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"Water Lord" will always be the symbol of Real Madrid.

As to whether Ramos really wants to play in China, a conclusion has finally been reached.

In the early morning of the 31st, Ramos personally admitted at his personal press conference that he would stay in Real Madrid, hoping to retire at the Bernabeu Stadium. However, he said, "I did receive an offer from China".

On the side of China women’s volleyball team, the girls swept the Korean women’s volleyball team 3-0 in Macao, China Station, winning the first place with three consecutive victories and nine points.

Ramos rejected the contract from the Super League.

Ramos: I want to play at Real Madrid until I retire.

"In order to repay the debt of up to 35 million euros, Ramos will come to the Super League to receive a three-year contract with an annual salary of 25 million euros after tax." A few days ago, when the news from European media spread like wildfire, football in China and Spain exploded.

Now, Ramos finally cleared up all the rumors at his personal press conference.

"I don’t want fans to live in doubt. I’m a Real Madrid activist and I want to retire at Real Madrid." Ramos said, "I want to finish the contract here and stay here to do great things. I have more years here."

Even though the controversy is full, Ramos is a symbol of this era of Real Madrid.

As for the invitation from the China team, Ramos is also outspoken."I did receive an invitation from China, and I don’t want to lie to you. I have been telling the chairman that I will never leave Real Madrid, and even without a contract, I will play here for free. I didn’t want to play in China in the past. I won’t leave for money. "

However, some reporters at the scene also asked, "Have you really not considered China’s contract?"

Ramos said:"The contract is on my desk, but there are some things I can’t do. Some ways in the contract are not what I want. I have never thought about going to China, and I will not go there with zero transfer fee. "

"I’m going to have a wedding in 15 days, and I want to give florentino a hug. I hope to work with you to build the future of Real Madrid. "

Zhu Ting started with 11 points and the China women’s volleyball team swept South Korea.

3-0 swept the Korean women’s volleyball team and scored 9 points in three games. The performance of China women’s volleyball team in the World Women’s Volleyball League in Macao, China left infinite expectations for the future.

This is the first appearance of the main members of China women’s volleyball team this season. Although there is still a certain gap between the strength of the three opponents and that of China, we can still see the changes of the team through this competition.

This time, the China women’s volleyball team, which aims at running-in the lineup, gave many surprises to the fans. Not only did Zhu Ting take the lead, but the partner of Zhang Changning and Li Yingying in the main attack line also made people shine in the international competition.

After the test of injury, Zhang Changning, who took off the protective gear on her leg, appeared very capable on the court, and her performance was almost impeccable in several consecutive games, whether passing or defending. He scored in double figures in all three games, and contributed 17 points to the team in the last game, winning the scoring title in the team.

Zhu Ting was named the most popular player.

Li Yingying, a teenager, made his debut with the main team for the first time this year after going through the Swiss competition. Li Yingying started two of the three games. In the Belgian game, Li Yingying made 13 of 21 deductions and scored the highest score of 17 points.

Gong Xiangyu, 22, has also made great progress. With Li Yingying and Zhang Changning starting at the same time, Gong Xiangyu has the important task of passing one pass after another. Against Thailand, however, she beat the two main attackers to become the main firepower of China women’s volleyball team, and scored 12 out of 21, plus serving, and got the highest score of 14 points.

"The women’s volleyball team can’t rely solely on Zhu Ting", which has been repeated countless times. However, in the competition in Macao, China, we saw that the veteran’s state was warming up, the young players were making continuous progress, and the China women’s volleyball team seemed to have more Zhu Ting.

Cole is also anxiously waiting for Durant.

Durant Finals Game 2 is still hard to come back.

On May 31st, according to the San Jose Mercury News, Cousins will return in the first game of the finals, but Durant is still recovering. According to coach steve kerr, it is unrealistic for Durant to resume full training before the second game of the finals, and it is almost impossible for him to return in the second game.

The injury that restricted Durant’s appearance appeared in the fifth game of the Western Conference semifinals. Durant pulled his right calf in the "Fire Bravery" and then missed five games in a row.

"His next step is to train with the team, but we don’t know when this will happen." Coach Cole said.

Cousins has recovered from injury and participated in joint training.

Then the question is, why did Durant go to Toronto with the team when he was unable to play in a high probability? Is it just to cheer for the warriors?

According to the San Jose Mercury News, Durant can communicate directly with the Warriors team doctors in the training room to continuously monitor his recovery. Secondly, Durant can complete personal training on the court; Finally, traveling with the team can also allow Durant to participate in the team’s video lessons and meetings.

"He is an important part of our team and everyone has been cheering for him." Cole said, "It’s an honor to be on the stage of NBA Finals. You hate anyone getting hurt. For us, the most important thing at present is to hope that Durant will return to health. "

James caused the ratings to drop? The league will adjust the game time.

In the past few days, the discussion about the decline of NBA ratings has continued to ferment throughout the league. In an interview with the media, NBA President Adam Xiao Hua also mentioned James’ influence. He admitted that he might consider adjusting the Lakers’ game time in the future.

"We will not escape this phenomenon," Xiao Hua said in an interview. "James reached the finals for eight consecutive years, and he was still playing in the east. This is just a mathematical problem. After all, 50% of the audience in the country are concentrated on the east coast."

Xiao Hua also said that he would consider adjusting the game time. "At present, most games are held at 8 pm or 10: 30 pm. Can we change it to 7 pm or 9: 30 pm? This is the reform direction we will consider in the future, so that more East Coast fans will watch the western team’s game. "

"But there will also be a drawback. Some West Coast fans will complain,’ How can we go to the game when we are not off work’? All in all, you need to balance the time differences in different regions, so as to maximize the number of people watching the game. "

If it is difficult to change the game time in the Western Conference as a whole, has Xiao Hua considered adjusting the game time of the Lakers separately? Xiao Hua said: "Change the game time for the Lakers? I haven’t thought about it before, but this proposal is very interesting and we will consider it then. "

Wang Qiang is in the game.

Wang Qiang lost in one day and shed tears at the French Open after the game.

In the early morning of May 31, the 2019 French Open ended the competition on the fifth match day. Djokovic, Zvilev Jr. and Williams all won easily; Naomi Osaka, Delporte Rowe and Tim won tenaciously in the face of challenges.

However, China Jinhua Wang Qiang lost in one day, and both women’s singles and women’s doubles were eliminated; This also means that after two rounds of women’s singles, China Jinhua has all been eliminated.

As the 16th seed, Wang Qiang only resisted for 53 minutes in the women’s singles competition and lost 3-6 and 0-6 to 18-year-old Polish starlet Sviatek.

After the game, Wang Qiang, who was depressed, shed tears at the post-game press conference. And perhaps the exit of the women’s singles has somewhat affected her play in the women’s doubles. Subsequently, Wang Qiang and Rulu played together in women’s doubles, losing 2-6 to 2018 Australian Open women’s doubles champion Babos/Meladnovich.

Fortunately, the golden flowers of China in the women’s doubles still have a good news. As the 4th seed of the tournament, Xu Yiqian/Daniel Dabrowski eliminated the multinational group Bala/Yakubovich 6-1/1-6/6-2 in a three-set battle, and Xu Yiqian/Daniel Dabrowski will compete with Han Xinyun/Wang Yafan for a place in the top 16 of women’s doubles in the next round.

Zhang Shuai/Stosur, as the No.5 seed combination of women’s doubles, won seven games in a row and sent eggs twice in the final stage to eliminate Kudmetova/Vaskopoyeva.

No.13 seed Yang Zhaoxuan/Luo Solska beat Herko Ge/Rodina 6-2, and the next round will be against Ferro/Parry, a local French group with wild cards.

Shanghai delegation of NYOGOC established.

There are still more than two months before the opening of the 2nd National Youth Games. On May 29th, the Shanghai delegation of the 2nd Youth Games was established in the Oriental Sports Center.

The second National Youth Games will be held in Shanxi Province from August 8 to 18, and will be open to all young people, including young students. There are 49 major events and 1868 minor events in this Youth Games.

As of May 25th, a total of 1,312 athletes (670 males and 642 females) in Shanghai have registered for 58 sports (38 sports schools and 20 social clubs) and 670 sports.

19 events completed the preliminary competition, and 391 athletes (183 males and 208 females) qualified for the finals. Four events completed the early finals and won two gold medals, three silver medals and three bronze medals.

Tour de France Challenge Came to Zhuji, Xi Shi’s hometown.

On May 26th, Zhuji, the hometown of Xi Shi, the 2019 Tour de France Challenge, ended in the presence of more than 2,000 contestants. Hu Hao and Emily Rosicky won the men’s and women’s championships in the whole group of this challenge.

Zhuji Station, Xi Shi’s hometown, is not only the first stop of the Tour de France in Asia in 2019, but also the first appearance of the Tour de France in the Yangtze River Delta region. After the end of this challenge, the Tour de France sign will be retained. The event operator Ed Weixuan and Zhuji Municipal Government hope to promote the development of cycling in China by enhancing the public atmosphere of cycling.

In fact, during the two years since the Tour de France China series was introduced to China, a good report card has been handed over: more than 10,000 riders, 500,000 spectators and 300 million people participated in this international event by watching.

Under the guidance of similar top-level events, the average annual growth rate of cycling enthusiasts exceeds 30%, and the compound growth rate of cycling market in the next five years is about 10%; Events and outings have gradually become essential items for deep cycling users; In 2018, the number of sports cyclists reached 15 million.

　　On the morning of June 22nd, the roof of the foundation pit was finally poured on the southeast side of the intersection of G40 Hushan Expressway and Jin ‘an Road in Changxing Island, Chongming, Shanghai, which marked the successful capping of the main structural project of the 108-size shield transfer section of Chongming Line of Shanghai rail transit and became the first unit project of Shanghai Chongming Line.

　　Shanghai Chongming Line will cross the Yangtze River twice in the form of full underground for the first time, and the foundation pit of the 108-standard shield transfer section will be constructed by open excavation method, which is arranged in the north-south direction and is a single-column double-span concrete box structure with two floors above the ground and four floors underground (partially underground).

　　As a large-diameter slurry-water balanced shield tunnel with the longest one-time tunneling distance in domestic rail transit, the two large and small shield conversion sections at Bid 108 and Bid 111 on Changxing Island will be the most important conversion points between Chongming Line’s single-hole double-line oversize shield and Changxing Island Station’s double-hole double-line small shield, and it is also one of the most important and difficult engineering nodes to realize crossing the Yangtze River.

　　After the resumption of project construction, the main structure of the 108-bid project was successfully capped, which created favorable conditions for the subsequent success of the 13-meter super-large shield crossing the Yangtze River and the promotion of the construction of the entire Chongming Line.

　　Since the beginning of May, the construction units of Shanghai rail transit have strictly followed the epidemic prevention requirements and made every effort to catch up with the progress of the project construction. At present, eight major projects, such as shanghai metro line 13 West Extension, Line 17 West Extension, Line 18 Phase II and Chongming Line, have reached production on June 20, and all 59 work sites involved in the whole network will reach production by the end of June.

　　(CCTV reporter Sheng Yuyu Shi Chenyang)

The complaint reporting department of the discipline inspection and supervision organ accepts the relevant complaint reporting under centralized jurisdiction, and reports and accusations should reflect the problems in a legal, objective, real, rational and orderly manner, and never allow people with ulterior motives to falsely accuse and frame others in the name of reporting.

1. What is false accusation and framing?

By fabricating facts, forging materials and other ways to reflect the problem, with the intention of causing others to suffer adverse political influence, loss of reputation or accountability, it belongs to false accusation and framing.

Key tips

False accusation and frame-up usually means that the whistleblower is subjectively malicious and portrays something that is "out of nothing", with the aim of making others suffer bad influence.

Second, what behaviors belong to false accusation?

Catch shadows, make assumptions, scare stories, spread them everywhere, and report maliciously. Some fabricate facts, frame, discredit and vilify others because unreasonable demands are not met; Some cadres touched others’ "cheese" in the process of starting a business and promoting reform, and were retaliated …

Key tips

False accusation and frame-up destroy the political ecology, pollute the social atmosphere, disturb the reporting order, waste the resources of supervision and discipline enforcement, and damage the entrepreneurial enthusiasm of party member and cadres and officers. We must resolutely stop this kind of behavior.

Related clauses

Article 41 of the Working Rules for Handling Reports and Accusations by Discipline Inspection and Supervision Organs shall be dealt with severely in any of the following circumstances:

(a) bad means, resulting in adverse effects;

(two) seriously interfere with the general election or the selection and appointment of cadres;

(three) after investigation has a clear conclusion, but still falsely accused of framing others;

(4) Forcing or instigating others to falsely accuse or frame up;

(five) other serious consequences.

Third, the responsibility of falsely accusing and framing others

It is the right of party member and the masses to report and accuse. If you "splash dirty water" or "discredit" the relevant units or individuals just for your own selfish interests or anger, you will be severely investigated and punished, and you may even be sued.

Extended reading

[Case 1] He Jian, the former secretary of the Political and Legal Committee of Honghe Prefecture Committee of Yunnan Province, failed to ask for treatment after retirement, and instead falsely accused others by sending anonymous text messages and spreading open letters, which not only caused bad influence, but also involved many serious violations of discipline and law. Finally, He Jian was expelled from the party and canceled his retirement benefits. He was sentenced to nine years in prison for accepting bribes.

[Case 2] Li, an ordinary citizen of a county. Because he failed to meet the unreasonable compensation requirements, he repeatedly fabricated facts to report the leaders of relevant departments of the county to the State Bureau for Letters and Calls, the provincial and municipal anti-vice offices, and the provincial, municipal and county commission for discipline inspection and supervision, and published false pictures, texts and videos in his registered WeChat official account, which caused adverse effects. In the end, Li was sentenced to one year and six months in prison by the court for the crime of false accusation and frame-up.

Key tips

The discipline inspection and supervision organs shall seriously deal with the accusations of false accusation and frame-up according to the rules and discipline, or hand them over to the relevant authorities for handling according to law. If the person who falsely accuses or frames is the object of supervision by party member of the Communist Party of China, depending on the seriousness of the case, he shall be given corresponding organizational treatment or disciplinary action; The person who falsely accused and framed was a person other than party member of the Communist Party of China and the object of supervision, and was transferred to the public security organ for investigation. Those who falsely accuse the framed person of being suspected of violating the law and committing crimes shall be transferred to judicial organs for handling.

Source/Website of Yunnan Provincial Commission for Discipline Inspection and Supervision

Original title: "Reporting can’t be willful, falsely accusing and framing will take responsibility! 》

Read the original text

Jiangfuconstruct〔2022〕ninenumber

County (city, district) people’s governments and relevant municipal units:

In order to implement the Opinions of the General Office of the State Council on Comprehensively Strengthening Language and Literature Work in the New Era (Guo Ban Fa [2020] No.30) and promote the high-quality development of language and literature work in our city in the new era, according to the document requirements of the Notice of the General Office of the People’s Government of Guangdong Province on the Establishment of Guangdong Language and Literature Work Committee (Guangdong Office Letter [2021] No.223),Combined with the actual situation of our city, the municipal government decided to set up Jiangmen Language and Literature Working Committee (hereinafter referred to as the Municipal Language Committee), and the relevant matters are hereby notified as follows:

I. Main responsibilities

Implement the decision-making arrangements of the state, the provincial party committee and the provincial government on language work and the work requirements of the municipal party committee and the municipal government, and study and formulate the development plans and plans for language work in our city. Make overall plans to promote the popularization of the national common language, strengthen the standardization, standardization and information construction of the language, and effectively enhance the language service ability. Coordinate and guide the relevant departments of counties (cities, districts) and cities to promote the implementation.

Second, the members

　　The director of the Municipal Language Committee is concurrently appointed by the deputy mayor in charge of education, and the deputy director is concurrently appointed by the deputy secretary-general of the municipal government to coordinate education and the director of the Municipal Education Bureau. Member units include the Propaganda Department of the Municipal Party Committee, the United Front Work Department of the Municipal Party Committee, the Network Information Office of the Municipal Party Committee, the Municipal Education Bureau, the Municipal Science and Technology Bureau, the Municipal Bureau of Industry and Information Technology, the Municipal Public Security Bureau, the Municipal Civil Affairs Bureau, the Municipal Human Resources and Social Security Bureau, the Municipal Transportation Bureau, the Municipal Bureau of Commerce, the Municipal Bureau of Culture, Radio, Film, Television, Tourism and Sports, the Municipal Health Bureau, the Municipal Market Supervision Bureau, the Municipal Social Science Federation, the Communist Youth League Committee, the Municipal Women’s Federation, the Municipal Disabled

Iii. Responsibilities of member units of the Municipal Language Committee

(1) The Municipal Education Bureau is responsible for studying and formulating the overall development plan and plan of the city’s language and writing work, studying and determining the major policies to strengthen the language and writing work, determining the major issues that need to be reported to the municipal party committee and municipal government, urging the implementation of plans, plans and related major work, coordinating major language and writing activities among departments, and promoting the rapid and healthy development of language and writing work jointly by all departments and the whole society. Supervise and inspect schools at all levels to carry out standardized teaching of Putonghua and Chinese characters.

(2) The Propaganda Department of the Municipal Party Committee is responsible for supervising and inspecting the implementation of the national language standards for Chinese textbooks, newspapers, dictionaries and other publications, guiding the training of editors, journalists and proofreaders in the national common language, and formulating and supervising the implementation of the quality inspection system for the standardized use of the national common language in Chinese publications.

(3) The United Front Work Department of the Municipal Party Committee is responsible for contacting relevant organizations in Hong Kong, Macao and overseas, and guiding and promoting activities such as language and cultural exchanges between Hong Kong, Macao and overseas Chinese; Responsible for the ethnic work department to cooperate with the language work department to promote the national common language in ethnic areas.

(4) The Information Office of the Municipal Party Committee is responsible for guiding citizens to use the national common language in a civilized and standardized way on the Internet, and guiding the development of the national common language training for Internet news information practitioners.

(five) the Municipal Science and Technology Bureau is responsible for the implementation of the norms and standards of the national common language in the formulation of scientific and technological standards, the creation of scientific and technological documents, and the popularization and exchange of science.

(VI) The Municipal Bureau of Industry and Information Technology is responsible for promoting the development, popularization and application of language and writing software, guiding information technology and intelligent software and hardware products to implement the national common language and writing standards, and cooperating with the municipal language and writing department to organize the standardization and intelligentization of language and writing information technology.

(seven) the Municipal Public Security Bureau is responsible for managing and supervising the use of the national common language in household registration management, public security traffic management, entry and exit management and border control.

(8) The Civil Affairs Bureau is responsible for the management and supervision of the use of the national common language and characters in the names of place names, place names signs and social organizations, and for the transliteration and transliteration of place names and names in minority languages.

(nine) the Municipal Human Resources and Social Security Bureau is responsible for organizing and guiding the national common language training and testing of teachers and students in technical colleges.

(ten) the Municipal Transportation Bureau is responsible for strictly regulating the words used in public places such as stations, docks and highway service areas.

(eleven) the Municipal Bureau of Commerce shall cooperate with the education department to promote the standardization of the language of this system, and promote the use of Putonghua in the business service industry and economic and trade activities.

(12) The Municipal Bureau of Culture, Radio, Film, Tourism and Sports is responsible for the management and supervision of cultural venues, tourist attractions, hotels, travel agencies and other cultural tourism units and the use of words in Internet cultural products, and guiding the development of national common language training for drama actors, tour guides and commentators. Be responsible for incorporating the standardized use of the national common language into the quality inspection system of radio and television programs and online audio-visual programs and the system of holding certificates for announcers, presenters and reporters, and guiding the training and testing of Putonghua for announcers, presenters and reporters. Strictly regulate the words used in sports venues and sports activities, and put forward the requirements of Putonghua level for athletes in the city.

(thirteen) the Municipal Health Bureau is responsible for the management and supervision of the use of the national common language of medical institutions and medical personnel, and guiding the development of the national common language training for medical personnel.

(fourteen) the Municipal Market Supervision Bureau is responsible for the management and supervision of enterprise names, advertisements and the names, signs, packaging and descriptions of goods sold in China.

(fifteen) the Municipal Social Science Association is responsible for organizing and carrying out scientific research on language and writing, and improving the scientific research level of language and writing work.

(sixteen) the Communist Youth League Committee in conjunction with the administrative department of education and the language work department to organize and carry out publicity and promotion of the national common language and social practice activities for primary and secondary school students.

(seventeen) the Municipal Women’s Federation is responsible for organizing the national common language training for women in small and medium-sized towns and rural areas.

(18) The Municipal Disabled Persons’ Federation is responsible for promoting the use of national common sign language and national common braille in conjunction with the language and writing departments and the education administrative departments, managing and supervising the use of national common sign language and national common braille, organizing and guiding all localities to carry out training for national common sign language and national common braille backbone teams, and promoting the standardized information construction and information technology product development of national common sign language and national common braille.

(nineteen) Jiangmen Military Division is responsible for coordinating the troops stationed in Jiang to carry out language and writing work, and actively promoting Putonghua among the officers and men of the army; Manage and supervise the use of language and characters in this system; Strictly regulate the language and characters of subordinate units in various social activities.

Fourth, the working mechanism

(a) the Municipal Language Committee, as a special working group, is not included in the management of municipal deliberation and coordination institutions.

(two) the office of the Municipal Language Committee is located in the Municipal Education Bureau and undertakes the daily work. Members of the Municipal Language Committee shall, after being approved by the main responsible comrades of the Municipal Language Committee in accordance with the procedures, issue a document in the name of the Municipal Language Committee to determine.

(3) The Municipal Language Committee shall establish a liaison officer system, with one responsible comrade from the relevant business departments of each member unit as the liaison officer.

(four) the members of the Municipal Language Committee shall, in principle, report the work to the Municipal Language Committee once a year, and report the major issues in a timely manner.

Jiangmen Municipal People’s Government Office

February 22, 2022

What is Bioaccumulation?

What do you get when you decompose the term "bioaccumulation"? The word accumulation meansSomethingThe accumulation of, and the prefix bio- meanlife. Put it together, it is.Something accumulates in living things.To defineBioaccumulation.

Then biological accumulation is used to refer toChemical substances in organismsThe accumulation of. These substancesCann’t be metabolized , it accumulates in organisms and accumulates through the food habits of consumers at all levels in the food chain.The higher the level, the higher the cumulative concentration in the body of consumers.The phenomenon.

How does bioaccumulation occur?

One way is to let a certain amount of chemicals enter the organism.Faster thanThe rate at which organisms decompose and use it. This means that more chemicals enter than are discharged, leading to the accumulation of chemicals in organisms.

Another main way is that chemicals enter organisms, and organismsIt cannot be decomposed or excreted in some way.. So chemicals will continue to accumulate,Until it eventually becomes fatal to organisms..

All organismsThe problems we face are allThe result of dynamic balance between absorption and elimination. biological accumulationThe degree of occurrence determines the toxic effect.. In some cases, the protection mechanism is protected from certain undesirable substances deposited in special parts to prevent them.Participate in metabolic reaction.

The bioaccumulation description in this paper is used to evaluate the accumulation of drugs and their harmful metabolites in intestinal bacteria.

Therapeutic drugs will have a strong impact on intestinal microflora, and vice versa.Potential drug-bacterial interactions can be mediated by biologicalTransformation reduces microbial adaptability or changes drug availability.. The latter can have a positive or negative impact on drug activity and efficacy. Although drugs such as lovastatin and sulfasalazine will be chemically affected by intestinal bacteria.Convert into active formBut bacterial metabolism can make digoxin and so on.Drug inactivation, or like irinotecan (irinotecan).toxic effect. In order to further increase the diversity of susceptible drugs, it was recently reported that more than 100 molecules were chemically modified by intestinal bacteria.However, the mechanism of these interactions is mainly limited to drug biotransformation..

Lovastatin (lovastatin)

Lovastatin can reduce the synthesis of cholesterol and increase the synthesis of low-density lipoprotein receptor, mainly in the liver, resulting in the reduction of blood cholesterol and low-density lipoprotein cholesterol levels, thus playing a role in the prevention and treatment of atherosclerosis and coronary heart disease (source: Baidu Encyclopedia).

Sulfasalazine (sulfasalazine)

Sulfasalazine (sulfanilamide) is an antibacterial agent. It is a sulfonamide which is not easily absorbed by oral administration. The absorbed part is decomposed into 5-aminosalicylic acid and sulfapyridine under the action of intestinal microorganisms. 5-aminosalicylic acid stays in the intestinal wall tissue for a long time after complexing with the intestinal wall connective tissue, which plays an antibacterial, anti-inflammatory and immunosuppressive role, such as reducing Escherichia coli and Clostridium, and inhibiting the synthesis of prostaglandin and leukotrienes (source: Baidu Encyclopedia).

Digoxin

Digoxin is an intermediate cardiac glycoside, which is white crystal or crystalline powder. Odorless; It tastes bitter. In the treatment, the effect on the heart is positive inotropic effect, slowing down the heart rate and inhibiting heart conduction. It is suitable for congestive heart failure with low output, atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia.

Bacteria in the intestine can regulate the availability and efficacy of therapeutic drugs. However, the potential mechanism of the interaction between drugs and bacteria is the chemical transformation or biological transformation of drugs by microorganisms.

A team of scientists from Heidelberg, Germany and Cambridge, England just published in Nature, and successfully studied the consumption of 15 drugs with different structures by 25 representative intestinal bacterial strains. 70 kinds of bacteria and drug interactions were revealed, 29 of which were not reported before. More than half of the new interactions can be attributed to biological accumulation.

This biological accumulation of intestinal bacteria may be a common mechanism to change drug availability and bacterial metabolism, which may have little effect on individuals.Biota composition, pharmacokinetics, side effects and drug reactionsHave an impact.

01

Drug non-metabolic accumulation

For a more detailed investigationDrugs and bacteriaA systematic map of the interaction between scientists.Two analytical methodsNuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) were used to systematically analyze 1.Five human targeted drugs and 25 human intestinal bacteria.Interaction between Bifidobacterium longum, Escherichia coli and other subspecies or strains of the same species of Bacteroides Homogeneous. Select bacterial species to cover those representing healthy microbial communities.Extensive phylogeny and metabolic diversity. In terms of drugs, 12 kinds of oral small molecular drugs (molecular weight less than 500 Da) were selected, which can be quantified based on ultra-high performance liquid chromatography combined with ultraviolet detection (UPLC-UV) toCross different chemical, indication areas and side effects.

Bacterial-drug interaction network. Left network: biotransformation or accumulation of drugs by intestinal bacteria. Right network: the influence of drugs detected in at least two independent screening on the growth of intestinal bacteria (Student’s t test, α = 0.05). The full names of bacteria not mentioned in this paper are as follows: Bacteroides fragilis, Bacteroides vulgaris and Bifidobacterium animalis subspecies. Lactobacillus BI-07, Coprococcus come, Clostridium, Clostridium, lactobacillus paracasei, Ruminococcus gnavus.

Among the 29 newly discovered interactions (14 drugs and 4 drugs), as many as 17 species are bioaccumulation events.; That is to say,Drugs are stored by bacteria without changing it.. the rest Twelve interactions (8 drugs and 5 drugs) may represent biotransformation events.. Two of the five drugs: levamisole and ezetimibe, were indeedOther intestinal bacterial chemistry coursesDecorate.

Among bioaccumulative drugs,Antidepressant Duloxetine/Cymbalta(duloxetine) andRosiglitazone, a hypoglycemic drug.beThe only bioaccumulative drugEach species accumulates in many different species.

However, biodegradation and bioaccumulationInteraction is not mutually exclusive.. Montelukast (for asthma) and roflumilast (for chronic obstructive pulmonary disease)Bioaccumulation by some bacteria and degradation by other bacteria.. In terms of bacteria, all strains except Fusobacterium nucleatum showed two types of interactions. In addition to the interaction with widely interacting control drugs sulfasalazine and metronidazole, the same strains of Bifidobacterium (B. uniformis) and Escherichia coli (E. coli) were found to be in the same strain.There is no overlap in interaction.. Because individuals usually have different strains, bioaccumulation is interactive.The prevalence rate may be higher than the research results..

Levamisole (levamisole)Levamisole is a broad-spectrum anthelmintic drug, which is mainly used to repel ascaris and hookworms. It can improve the resistance of patients to bacterial and viral infections. At present, it is used as adjuvant therapy for lung cancer and breast cancer after surgery or acute leukemia and malignant lymphoma after chemotherapy.

Ezetimibe (ezetimibe)Selective cholesterol absorption inhibitor is a lipid-lowering drug.

Duloxetine/Simpatine, mainly used to treat depression. It mainly regulates the balance of neurochemicals in brain tonic by inhibiting the recovery of serotonin and norepinephrine.

Rosiglitazone (rosiglitazone)Rosiglitazone and pioglitazone are thiazolidinedione hypoglycemic agents commonly used in clinical treatment in China at present. This product is an insulin sensitizer. By increasing the sensitivity of skeletal muscle, liver and adipose tissue to insulin and improving the utilization of glucose by cells, it can significantly reduce fasting blood glucose, insulin and C-peptide levels, and also reduce postprandial blood glucose and insulin. However, patients are required to have a certain ability to secrete insulin.

The World Health Organization’s International Agency for Research on Cancer listed rosiglitazone in the list of three carcinogens.

Due to manyHuman targeted drugs have been proved to affect the growth of intestinal bacteria.. The study examined the identifiedCan bacterial-drug interactions also lead to growth changes?. Although more than 30 major inhibitory drug-bacteria interactions have been detected, only.The three kinds of interactions involve both modifying growth and changing drug concentration.(excluding control drugs sulfasalazine and metronidazole). Therefore,The interaction between bacteria-drugs and drugs-bacteria seems to be largely independent..

In order to confirm the bioaccumulation of the interaction between bacteria and drugs, the study usedThe other two analytical methods are nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS).. As a case in point,Duloxetine, a widely used antidepressant, was found to be bioaccumulated by eight kinds of bacteria. Nuclear magnetic resonance spectroscopy can clearly detect duloxetine and confirm it.Four selected strains(Streptococcus salivarius, Bacteroides simplex, Escherichia coli IAI1 and Escherichia coli ED1a) were removed from the culture medium without biotransformation. LC-MS analysis in compound GMM medium also confirmed it.Clostridium saccharides and Escherichia coliBioaccumulation of IAI1 in the concentration range of 30 to 70.

Nuclear magnetic resonance analysis showed that Streptococcus salivarius was sensitive to duloxetine.biotic pyramid

02

Biological accumulation affects cell metabolism.

Although biotransformation can be attributed tometabolic enzymeHowever, drug bioaccumulation is in mechanism.It’s even harder to imagine. In order to study the molecular basis of drug bioaccumulation by intestinal bacteria, scientists set out to determine the concentration of duloxetine in bioaccumulative strains.Protein target. Firstly, an acetylized, "clickable" molecular version was constructed and used as bait.　　

Click chemistry and thermal protein group analysis (TPP) showed that protein binding was a contributing factor to duloxetine bioaccumulation. This raises the question of whyThese two strains of E.coli showed different degrees of duloxetine bioaccumulation in GMM.. Two strains of Escherichia coli were compared in two different TPP assays, in which drugs were added to lysed cells or whole cells. Although TPP in cell lysate can find protein which is stable or unstable due to the direct binding of duloxetine, intact cell TPP can also capture the changes of cell reaction (changes of protein interaction and activity) in vivo.

Note: Click Chemistry, which aims to create various functional substances (candidate drug compounds, biological probes, soft materials, etc.), is a very widely used reaction. As a basic technology, it is characterized by high chemical selectivity, high yield, fast reaction speed and easy formation of strong chemical bonds.

In a complete cell assay,biotic pyramidThe IAI1 strain is more abundant than the abiotic ED1a strain.Has almost twice as muchDrug-reactive protein, and thermostable.The overall change is stronger. Consistent with the fact that duloxetine changed cell physiology more significantly in bioaccumulative strains, IAI1 strain also showed it in differentially expressed protein.A more obvious reaction.

In contrast, these two strains show very similar characteristics in TPP based on lysate, in which the lack of cell envelope enables drugs to reach all intracellular protein. Therefore,The strain specificity of bioaccumulation is probably due to the difference of absorption and consumption systems, which is similar to the transporter-dependent specificity observed in drug-drug interaction..

The combination of duloxetine and metabolic enzymes shows that the biological accumulatorMetabolism has changed.. To test this, two complementary metabolomics platforms were used-Flow injection analysis mass spectrometry (FIA-MS) and hydrophilic interaction chromatography combined with tandem mass spectrometry (HILIC-MS/MS).Methods: To analyze the effects of duloxetine treatment on six bacterial strains (four bioaccumulative and two non-bioaccumulative)Small molecule secretion.

Among the four strains, there are three bioaccumulative types (C. saccharolyticum, Lactobacillus plantarum and E.coli IAI1) and one non-bioaccumulative type (Lactococcus lactis), which show their characteristics after drug treatment in GMM.A significant shift in metabonomic patterns. The drug-induced changes in the ectometabolism group are equivalent to the interspecific differences.　

In addition, the drug reaction was concentration-dependent, and no effect was observed on the non-bioaccumulated roflumilast. The concentration-dependent reaction to duloxetine was further verified by a subset of 71 metabolites, in which the chemical characteristics were presumed to be assigned-two metabolites confirmed by chemical standards-using tandem mass spectrometry. Clostridium saccharolyticum also showed a strong metabolic response to duloxetine when detected in nutrient-deficient PBS buffer.

Anyway,Protein omics and metabonomics data show that duloxetine binds to abundant metabolic enzymes to support its intracellular storage..

three

Biological accumulation leads to cross-feeding

Metabolic interaction is the basis of shaping the composition of intestinal microbial community.. So, will the metabolic changes related to biological accumulation affect the community composition?

In order to solve this problem, the researchers assembled five stable communities of intestinal bacterial species (Bacteroides thetaiotaomicron, Eubacterium rectale, Lactobacillus gasseri, Ruminococcus bolts, Streptococcus salivarius) with and without duloxetine. One of these five species is S. salivarius, and the other is directly inhibited by E. rectale. These five species were co-inoculated in GMM and then transferred to fresh medium every 48 hours.　

The existence of duloxetine significantly changed the community composition.Compared with the situation without drugs,The abundance of E.coli in rectum has increased by more than 100 times.. This is noteworthy because of the five species used by researchers,Rectal Escherichia coli is the most sensitive to duloxetine.. Consistent with Streptococcus salivarius as a bioaccumulator, duloxetine is exhausted in the supernatant of the community. Although decreasing the concentration of duloxetine can protect the rectal Escherichia coli in the community, it takes longer to reproduce in the presence of duloxetine.

Duloxetine bioaccumulation changes community assembly and host response.

supposesalivaChanges in the secretion of duloxetine metabolites by Streptococcus liquidus can promote rectal Escherichia coli.. Supporting this, the used culture medium from S. salivarius grown in the presence of drugs improved the growth of E. rectale. Non-targeted metabolomics data from FIA-MS and HILIC-MS/MS further support the cross-feeding hypothesis.　

Therefore, it was found that several metabolites were accumulated in the culture process of S. salivarius and then exhausted in the growth process of E. rectale. Among them, five metabolites are presumed to be annotated,Linolenic acid and cholic acidIt is confirmed by using analytical standards (methods). The changes of nucleotide-related metabolites (such as uridine -5′- diphosphate) are consistent with the critical nature of protein and metabolites influenced by duloxetine and E. rectale. Therefore,Human targeted drugs can regulate intestinal microbial community, not only by direct inhibition, but also by creating cross-feeding opportunities..

04

Bioaccumulation affects host response.

Then, the researchers used Caenorhabditis elegans as a model system to study the effect of duloxetine bioaccumulation on host response. Duloxetine as a kind ofSerotonin-norepinephrine reuptake inhibitorAnd regulate the behavior (muscle movement) of Caenorhabditis elegans in a concentration-dependent manner.　

In the presence of bioaccumulative species (Escherichia coli IAI1) as part of the growth medium of Caenorhabditis elegans, animal movements were examined as behavioral readings. As a closely related control, the researchers used E.coli ED1a strain which did not bioaccumulate in complex growth medium. In fact,Only strain IAI1, a bioaccumulation strain of duloxetine, weakened the influence of duloxetine on the host.Although the intestine of C. elegans is colonized by facultative anaerobic bacteria and obligate aerobic bacteria, it is likely to be aerobic, but the results are very consistent with the biological accumulation observed in anaerobic culture experiments.

Therefore, it is necessary to further study the microbiome-duloxetine-host interaction in other model systems or clinical environments.

05

Total knot

The results reveal that the therapeutic effect of host-targeted drugs can be achieved by intestinal bacteria in two ways.biotic pyramidTo adjust:

First, the main effect produced by reducing the availability of drugs;

Second, the secondary effect produced by changing the secretion of metabolites.　

The latter willLead to changes in community composition.This is related to some drugsassistantAction and even the mode of action.. For the case drug duloxetine in this study, the intestinal bacterial interaction is indeed related to the side effects such as weight gain and its mode of action.

editorial comment/note

Bacteria in the intestine can affect the activity or efficacy of drugs. Recent studies show that this effect is not only biotransformation (changing the composition of drugs or metabolizing them into new substances),Bioaccumulation of drugs stored in cells by specific bacteriaIt may be another important influence (accounting for more than half of the newly discovered role). By accumulating drugs in cells, it willGreatly changes the efficacy of many dose-dependent drugs.(such as the antidepressant duloxetine under study), and it absorbs the bacteria that have accumulated drugs.Metabolism will change., which in turn willaffectInteracting with itOther bacteriaAnd finally change the composition of the flora.

References:

Klünemann M, Andrejev S, Blasche S, Mateus A, Phapale P, Devendran S, Vappiani J, Simon B, Scott TA, Kafkia E, Konstantinidis D, Zirngibl K, Mastrorilli E, Banzhaf M, Mackmull MT, H?velmann F, Nesme L, Brochado AR, Maier L, Bock T, Periwal V, Kumar M, Kim Y, Tramontano M, Schultz C, Beck M, Hennig J, Zimmermann M, Sévin DC, Cabreiro F, Savitski MM, Bork P, Typas A, Patil KR. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature. 2021 Sep 8. doi: 10.1038/s41586-021-03891-8. Epub ahead of print. PMID: 34497420.