We are familiar with the “85 flowers”-Yang Mi, Zhao Liying, Liu Shishi, Liu Yifei, Tang Yan, angelababy, when will they get the rear-view and shadow queen? So far, only Zhao Liying has won the Golden Eagle Award, and only baby has won the Hundred Flowers Award for Best Supporting Actress, and none of the others have won any decent awards.
Let’s take a look at the film and television inventory of “post-85 actresses”. The largest number is Zhang Yuqi, with as many as 4. After Zhang Yuqi became popular because of “Sister Riding the Wind and the Waves”, she was really out of control. In many fashion occasions and awards ceremonies, Zhang Yuqi can be equal to Yang Mi, Liu Shishi, Liu Yifei, Tang Yan, and baby.

Of the four TV series Zhang Yuqi, two are first and two are second, the gold content is still very high. The three stocks are Jiang Shuying, Yang Mi, Song Qian, Mao Xiaotong, Ma Sichun and Ni Ni. Among these 6 actresses, Yang Mi and Ma Sichun have the highest gold content, because they starred in the same film and television dramas. The two stocks are Tong Yao, Liu Yifei, Zhao Liying, and Baby, and the most valuable are Liu Yifei and Zhao Liying. They starred in the film and television dramas. In particular, Zhao Liying would like to say in particular that she is very likely to become the first “85 Flower Grand Slam Queen” by virtue of “Happiness to Ten Thousand Homes”-winning the Magnolia Award and Feitian Award. Tang Yan, Liu Shishi, and Jing Tian have 1 inventory. Liu Shishi is the most pitiful. Her inventory is a guest appearance-the main melody movie “1921”. Tang Yan’s inventory is very strong. It is the TV series “Flowers” starring with Hu Ge and Ma Yili, but Ma Yili is more likely to win an award than Tang Yan, unless Ma Yili has fewer roles than Tang Yan. Zhang Xiaofei is more pitiful than Liu Shishi. She has no stock. She starred in the movie “Hello, Li Huanying” with a box office of 5.4 billion, but she hasn’t received a new drama for 4 months? Is the boss Jia Ling too greedy? High asking price? Did Zhang Xiaofei not care about it? Or is Zhang Xiaofei’s drama too narrow and can only act in films directed by Jia Ling? A terrible thing: Except for Zhao Liying, there is no one in the inventory of Yang Mi, Liu Shishi, Liu Yifei, Tang Yan, and baby that can compete for the rear-view. And Tong Yao’s “Heart in the Heart” is very competitive, and it is hopeful that it will be viewed behind. The task of stopping Tong Yao was left to Zhao Liying to save face for the “85 Flowers”. Discussion: Who is your favorite actress after 1985?

As reflected in the name of TIM-3, current research on it is mainly focused on T cells. TIM-3 is regarded as a marker molecule of T cell exhaustion in chronic viral infection and cancer models[2].

Although multiple drugs targeting TIM-3 have entered clinical trials[1], but The mechanism of blocking TIM-3’s anti-tumor activity is still a bit vague Because TIM-3 is also expressed on many other immune cells, do immune cells other than T cells participate in its anti-cancer effect, or even play a more important role?

On June 9, 2021, the Vijay K. Kuchroo team from Harvard Medical School published important research results in the journal Nature. They found Blocking TIM-3 on dendritic cells (DCs) may play a more critical role in enhancing anti-tumor immunity [3]!

Screenshot of the paper’s homepage

In order to understand the specific functional mechanism of TIM-3, the researchers used a large number of conditional knockout mouse models.They found that in After knocking out TIM-3 in CD4 and CD8+ T cells at the same time, tumor growth was inhibited to a certain extent, but not very significant ;and Specific knockout of TIM-3 in CD8+ T cells, regulatory T cells or NK cells does not affect tumor growth .

This result is a bit surprising, but the researchers quickly thought, would TIM-3 on myeloid cells have a more important function?

The researchers found through single-cell sequencing combined with flow cytometry that High expression of TIM-3 in DC1s and migDCs (migDCs) in tumors .in After specifically knocking out TIM-3 in DCs, tumor growth was significantly inhibited, and This effect is stronger than TIM-3 knocking out T cells .

Knock out TIM-3 in dendritic cells (gene name is Havcr2), the tumor is significantly suppressed

So, how does TIM-3 on DCs affect the anti-tumor immune response?

With the help of single-cell sequencing results, the researchers found that after knocking out TIM-3 in DCs, the number of CD8+ T cells infiltrated in the tumor increased. A more detailed analysis found that Early activation, effect, memory, memory precursor T cells increased , These T cells play a key role in the anti-tumor immune response[4].

Streaming analysis also confirmed that in After conditionally knocking out the TIM-3 of DCs, the memory precursor CD8+ T cells and effector T cells infiltrated in the tumor increased significantly .

After knocking out TIM-3 of DCs, memory precursor CD8+ T cells (TCF1) and effector T cells (CX3CR1, T-bet, Ki67) increased

One of the main functions of DCs is to promote the anti-tumor immune function of antigen-specific CD8+ T cells through antigen presentation[5].Further analyzing the myeloid cells in single-cell sequencing, the researchers found Some genes related to MHC class I antigen presentation are significantly elevated .

Mouse experiments also confirmed that after knocking out the TIM-3 of DCs, the proportion of antigen-specific CD8+ T cells in the tumor was significantly increased, and it had a stronger killing potential.Description Inhibition of TIM-3 can enhance antigen-specific immune response .

After knocking out the TIM-3 of DCs, the proportion of antigen-specific CD8+ T cells increases and has a stronger killing potential

After studying the mechanism at the cellular level, the researchers began to further explore more detailed molecular mechanisms.

The researchers first analyzed the interaction between CD8+ T cells and DCs based on single-cell sequencing technology. The results showed that after knocking out the TIM-3 of DCs, the ligand-receptor interaction scores of Il18–Il18r1 and Il18–Il18rap increased significantly.Analysis of cytokines in tumor homogenate also found Significantly increased levels of IL-1β and IL-18 .

Friends who are familiar with inflammasomes must be able to think that inflammasomes mediate the activation and release of IL-1β and IL-18. Does knocking out TIM-3 activate the inflammasomes?

Pattern diagram of inflammasome activation[6]

Sure enough, analyzing single-cell sequencing data, the researchers found that in the TIM-3 knockout DCs, inflammasome-related gene characteristics were significantly enriched.

Inflammasomes can be activated by pathogen-related molecular patterns (PAMP) and damage-related molecular patterns (DAMP)[7]Since the research here did not involve pathogens, researchers naturally wondered whether endogenous DAMP (such as reactive oxygen species, oxidized lipids, and oxidized DNA) activated the inflammasomes?

Researchers found that in TIM-3 knock-out DCs, the enrichment level of oxidative stress-related gene characteristics was significantly increased, and flow analysis also confirmed Increased ROS levels in DC1s and mDCs .Furthermore, the researchers treated mice with tumors with antioxidants (N-acetylcysteine) and found that The tumor suppressor effect brought by knocking out TIM-3 is completely eliminated, and the increase in IL-1β levels in the tumor is also completely eliminated .

After knocking out TIM-3, the level of ROS in DC1s and migDCs increased

So, is the activation of the inflammasome pathway the reason for the enhanced anti-tumor immune response?

Researchers used three ways to inhibit the inflammasome pathway (inhibition of caspase1, inhibition of NLRP3 inflammasome, inhibition of IL-1β/IL-18, friends can check the above schematic diagram), and found The anti-tumor effect enhanced by knocking out TIM-3 completely disappears, and the function-enhancing effect of CD8+ T cells is also eliminated .

Inhibition of the inflammasome pathway can eliminate the immune enhancement effect of blocking TIM-3

Overall, this study found that compared to T cells, TIM-3 on DCs may play a more critical role in tumor immunity , This discovery has a certain subversive significance to people’s previous cognition.

The author analyzes the mechanism from the perspectives of cell function changes in the tumor microenvironment and changes in molecular pathways in DCs, but this article still leaves many unanswered questions.

For example, how does knocking out TIM-3 lead to increased levels of oxidative stress in DCs? In addition, the experimental evidence of the relationship between oxidative stress and inflammasome activation in this article is still weak. In this model, is it possible that the inflammasome may be activated by other factors?

How does the activation of inflammasome affect the function of DCs and T cells? Is it possible that TIM-3 may affect the function of DCs through other mechanisms?For example, in the latest issue of Immunity, Brian Ruffell and others believe that Blocking TIM-3 contributes to the activation of the cGAS-STING pathway in DCs, thereby promoting the anti-tumor immune response [8].

Although TIM-3 still has a lot to be studied, it is worth looking forward to that many TIM-3 antibodies have entered clinical trials, including some domestic drugs. It is hoped that these drugs can be marketed as soon as possible and benefit more patients.

references

1. Siddiqui I, Schaeuble K, Chennupati V, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity. Jan 15 2019;50(1):195-211 e10. doi:10.1016/j.immuni.2018.12.021

2. Roberts EW, Broz ML, Binnewies M, et al. Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell. Aug 8 2016; 30(2):324-336. doi:10.1016/j.ccell.2016.06.003

3. Terlizzi M, Casolaro V, Pinto A, Sorrentino R. Inflammasome: cancer’s friend or foe? Pharmacol Ther. Jul 2014;143(1):24-33. doi:10.1016/j.pharmthera.2014.02.002

4. de Mingo Pulido A, Hanggi K, Celias DP, et al. The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. Immunity. Jun 8 2021;54( 6):1154-1167 e7. doi:10.1016/j.immuni.2021.04.019

Check cosmetic ingredients: When choosing to buy cosmetics, you should choose cosmetics with ingredients suitable for your skin type by trying the product right at the store. You should choose cosmetics that do not clog pores to avoid skin irritation and acne. Stay away from oils: Most of us have no problem with oil-based cosmetics, however if you have sensitive skin, you should be careful with oils like mineral oil, sesame oil or oil. coconut. Instead, you should choose cosmetics containing silicone to reduce the risk of skin irritation. Know the order of makeup: You should use foundation before concealer, because this will help concealer stick to foundation to stick on and you won’t need to spend too much concealer. Start with primer: Acne-prone skin tends to produce a lot of oil, so makeup quickly wears off or smudges. You should use primer first to ensure that the foundation stays on for a long time. Use color corrector to cover acne: Instead of using a thick foundation and concealer to cover acne, you should use green color corrector to neutralize the red color of acne. Use your hands to apply cream: Unless you are extremely sure that your makeup tools are free of bacteria, you should wash your hands with soap and use your hands to apply foundation and concealer. Start with a small amount of cream: Applying a thick layer of makeup on your face only makes your flaws more obvious. You should start with a very thin layer of cream, then increase the amount of cream where needed. Consider using powder: If your skin is too sensitive to makeup products, you can consider using powdered powders instead of liquid creams. Chalks are usually free of preservatives and emulsifiers, and help control oil better than liquid products. Check powder ingredients: Dry and cracked makeup only makes facial imperfections more obvious, so you should choose the right powder. For a natural look, choose powders containing nylon and kaolin. Remember to remove makeup: A rule that every woman needs to know by heart is to remove makeup before going to bed. Leaving makeup and dirt on your face overnight will clog pores, preventing skin from being able to regenerate while you sleep.

Illustration. Usually we have the habit of touching our face, whenever something strange appears. However, you must know that hands are the place to come into contact with surrounding objects, so they will accumulate a lot of dirt and bacteria. Since then, the habit of regularly touching your face has inadvertently created an opportunity for dirt and bacteria to enter the skin most easily and cause acne. Therefore, to soon improve the condition of acne, you should first remember not to touch your face with your hands. In addition, do not forget to wash your hands thoroughly before applying cosmetics or performing daily facial care steps. Do not arbitrarily pop acne On the other hand, many people’s habit of arbitrarily squeezing acne with their hands also makes acne worse. You may think that squeezing acne is an effective acne solution, but it is still a “double-edged sword” that makes your skin worse every day, also because you squeeze acne incorrectly or because acne cysts are damaged. Injuries take longer to recover. Use only oil-free skin and hair care products Makeup powders, hair gels and other cosmetics should be oil-free. Oil clogs the pores, causing acne to develop. Use products labeled “oil-free”, “non-acnegenic”, “noncomedogennic”, “non-comedogenic”. feathers” (won’t clogpores). Apply acne medication before makeup This helps make-up not affect acne and also does not lose the effect of the drug. Continue using the medicine when the skin is clear of acne To maintain results and prevent acne from returning, at least one acne medication is needed in most cases. If you are using an over-the-counter medication, you can reduce the frequency of application to a few times per week.

Consumers should buy cotton makeup remover with 2 cotton sides sewn together in the form of bags or tightly pressed so as not to stick to the skin during use. Makeup remover is an indispensable product in the skin care process. Photo: Elle. Uses of cotton pads Makeup remover cotton is used to clean the skin, when combined with makeup remover oil will gently remove makeup. Cotton pads can be used to absorb sebum on acne-prone areas such as forehead, chin, and excess oil around the nose. Cotton makeup remover is also used as a moisturizing mask, helping to retain water and moisture for the skin. Besides, the product will promote the effect with the nutrients contained in the cosmetic in an optimal way. Towels should be washed after use. However, in the cleaning process, it is also easy to contact bacteria and expose it to the outside environment, creating conditions for dirt to stick. Cotton makeup remover is also chosen by many people as an alternative, because the product is specialized for the skin and can provide better protection than cotton towels. Makeup removers have many different uses. Photo: Cosmopolitan. The harm behind the makeup remover In addition to being used for the skin, some cotton pads contain ingredients that help remove all the facial oil, makeup, and dirt. When used, users are rubbing bacteria, causing irritation to the skin and worse, pushing dirt and bacteria straight into the pores on the face. Besides, wiping too much makeup remover cotton will hurt and create many wrinkles on the skin. Using makeup remover cotton with too fibrous or rough material will adversely affect the skin. Most pipe cotton is made from fibrous plastic and takes hundreds of years to decompose. Many people have a habit of putting used makeup remover cotton in the toilet, which easily causes environmental problems, as well as clogs the wastewater treatment system. According to studies on makeup remover cotton, 93% of the cause of sewage system blockage is due to wet wipes and cotton swabs. Used products will be dumped into the sea, polluting the water environment and marine life.

Spam calls have plummeted The Telecommunications Department said that 17,276 subscribers who distributed spam calls were handled in March 2021. This is 2.3 times the figure recorded in February of this year. Thus, since the operators started the “campaign” to clean up telecommunications trash (July 2020), 128,970 subscribers spreading spam calls have been successfully filtered. In particular, only in the first quarter of 2021, there were more than 39,000 subscribers distributing spam calls handled by the operators, showing the determination of the Ministry of Information and Communications and carriers in blocking calls. junk consumer harassment. Before that, in the last 6 months of 2020, on average, each month, operators successfully blocked about 15,000 subscribers from spreading spam calls. According to the majority of consumers, over the past time, spam calls have decreased sharply. However, many advertising calls and service introduction still arise but are done more sophisticatedly. Ms. Bui Hang (Thanh Xuan – Hanoi) said: “For a long time there have been no spam calls to my phone, but since the day I applied for stock account registration, advertising calls appear thick. Special, 2-3 days. There was a conversation I had, the other end said that I knew I had submitted the application, but it was a stock trading profile in the domestic market. That employee invited me to join international stocks for more benefits. Why do they know my information so well? “. According to the reflection of Mr. Le Manh Dung (Long Bien-Hanoi), recently, this customer is often tapped. When calling back, there are also introductory content, advertising services. According to the Telecommunications Department, next time, the Department will continue to promote measures to manage and handle violations related to telecommunications waste (spam sim, spam calls, spam messages); At the same time, there are solutions to prevent fake phone calls, prevent the sale of pre-activated sims … contributing to ensuring security and order.

26-year-old excavator driver Abdallah Abdelgawad The incident attracted worldwide attention. As a very important trade route for the world economy, the temporary closure of the canal caused the name Suez to appear in newspapers and social media posts. Photo: Reuters The size difference was too great between the two objects The image shared with dizzying speed of a small excavator trying to rescue the giant ship has surprised many people. The huge difference in the size of the two objects makes one think of an ant trying to get an elephant out of troubled waters. Abdallah Abdelgawad, who operated the small excavator, did not expect to become famous on social media one day. However, from anonymity, he actually became a star widely praised. At 7:00 a.m. on Tuesday, March 23, Abdelgawad arrived at his workplace as usual. However, the gates are closed and prohibited from entering. “I asked a person and he said there was a boat blocking the canal,” said Abdelgawad, 26. He and his colleagues returned to their residence at Al Arbain, 30 minutes away. An hour later, Abdelgawad received a call from his manager, asking him to immediately go to the east bank of the canal. A Suez Canal Authority car was waiting to take him away. “I told him we were not allowed into the work site because a ship was blocking the channel,” the manager said. “You will come to work on that ship,” recalled Abdelgawad. While the authorities attempted to rescue the ship, Abdelgawad alone dug the silt under the giant ship’s bow. He worked nonstop for more than a day until someone else changed his shift. For the next 5 days, he only had 3-4 hours of rest in each working day to clear the maritime route connecting the Red Sea to the Mediterranean. After extraordinary efforts, including a contribution from Abdelgawad, the super ship Ever Given was successfully rescued. In those days, when his family was worried about his health and phoned every day to inquire, pictures of the giant ship by the excavator were circulating on the Internet. “On social media, they said the excavator and me with the ship were like” ants and an elephant. ” At first I was sad, but then it felt normal that we were finally able to rescue the ship, ”Abdelgawad said in an interview. “On Monday, I was really exhausted. But when the ship was successfully rescued, I caught a video as it started to move,” he said proudly. My Facebook account and said that this achievement is due to my tiny miner. I feel as if I have won a war, “he added. Abdallah Abdelgawad takes a selfie with his excavator. – Photo: Facebook Abdallah Abdelgawad Abdallah Abdelgawad poses with workers at the spot along the Suez Canal, where the container ship Ever Given was stranded. Abdelgawad is paid 3,000 Egyptian pounds ($ 190) a month for his work as a excavator. After this incident, he was greeted as a “hero” when he returned to his small village on the outskirts of the city of Shirbin in Daqhaliyah province. “I know I did something big, when everyone gathered around me I felt proud and my dad said,” You made me proud. ” My phone still keeps ringing. I want to sleep, but I can’t sleep, ”he laughed. “My life has changed because of those pictures.” Even though his social media posts have earned him popularity, Abdelgawad has a message he wants to reach out to all those who mock him. “Don’t make fun of the weak or look down on them. This tiny excavator played a huge role in moving a ship more than 500 times its size. Now, I feel extremely proud of what I have done. I hope you all are proud of me too. ” Said Abdelgawad.