 126
Chapter 125
Chapter 124
Chapter 123
Chapter 122
Chapter 121
Chapter 120
Chapter 119
Chapter 118
Chapter 117
Chapter 116
Chapter 115
Chapter 114
Chapter 113
Chapter 112
Chapter 111
Chapter 110
Chapter 109
Chapter 108
Chapter 107
Chapter 106
Chapter 105
Chapter 104
Chapter 103
Chapter 102
Chapter 101
Chapter 100
Chapter 99
Chapter 98
Chapter 97
Chapter 96
Chapter 95
Chapter 94
Chapter 93
Chapter 92
Chapter 91
Chapter 90
Chapter 89
Chapter 88
Chapter 87
Chapter 86
Chapter 85
Chapter 84
Chapter 83
Chapter 82
Chapter 81
Chapter 80
Chapter 79
Chapter 78
Chapter 77
Chapter 76
Chapter 75
Chapter 74
Chapter 73
Chapter 72
Chapter 71
Chapter 70
Chapter 69
Chapter 68
Chapter 67
Chapter 66
Chapter 65
Chapter 64
Chapter 63
Chapter 62
Chapter 61
Chapter 60
Chapter 59
Chapter 58
Chapter 57
Chapter 56
Chapter 55
Chapter 54
Chapter 53
Chapter 52
Chapter 51
Chapter 50
Chapter 49
Chapter 48
Chapter 47
Chapter 46
Chapter 45
Chapter 44
Chapter 43
Chapter 42
Chapter 41
Chapter 40
Chapter 39
Chapter 38
Chapter 37
Chapter 36
Chapter 35
Chapter 34
Chapter 33
Chapter 32
Chapter 31
Chapter 30
Chapter 29
Chapter 28
Chapter 27
Chapter 26
Chapter 25
Chapter 24
Chapter 23
Chapter 22
Chapter 21
Chapter 20
Chapter 19
Chapter 18
Chapter 17
Chapter 16
Chapter 15
Chapter 14
Chapter 13
Chapter 12
Chapter 11
Chapter 10
Chapter 9
Chapter 8
Chapter 7
Chapter 6
Chapter 5
Chapter 4
Chapter 3
Chapter 2
Chapter 1
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