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August 29, 2013

Carbonation Countdown: The Effect of Temperature of Reaction Time

Seltzer science from Science Buddies

By Science Buddies

Key concepts Chemical reactions Molecules Carbonation Temperature

Introduction Have you ever wondered why bubbles form when an Alka-Seltzer tablet is dropped into water? If you've ever tried it, you've seen that the tablet fizzes furiously. The moment the tablet starts dissolving a chemical reaction occurs that releases carbon dioxide gas. This is what comprises the bubbles. Some factors can change how quickly the carbon dioxide gas is produced, which consequently affect how furiously the tablet fizzes. In this activity you'll explore whether you can make an Alka-Seltzer tablet fizz faster or slower by changing the water’s temperature. How does this affect the reaction?

Background Alka-Seltzer is a medication that works as a pain reliever and an antacid. (Antacids help neutralize stomach acidity, which can cause heartburn.) The pain reliever used is aspirin and the antacid used is baking soda, or sodium bicarbonate. The tablets also include other ingredients, such as citric acid (a weak acid that adds flavor—as well as provides important hydrogen ions, which will come into play as you shall soon see).

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To take the tablets, they're fully dissolved in water, where they famously undergo a chemical reaction that produces lots of carbon dioxide bubbles—or fizz. Why is this? As the tablets dissolve, the sodium bicarbonate splits apart to form sodium and bicarbonate ions. The bicarbonate ions react with hydrogen ions from the citric acid to form carbon dioxide gas (and water). This is how the bubbles are made.

How is temperature related to this reaction? For the reaction to occur, the bicarbonate ions must come into contact with the hydrogen ions in just the right way. The probability of the bicarbonate and hydrogen ions doing this is affected by temperature: the higher the temperature, the faster the molecules move; the lower the temperature, the slower they move. (The temperature of a solution is a measure of its molecules’ average motion and energy.) Can you guess whether fast-moving molecules or slow-moving ones will speed the reaction time?

Materials • Two identical jars (You can also use drinking glasses, clear plastic cups, bottles or vases.) • Spoon • Enough ice cubes to fill one of the jars halfway • Cold tap water • Hot tap water • Two Alka-Seltzer tablets • Timer or clock that shows seconds • Optional: helper

Preparation • Fill one of the jars halfway with ice cubes. Add cold tap water to about an inch from the rim. Stir the ice cubes in the jar for about a minute so that the temperature evens out. Right before you start the activity use a spoon to remove the cubes. • Add hot tap water to the second, empty jar until it is about an inch from the rim. Be careful when handling the hot water. • Continue with the procedure immediately after preparing the jars (so that the water in the jars is still very cold or very hot).

Procedure • Drop an Alka-Seltzer tablet into the jar with hot water. Time how long it takes for the tablet to disappear. You may want to have a helper time the reaction. How long does it take the tablet to disappear? How vigorous are the bubbles? • Drop an Alka-Seltzer tablet into the jar with the ice-cold water (after having removed the ice cubes with a spoon). Again time how long it takes the tablet to disappear. How long does it take the tablet to disappear in the colder water? • Do you notice other differences in how the reaction happens in the colder versus in the hotter water? • Why do you think you got the results you did? • Extra: Test Alka-Seltzer tablets in a wider range of temperatures, and then draw a graph showing the time it takes a tablet to dissolve in water at each temperature (check with a thermometer). What temperature change is required to increase the reaction time by a factor of two (make it as twice as fast)? What about decreasing the reaction time by a factor of two? • Extra : Compare whole Alka-Seltzer tablets to pieces of Alka-Seltzer tablets. If there is a greater surface area (that is, a tablet is broken up into more pieces to expose more surface), does the same amount of tablet result in the reaction happening faster or slower? • Extra : You can turn this activity into a homemade lava lamp! To do this, you will use an empty container, such as a tall jar or clear plastic one- or two-liter bottle. Fill it with about two inches of water, add five drops of food coloring and then fill it at least three quarters full with vegetable oil before adding one quarter of an Alka-Seltzer tablet. You could repeat this activity using your homemade lava lamp at colder and warmer temperatures. (Because it contains oil, you should have an adult help you devise a safe way to warm or cool the contents of each container.) How does the bicarbonate reaction look in the homemade lava lamp? Observations and results Did the Alka-Seltzer tablet dissolve much faster in the hot water compared to the cold? Were there a lot more bubbles produced initially in the hot compared with the cold water?

After the Alka-Seltzer tablet was added to the hot water the tablet should have quickly dissolved, taking some 20 to 30 seconds to do so, depending on the exact temperature. After the tablet was added to the ice-cold water it should have taken much longer to dissolve, with most of the tablet disappearing after about two to three minutes, but with some bubbles still apparent after six minutes or longer. In the hot water the tablet should have more vigorously produced bubbles than in the cold water. The higher the temperature, the faster the molecules move—and the more likely it is that the bicarbonate will contact hydrogen in just the right way for the chemical reaction to occur and produce carbon dioxide bubbles.

More to explore Chemical Reactions , from Rader's Chem4Kids.com Factors Affecting the Speed-Rates of Chemical Reactions , from Doc Brown's Science Rates of Reaction Menu , from Chemguide Plop, Plop, Fizz Fast: The Effect of Temperature on Reaction Time , from Science Buddies

This activity brought to you in partnership with  Science Buddies

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• TeachEngineering
• Pill Dissolving Demo

Hands-on Activity Pill Dissolving Demo

Grade Level: 9 (9-12)

Time Required: 30 minutes

Expendable Cost/Group: US $4.80

Group Size: 28

Activity Dependency: How Antibiotics Work

Subject Areas: Biology, Life Science

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Biomedical engineers use experiments to discover how various chemical substances react in the human body, for example, the absorption of medication and how the body breaks down the outer coatings of pills and capsules. To test new medicines, scientists use solutions with chemical compositions similar to the environments found in the human body to model various body reactions. Engineers also create all sorts of devices and tools used in experiments, and creative medicine delivery materials and equipment, including syringes and patches, and even the factories for making different types of pills and bottling liquids.

After this activity, students should be able to:

• Describe what happens to a pill in the human stomach.
• Explain which pill form is absorbed the fastest.

Educational Standards Each TeachEngineering lesson or activity is correlated to one or more K-12 science, technology, engineering or math (STEM) educational standards. All 100,000+ K-12 STEM standards covered in TeachEngineering are collected, maintained and packaged by the Achievement Standards Network (ASN) , a project of D2L (www.achievementstandards.org). In the ASN, standards are hierarchically structured: first by source; e.g. , by state; within source by type; e.g. , science or mathematics; within type by subtype, then by grade, etc .

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Tennessee - science.

For the class demonstration:

• 3 small glass beakers
• ~ 2 cups vinegar
• 3 types of pills: chalk, gel capsule, gel tablet

We have been asked to determine which type of medicine works the fastest.

So many TV and magazine advertisements claim that their medicines offer the quickest relief.

So we are going to do our own experiment to observe three different pill forms to investigate whether the ads are truthful in their claims of offering quick relief, and to determine which type breaks down the fastest in the body.

How does medicine get into the bloodstream? The human stomach is filled with an acidic solution that breaks down all the food and liquid that we ingest.

How long do you think it takes for a pill to dissolve in the stomach? To create a similar environment, we will use vinegar.

Watch the pills carefully. You may be surprised at what happens!

• Gather materials on a table that is visible to everyone in the class.
• Fill each beaker with approximately one-quarter cup vinegar (or until beakers are half full).
• Introduce the demo to students using the information in the Introduction/Motivation section.
• Place one pill in each beaker. Note the start time on the clock.
• After several minutes, pick up the beakers and observe any change in color of the vinegar. Also, look for any changes in the pills.
• Consider a pill fully dissolved when the vinegar is clear (this does not include any remaining outer coverings).
• Lead a class discussion. Ask students the Investigating Questions.
• At this point, students should be able to determine what form of medicine to take (the shot) for speed. For homework, as described in Assessment section, assign students to write three suggestions of how to make the medicine work more quickly.

antibiotic: A chemical substance used to treat infections by destroying or inhibiting the growth of bacteria and other microorganisms.

bacteria: Single-celled microorganisms that can exist either as independent organisms or as parasites. Singular = bacterium; plural = bacteria.

Post-Activity Assessment

Short Answer Homework: Assign students to individually answer the following questions with short answers. Review their answers to gauge their comprehension of the subject. Tell the students: Earlier (in the associated lesson), you viewed a short animated video on medicine being injected into the blood stream. We then discussed how long it takes for the medicine in injections, as well as in pills and liquids, to typically take effect. Now, you have just observed an experiment to compare how quickly various types of pills dissolve in acidic environments. With this information, you are now able to answer the first part of the challenge question.

• Which pill form works the fastest? Why? (Answer: Fastest is chalk, then gel capsule, then gel tablet. This is because it takes longer for the gel coating to dissolve enough for the capsule/tablet to release the inner medicine.)
• Which form of medicine (pill, liquid or injection/shot) works the fastest? Why? (Answer: The fastest is medicine injected through a syringe [ a shot].)
• Describe three suggestions of what you might do to get medicine to work more quickly. Provide explanations of why you think they may work. (Answers will vary. Possible answers: 1) move around because increasing your heart rate increases blood flow, 2) eat something because this starts the digestive system, 3) stay warm because this opens the veins more. All of these actions assist your body in absorbing the medicine more quickly, especially pill/liquid forms.)

How does medicine get into the bloodstream? (Answer: Common ways are pills, liquids and shots. Medicines that reach the stomach are broken down so they can enter the bloodstream.)

How long does it take for a pill to dissolve in the stomach? (Answer: Ranges from 15-30 minutes.)

What does this imply about those in liquid form? (Answer: Liquid forms go through the same process as pills once they reach the stomach.)

What happens when you receive a shot? (Answer: The medicine bypasses the digestive process and goes directly into a person's bloodstream.)

For more advanced students, have them do their own experiments instead of the class demonstration. See the Protect That Pill activity in which students develop pill coatings that can withstand the churning actions and acidic environment found in the stomach. Teams test coating durability by using clear soda to simulate stomach acid.

To reinforce students' understanding of the human digestion process, the functions of several stomach and small intestine fluids are analyzed, and the concept of simulation is introduced through a short, introductory demonstration of how these fluids work. Students learn what simulation means and ho...

Students are introduced to a challenge question. Towards answering the question, they generate ideas for what they need to know about medicines and how they move through our bodies, watch a few short videos to gain multiple perspectives, and then learn lecture material to obtain a basic understandin...

Students reinforce their knowledge of the different parts of the digestive system and explore the concept of simulation by developing a pill coating that can withstand the churning actions and acidic environment found in the stomach. Teams test the coating durability by using a clear soda to simulat...

Students are challenged to think as biomedical engineers and brainstorm ways to administer medication to a patient who is unable to swallow. They learn about the advantages and disadvantages of current drug delivery methods—oral, injection, topical, inhalation and suppository—and pharmaceutical desi...

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The contents of this digital library curriculum were developed under National Science Foundation RET grant nos. 0338092 and 0742871. However, these contents do not necessarily represent the policies of the NSF, and you should not assume endorsement by the federal government.

Last modified: October 31, 2021

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• Why We’re Unique

The Effect of Temperature on the Rate of Dissolving.

Introduction: (initial observation).

Most solid chemicals need to be dissolved in water or solvents before they can be used. Knowing the best temperature for dissolving each specific chemical can help us save time and energy in the dissolving process.

Scientists often perform their own tests in order to learn about the effect of temperature on the rate of dissolving and create a graph that can help them for future reference.

In this project, you will study the effect of temperature on the rate of dissolving any specific chemical in water. The chemical that you select can be among the chemicals that are low hazard and can be found at home. Salt, baking soda, citric acid, and sugar are some good examples. You may obtain other chemicals such as copper sulfate, Calcium chloride and lime locally. After performing necessary experiments you must create a graph to show the rate of dissolving in different temperatures.

This project guide contains information that you need in order to start your project. If you have any questions or need more support about this project, click on the “Ask Question” button on the top of this page to send me a message.

If you are new in doing science project, click on “How to Start” in the main page. There you will find helpful links that describe different types of science projects, scientific method, variables, hypothesis, graph, abstract and all other general basics that you need to know.

Project advisor

Information Gathering:

Find out about dissolving as a molecular level interaction between solids and liquids. You may also learn about some related subjects such as the effect of polarity in dissolving and learn that ionic substances can only be dissolved in a polar liquid such as water and non-ionic substances can only be dissolved in non-polar liquids such as acetone. Read books, magazines or ask professionals who might know in order to learn about the methods that you may test the rate of dissolving in certain temperatures. Keep track of where you got your information from.

The following are samples of information that you may find.

Ionic solids (or salts) contain positive and negative ions, which are held together by the strong force of attraction between particles with opposite charges. When one of these solids dissolves in water, the ions that form the solid are released into solution, where they become associated with the polar solvent molecules.

Source…

Why is it important to know the temperatures that maximize solubility for each substance?

Solid chemicals do not react on each other. With exception of explosives, all other chemical reactions are done with liquid chemicals. You first make a solution of each ingredient, react the solutions and then you separate the products by methods such as crystallization, filtration or precipitation.

In all such reactions, we attempt to use the minimum amount of water because later we need to remove the excess water. Removing the excess water requires time, fuel and other costs associated with separation process.

By knowing the temperature in which a substance has the highest solubility we can avoid excess water and related expenses in chemical reactions and minimize the production cost.

Question/ Purpose:

What do you want to find out? Write a statement that describes what you want to do. Use your observations and questions to write the statement.

The purpose of this project is to learn how temperature affects the rate of dissolving of a certain solid in a certain liquid.

More specifically I will examine the effect of temperature on the rate in which table salt or rock salt dissolves in water.

Similar procedures can be used to determine the effect of temperature on the rate of dissolving for other solids and other liquids.

Identify Variables:

When you think you know what variables may be involved, think about ways to change one at a time. If you change more than one at a time, you will not know what variable is causing your observation. Sometimes variables are linked and work together to cause something. At first, try to choose variables that you think act independently of each other.

The independent variable (manipulated variable) is the temperature. (0ºC to 100ºC)

The dependent variable (responding variable) is the rate in which salt (a solute) dissolves in water (a solvent).

Controlled variables are air pressure and other environmental factors.

Constants are:

• The type of water
• The type of salt
• Experiment method
• Experiment location
• Tools and Instruments used in experiments

Hypothesis:

Based on your gathered information, make an educated guess about what types of things affect the system you are working with. Identifying variables is necessary before you can make a hypothesis.

Following is a sample hypothesis:

The rate of dissolving salt in water will increase by temperature. My hypothesis is based on my personal observations that heat accelerates dissolving.

Experiment Design:

Design an experiment to test each hypothesis. Make a step-by-step list of what you will do to answer each question. This list is called an experimental procedure. For an experiment to give answers you can trust, it must have a “control.” A control is an additional experimental trial or run. It is a separate experiment, done exactly like the others. The only difference is that no experimental variables are changed. A control is a neutral “reference point” for comparison that allows you to see what changing a variable does by comparing it to not changing anything. Dependable controls are sometimes very hard to develop. They can be the hardest part of a project. Without a control you cannot be sure that changing the variable causes your observations. A series of experiments that includes a control is called a “controlled experiment.”

Experiment:

Dissolving rate of salt in water at different temperatures.

Introduction: The rate at which Rock salt dissolves in water at 11 different temperatures is observed.

• Label 11 beakers with numbers 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 to represent the test temperatures in which you are testing the dissolving rate. Units are degrees of Celsius.
• Prepare 11 small plastic bags with 100 grams rock salt crystals in each bag.
• Prepare sufficient amount of ice water (0ºC) in a separate container. Add 200 ml water to the beaker labeled 0. Add 100 grams of rock salt to the water and stir it for 5 minutes.
• Carefully separate the remaining salt (whatever is not dissolved in water) , then dry it and weigh it to see how much of salt did not dissolve in water. Then subtract it from 100 to determine the amount of salt dissolved in water. Record your results.
• Prepare 200 ml water at 10ºC. You may need to adjust the temperature by adding some ice water or some hot water to regular tap water to do this. Add 100 grams of rock salt to the water and stir it for 5 minutes.
• Carefully separate, dry and mass any un-dissolved salt. Subtract it from 100 to determine the amount of dissolved water. Record your results.
• Repeat this experiment for 20ºC, 30ºC, 40ºC, 50ºC, 60ºC, 70ºC, 80ºC, 90ºC, and 100ºC waters. Use an electric heater to heat up the water as needed.

Your results table will look like this:

Amount of salt dissolved in water at different temperatures

Use the temperature column and dissolving rate column of your results table to draw a line graph.

Notes/ Remarks:

• To separate remaining un-dissolved crystals in a beaker, you may use a filter paper and a funnel. Coffee filter works fine.
• You may make your measurements in the American system instead of the metric system. For example instead of Celsius degrees, you may use Fahrenheit degrees. You may need to make necessary adjustments if you choose to do it that way.
• You may perform similar experiments on any other water soluble substance.

Make a graph:

When your results table is ready, use it to make a bar graph. You will only use the first and the last columns of your table to draw a graph. In this way your graph will show the relation between the temperature and the solubility.

Make one vertical bar for each of the temperatures you test. For example if you are testing four different temperatures, you will have four bars. The height of each bar represents the solubility rate at each specific temperature. For example you may use a 20″ bar for 20% solubility.

Make sure you write the temperature below each bar. Also write the solubility rate above or over each bar.

Materials and Equipment:

Salt crystals available from local hardware stores as rock. Please only use clean and large crystals if possible. tap water

Equipment: 500-mL beakers chemical scoop or spoon Thermometer Scale

Modification:

Clear plastic cups may be substituted for beakers. If you only have one beaker instead of 11, do your experiments one by one and wash the beaker after each test. You can either use a food thermometer or a laboratory-glass thermometer.

Results of Experiment (Observation):

Experiments are often done in series. A series of experiments can be done by changing one variable a different amount each time. A series of experiments is made up of separate experimental “runs.” During each run you make a measurement of how much the variable affected the system under study. For each run, a different amount of change in the variable is used. This produces a different amount of response in the system. You measure this response, or record data, in a table for this purpose. This is considered “raw data” since it has not been processed or interpreted yet. When raw data gets processed mathematically, for example, it becomes results.

Your results table and graph will appear here.

Calculations:

You will need to calculate the ratio of salt to water for each temperature.

Summary of Results:

Summarize what happened. This can be in the form of a table of processed numerical data, or graphs. It could also be a written statement of what occurred during experiments.

It is from calculations using recorded data that tables and graphs are made. Studying tables and graphs, we can see trends that tell us how different variables cause our observations. Based on these trends, we can draw conclusions about the system under study. These conclusions help us confirm or deny our original hypothesis. Often, mathematical equations can be made from graphs. These equations allow us to predict how a change will affect the system without the need to do additional experiments. Advanced levels of experimental science rely heavily on graphical and mathematical analysis of data. At this level, science becomes even more interesting and powerful.

Conclusion:

Using the trends in your experimental data and your experimental observations, try to answer your original questions. Is your hypothesis correct? Now is the time to pull together what happened, and assess the experiments you did.

Following is a sample conclusion.

Increasing the temperature increases the rate of dissolving because, at higher temperatures, the solvent molecules are moving more rapidly and therefore come into contact with and solvate the solute molecules more rapidly.

In Sodium Chloride or rock salt however; increase of solubility in higher temperatures is not much. As seen in the results table and graph, the solubility of salt in water increases from …….. to …….. when temperature changes from 0ºC to 100ºC.

Later I found the following graph on the Internet that confirms my results.

The light blue color is for table salt or rock salt. As you see in some chemicals like calcium chloride, solubility increases a lot by increase in temperature. On the other hand for Cerium Sulfate solubility decreases by temperature.

Related Questions & Answers:

What you have learned may allow you to answer other questions. Many questions are related. Several new questions may have occurred to you while doing experiments. You may now be able to understand or verify things that you discovered when gathering information for the project. Questions lead to more questions, which lead to additional hypothesis that need to be tested.

Possible Errors:

If you did not observe anything different than what happened with your control, the variable you changed may not affect the system you are investigating. If you did not observe a consistent, reproducible trend in your series of experimental runs there may be experimental errors affecting your results. The first thing to check is how you are making your measurements. Is the measurement method questionable or unreliable? Maybe you are reading a scale incorrectly, or maybe the measuring instrument is working erratically.

If you determine that experimental errors are influencing your results, carefully rethink the design of your experiments. Review each step of the procedure to find sources of potential errors. If possible, have a scientist review the procedure with you. Sometimes the designer of an experiment can miss the obvious.

I noticed that the temperature will change slightly during the time that I am stirring the solution. To prevent such change, I could wrap the beaker in insulating material and reduce the stirring time from 5 minutes to 2 minutes. A blanket or a Styrofoam box can be used as insulator. Alternatively I could heat up or cool off the beaker to maintain the temperature.

References:

Visit your local library and review the solubility articles or chapters of existing books or chemistry publications. Also see an encyclopedia for solubility. Following are some web based resources.

The Role of Charge in Solubility

http://www.woodrow.org/teachers/chemistry/institutes/1986/exp15.html

http://chemed.chem.purdue.edu/genchem/topicreview/bp/ch18/soluble.html

Solubility Tutorial

http://scidiv.bcc.ctc.edu/wv/09/0009-004-solub.html

http://www.chem.uncc.edu/faculty/murphy/1252/Chapter17B/

Need Chemicals? Attention Chemists, Schools, & Colleges ChemicalStore.com offers a large selection of chemicals for research and education at affordable price and convenience of online ordering. Visit ChemicalStore.com today.

It is always important for students, parents and teachers to know a good source for science related equipment and supplies they need for their science activities. Please note that many online stores for science supplies are managed by MiniScience.

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Dissolution rates of over-the-counter painkillers: a comparison among formulations

Affiliation.

• 1 Bayer S.p.A., Milan, Italy - [email protected].
• PMID: 27035158

Background: We wanted to compare the dissolution profile of several over-the-counter analgesics to understand whether the different formulation techniques employed to enhance absorption were associated with variations in the dissolution rate, a parameter known to affect drug absorption.

Methods: We considered 5 formulations currently marketed in Italy: aspirin tablets (Aspirina Dolore e Infiammazione®), ibuprofen tablets and liquid capsules (Moment®), ibuprofen lysine tablets (Nurofenimmedia®) and dexketoprofen trometamol tablets (Enantyum®). Dissolution tests were performed according to the current USP/NF monograph dissolution procedure. Drug dissolution was evaluated at 1, 3, 6, 15, and 30 minutes since the start of the test. Dissolution was evaluated at three different pH: 1.2, 4.5 and 6.8. Every test was repeated 12 times.

Results: The aspirin formulation was by far the most rapid dissolving formulation, among those tested, with more than 80% of the tablet dissolved at 6 minutes for every pH considered. At pH 1.2 and 4.5, only the dexketoprofen formulation was able to reach the dissolution level of aspirin at 30 minutes, but had lower levels of dissolution at the previous time points. Instead, at pH 6.8, most of the formulations approached aspirin dissolution level, but only after 15 minutes. Ibuprofen capsules had the slowest kinetics, with a lag phase the first 6 minutes.

Conclusions: Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia.

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• Mechanistic Approach to Understanding the Influence of USP Apparatus I and II on Dissolution Kinetics of Tablets with Different Operating Release Mechanisms. Lu Z, Fassihi R. Lu Z, et al. AAPS PharmSciTech. 2017 Feb;18(2):462-472. doi: 10.1208/s12249-016-0535-x. Epub 2016 Apr 22. AAPS PharmSciTech. 2017. PMID: 27106916
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• Correlation between dissolution characteristics and absorption of methaqualone from solid dosage forms. Chemburkar PB, Smyth RD, Buehler JD, Shah PB, Joslin RS, Polk A, Reavey-Cantwell NH. Chemburkar PB, et al. J Pharm Sci. 1976 Apr;65(4):529-33. doi: 10.1002/jps.2600650413. J Pharm Sci. 1976. PMID: 1271252

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• Published: 04 September 2024

CDK5–cyclin B1 regulates mitotic fidelity

• Xiao-Feng Zheng   ORCID: orcid.org/0000-0001-8769-4604 1   na1 ,
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• Kaimeng Huang   ORCID: orcid.org/0000-0002-0552-209X 1 , 5 ,
• Feng Li 1 ,
• Alan D. D’Andrea   ORCID: orcid.org/0000-0001-6168-6294 1 , 5 ,
• Amanda G. Paulovich   ORCID: orcid.org/0000-0001-6532-6499 3 ,
• Kavita Shah 2 ,
• Alexander Spektor   ORCID: orcid.org/0000-0002-1085-3205 1 , 5 &
• Dipanjan Chowdhury   ORCID: orcid.org/0000-0001-5645-3752 1 , 5 , 6  

Nature ( 2024 ) Cite this article

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CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression 1 . Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p39 2 . Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK–cyclin complexes and validation with mutational analysis indicate that CDK5–cyclin B1 can form a functional complex. Disruption of the CDK5–cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5–cyclin B1 functions as a canonical CDK–cyclin complex to ensure mitotic fidelity.

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Acknowledgements

We thank D. Pellman for comments on the manuscript; W. Michowski, S. Sharma, P. Sicinski, B. Nabet and N. Gray for the reagents; J. A. Tainer for providing access to software used for structural analysis; and S. Gerber for sharing unpublished results. D.C. is supported by grants R01 CA208244 and R01 CA264900, DOD Ovarian Cancer Award W81XWH-15-0564/OC140632, Tina’s Wish Foundation, Detect Me If You Can, a V Foundation Award, a Gray Foundation grant and the Claudia Adams Barr Program in Innovative Basic Cancer Research. A. Spektor would like to acknowledge support from K08 CA208008, the Burroughs Wellcome Fund Career Award for Medical Scientists, Saverin Breast Cancer Research Fund and the Claudia Adams Barr Program in Innovative Basic Cancer Research. X.-F.Z. was an American Cancer Society Fellow and is supported by the Breast and Gynecologic Cancer Innovation Award from Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute. A. Syed is supported by the Claudia Adams Barr Program in Innovative Basic Cancer Research. B.T. was supported by the Polish National Agency for Academic Exchange (grant PPN/WAL/2019/1/00018) and by the Foundation for Polish Science (START Program). A.D.D is supported by NIH grant R01 HL52725. A.G.P. by National Cancer Institute grants U01CA214114 and U01CA271407, as well as a donation from the Aven Foundation; J.R.W. by National Cancer Institute grant R50CA211499; and K.S. by NIH awards 1R01-CA237660 and 1RF1NS124779.

Author information

Bartłomiej Tomasik

Present address: Department of Oncology and Radiotherapy, Medical University of Gdańsk, Faculty of Medicine, Gdańsk, Poland

These authors contributed equally: Xiao-Feng Zheng, Aniruddha Sarkar

Authors and Affiliations

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Xiao-Feng Zheng, Aniruddha Sarkar, Aleem Syed, Huy Nguyen, Bartłomiej Tomasik, Kaimeng Huang, Feng Li, Alan D. D’Andrea, Alexander Spektor & Dipanjan Chowdhury

Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA

Humphrey Lotana & Kavita Shah

Translational Science and Therapeutics Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Richard G. Ivey, Jacob J. Kennedy, Jeffrey R. Whiteaker & Amanda G. Paulovich

Department of Biostatistics and Translational Medicine, Medical University of Łódź, Łódź, Poland

Broad Institute of Harvard and MIT, Cambridge, MA, USA

Kaimeng Huang, Alan D. D’Andrea, Alexander Spektor & Dipanjan Chowdhury

Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

Dipanjan Chowdhury

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Contributions

X.-F.Z., A. Sarkar., A. Spektor. and D.C. conceived the project and designed the experiments. X.-F.Z. and A. Sarkar performed the majority of experiments and associated analyses except as listed below. H.L. expressed relevant proteins and conducted the kinase activity assays for CDK5–cyclin B1, CDK5–p35 and CDK5(S46) variant complexes under the guidance of K.S.; A. Syed performed structural modelling and analysis. R.G.I., J.J.K. and J.R.W. performed MS and analysis. B.T. and H.N. performed MS data analyses. K.H. provided guidance to screen CDK5(as) knocked-in clones and performed sequence analysis to confirm CDK5(as) knock-in. F.L. and A.D.D. provided reagents and discussion on CDK5 substrates analyses. X.-F.Z., A. Sarkar, A. Spektor and D.C. wrote the manuscript with inputs and edits from all of the other authors.

Corresponding authors

Correspondence to Alexander Spektor or Dipanjan Chowdhury .

Ethics declarations

Competing interests.

A.D.D. reports consulting for AstraZeneca, Bayer AG, Blacksmith/Lightstone Ventures, Bristol Myers Squibb, Cyteir Therapeutics, EMD Serono, Impact Therapeutics, PrimeFour Therapeutics, Pfizer, Tango Therapeutics and Zentalis Pharmaceuticals/Zeno Management; is an advisory board member for Cyteir and Impact Therapeutics; a stockholder in Cedilla Therapeutics, Cyteir, Impact Therapeutics and PrimeFour Therapeutics; and reports receiving commercial research grants from Bristol Myers Squibb, EMD Serono, Moderna and Tango Therapeutics. The other authors declare no competing interests.

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Extended data figures and tables

Extended data fig. 1 inhibition of cdk5 in analogue-sensitive (cdk5- as ) system..

a , Schematics depicting specific inhibition of the CDK5 analogue-sensitive ( as ) variant. Canonical ATP-analogue inhibitor (In, yellow) targets endogenous CDK5 (dark green) at its ATP-binding catalytic site nonspecifically since multiple kinases share structurally similar catalytic sites (left panel). The analogue-sensitive ( as , light green) phenylalanine-to-glycine (F80G) mutation confers a structural change adjacent to the catalytic site of CDK5 that does not impact its catalysis but accommodates the specific binding of a non-hydrolysable bulky orthogonal inhibitor 1NM-PP1(In*, orange). Introduction of 1NM-PP1 thus selectively inhibits CDK5- as variant (right panel). b , Immunoblots showing two clones (Cl 23 and Cl 50) of RPE-1 cells expressing FLAG-HA-CDK5- as in place of endogenous CDK5. Representative results are shown from three independent repeats. c , Proliferation curve of parental RPE-1 and RPE-1 CDK5- as cells. Data represent mean ± s.d. from three independent repeats. p -value was determined by Mann Whitney U test. d , Immunoblots showing immunoprecipitated CDK1-cyclin B1 complex or CDK5- as -cyclin B1 complex by the indicated antibody-coupled agarose, from nocodazole arrested RPE-1 CDK5- as cells with treated with or without 1NM-PP1 for inhibition of CDK5- as , from three independent replicate experiments. e , In-vitro kinase activity quantification of immunoprecipitated complex shown in d . Data represent mean ± s.d. from three independent experiments. p -values were determined by unpaired, two-tailed student’s t-test. f , Immunoblots of RPE-1 CDK5- as cells treated with either DMSO or 1NM-PP1 for 2 h prior to and upon release from RO-3306 and collected at 60 min following release. Cells were lysed and blotted with anti-bodies against indicated proteins (upper panel). Quantification of the relative intensity of PP4R3β phosphorylation at S840 in 1NM-PP1-treated CDK5- as cells compared to DMSO-treatment (lower panel). g , Experimental scheme for specific and temporal abrogation of CDK5 in RPE-1 CDK5- as cells. Data represent mean ± S.D from quadruplicate repeats. p -value was determined by one sample t and Wilcoxon test. h , Hoechst staining showing primary nuclei and micronuclei of RPE-1 CDK5- as with indicated treatment; scale bar is as indicated (left panel). Right, quantification of the percentage of cells with micronuclei after treatment. Data represent mean ± s.d. of three independent experiments from n = 2174 DMSO, n = 1788 1NM-PP1 where n is the number of cells. p- values were determined by unpaired, two-tailed student’s t-test. Scale bar is as indicated. Uncropped gel images are provided in Supplementary Fig. 1 .

Extended Data Fig. 2 Degradation of CDK5 in degradation tag (CDK5- dTAG ) system.

a , Schematic depicting the dTAG-13-inducible protein degradation system. Compound dTAG-13 links protein fused with FKBP12 F36V domain (dTAG) to CRBN-DDB1-CUL4A E3 ligase complex, leading to CRBN-mediated degradation. b , Immunoblots showing two clones of RPE-1 cells that express dTAG -HA-CDK5 in place of endogenous CDK5 (Cl N1 and Cl N4). Representative results are shown from three independent repeats. c , Proliferation curve of parental RPE-1 and RPE-1 CDK5-dTAG. Data represent mean ± s.d. of three independent repeats. p -value was determined by Mann Whitney U test. d and e , Representative images of RPE-1 CDK5- dTAG clone 1 (N1) ( d ) and RPE-1 CDK5- dTAG clone 4 (N4) ( e ) treated with DMSO or dTAG-13 for 2 h prior to and upon release from G2/M arrest and fixed at 120 min after release (top panel); quantification of CDK5 total intensity per cell (lower panels). Data represent mean ± s.d. of at least two independent experiments from n = 100 cells each condition. p- values were determined by unpaired, two-tailed student’s t-test. f , Immunoblots showing level of indicated proteins in RPE-1 CDK5- dTAG cells. Cells were treated with either DMSO or dTAG-13 for 2 h prior to and upon release from RO-3306 and lysed at 60 min following release (upper panel). Quantification of the relative intensity of PP4R3β phosphorylation at S840 in dTAG13-treated CDK5- dTAG cells compared to DMSO-treatment (lower panel). Data represent mean ± s.d. of four independent experiments. p -value was determined by one sample t and Wilcoxon test. g , Experimental scheme for specific and temporal abrogation of CDK5 in RPE-1 CDK5- dTAG cells. h , Hoechst staining showing primary nuclei and micronuclei of RPE-1 CDK5- dTAG with indicated treatment; scale bar is as indicated (left panel). Right, quantification of the percentage of cells with micronuclei after treatment. Data represent mean ± s.d. of three independent experiments from n = 2094 DMSO and n = 2095 dTAG-13, where n is the number of cells. p- values were determined by unpaired, two-tailed student’s t-test. Scale bar is as indicated. Uncropped gel images are provided in Supplementary Fig. 1 .

Extended Data Fig. 3 CDK5 abrogation render chromosome alignment and segregation defect despite intact spindle assembly checkpoint and timely mitotic duration.

a and b , Live-cell imaging snapshots of RPE-1 CDK5- as cells ( a ) and RPE-1 CDK5- dTAG cells ( b ) expressing mCherry-H2B and GFP-α-tubulin, abrogated of CDK5 by treatment with 1NM-PP1 or dTAG-13, respectively. Imaging commenced in prophase following release from RO-3306 into fresh media containing indicated chemicals (left); quantification of the percentage of cells with abnormal nuclear morphology (right). c and d , Representative snapshots of the final frame prior to metaphase-to-anaphase transition from a live-cell imaging experiment detailing chromosome alignment at the metaphase plate of RPE- CDK5- as (c) and RPE-1 CDK5- dTAG ( d ) expressing mCherry-H2B, and GFP-α-tubulin (left); quantification of the percentage of cells displaying abnormal chromosome alignment following indicated treatments (top right). e , Representative images showing the range of depolymerization outcomes (low polymers, high polymers and spindle-like) in DMSO- and 1NM-PP1-treated cells, as shown in Fig. 2e , from n = 50 for each condition, where n is number of metaphase cells . f , Quantifications of mitotic duration from nuclear envelope breakdown (NEBD) to anaphase onset of RPE-1 CDK5- as (left ) and RPE-1 CDK5- dTAG (right) cells, following the indicated treatments. Live-cell imaging of RPE-1 CDK5- as and RPE-1 CDK5- dTAG cells expressing mCherry-H2B and GFP-BAF commenced following release from RO-3306 arrest into fresh media containing DMSO or 1NM-PP1 or dTAG-13. g , Quantifications of the percentage of RPE-1 CDK5- as (left) and RPE-1 CDK5- dTAG (right) cells that were arrested in mitosis following the indicated treatments. Imaging commenced in prophase cells as described in a , following release from RO-3306 into fresh media in the presence or absence nocodazole as indicated. The data in a, c , and g represent mean ± s.d. of at least two independent experiments from n = 85 DMSO and n = 78 1NM-PP1 in a and c ; from n = 40 cells for each treatment condition in g . The data in b , d , and f represent mean ± s.d. of three independent experiments from n = 57 DMSO and n = 64 dTAG-13 in b and d ; from n = 78 DMSO and n = 64 1NM-PP1; n = 59 DMSO and n = 60 dTAG-13, in f , where n is the number of cells. p- values were determined by unpaired, two-tailed student’s t-test. Scale bar is as indicated.

Extended Data Fig. 4 CDK5 and CDK1 regulate tubulin dynamics.

a, b , Immunostaining of RPE-1 cells with antibodies against CDK1 and α-tubulin ( a ); and CDK5 and α-tubulin ( b ) at indicated stages of mitosis. c, d , Manders’ overlap coefficient M1 (CDK1 versus CDK5 on α-tubulin) ( c ); and M2 (α-tubulin on CDK1 versus CDK5) ( d ) at indicated phases of mitosis in cells shown in a and b . The data represent mean ± s.d. of at least two independent experiments from n = 25 cells in each mitotic stage. p- values were determined by unpaired, two-tailed student’s t-test.

Extended Data Fig. 5 Phosphoprotoemics analysis to identify mitotic CDK5 substrates.

a , Scheme of cell synchronization for phosphoproteomics: RPE-1 CDK5- as cells were arrested at G2/M by treatment with RO-3306 for 16 h. The cells were treated with 1NM-PP1 to initiate CDK5 inhibition. 2 h post-treatment, cells were released from G2/M arrest into fresh media with or without 1NM-PP1 to proceed through mitosis with or without continuing inhibition of CDK5. Cells were collected at 60 min post-release from RO-3306 for lysis. b , Schematic for phosphoproteomics-based identification of putative CDK5 substrates. c , Gene ontology analysis of proteins harbouring CDK5 inhibition-induced up-regulated phosphosites. d , Table indicating phospho-site of proteins that are down-regulated as result of CDK5 inhibition. e , Table indicating the likely kinases to phosphorylate the indicated phosphosites of the protein, as predicted by Scansite 4 66 . Divergent score denotes the extent by which phosphosite diverge from known kinase substrate recognition motif, hence higher divergent score indicating the corresponding kinase is less likely the kinase to phosphorylate the phosphosite.

Extended Data Fig. 6 Cyclin B1 is a mitotic co-factor of CDK5 and of CDK1.

a , Endogenous CDK5 was immunoprecipitated from RPE-1 cells collected at time points corresponding to the indicated cell cycle stage. Cell lysate input and elution of immunoprecipitation were immunoblotted by antibodies against the indicated proteins. RPE-1 cells were synchronized to G2 by RO-3306 treatment for 16 h and to prometaphase (M) by nocodazole treatment for 6 h. Asynch: Asynchronous. Uncropped gel images are provided in Supplementary Fig. 1 . b , Immunostaining of RPE-1 cells with antibodies against the indicated proteins at indicated mitotic stages (upper panels). Manders’ overlap coefficient M1 (Cyclin B1 on CDK1) and M2 (CDK1 on Cyclin B1) at indicated mitotic stages for in cells shown in b (lower panels). The data represent mean ± s.d. of at least two independent experiments from n = 25 mitotic cells in each mitotic stage. p- values were determined by unpaired, two-tailed student’s t-test. c , Table listing common proteins as putative targets of CDK5, uncovered from the phosphoproteomics anlaysis of down-regulated phosphoproteins upon CDK5 inhibition (Fig. 3 and Supplementary Table 1 ), and those of cyclin B1, uncovered from phosphoproteomics analysis of down-regulated phospho-proteins upon cyclin B1 degradation (Fig. 6 and Table EV2 in Hegarat et al. EMBO J. 2020). Proteins relevant to mitotic functions are highlighted in red.

Extended Data Fig. 7 Structural prediction and analyses of the CDK5-cyclin B1 complex.

a , Predicted alignment error (PAE) plots of the top five AlphaFold2 (AF2)-predicted models of CDK5-cyclin B1 (top row) and CDK1-cyclin B1 (bottom row) complexes, ranked by interface-predicted template (iPTM) scores. b , AlphaFold2-Multimer-predicted structure of the CDK5-cyclin B1 complex. c , Structural comparison of CDK-cyclin complexes. Left most panel: Structural-overlay of AF2 model of CDK5-cyclin B1 and crystal structure of phospho-CDK2-cyclin A3-substrate complex (PDB ID: 1QMZ ). The zoomed-in view of the activation loops of CDK5 and CDK2 is shown in the inset. V163 (in CDK5), V164 (in CDK2) and Proline at +1 position in the substrates are indicated with arrows. Middle panel: Structural-overlay of AF2 model of CDK5-cyclin B1 and crystal structure of CDK1-cyclin B1-Cks2 complex (PDB ID: 4YC3 ). The zoomed-in view of the activation loops of CDK5 and CDK1 is shown in the inset. Cks2 has been removed from the structure for clarity. Right most panel: structural-overlay of AF2 models of CDK5-cyclin B1 and CDK1-cyclin B1 complex. The zoomed view of the activation loops of CDK5 and CDK1 is shown in the inset. d , Secondary structure elements of CDK5, cyclin B1 and p25. The protein sequences, labelled based on the structural models, are generated by PSPript for CDK5 (AF2 model) ( i ), cyclin B1 (AF2 model) ( ii ) and p25 (PDB ID: 3O0G ) ( iii ). Structural elements ( α , β , η ) are defined by default settings in the program. Key loops highlighted in Fig. 4d are mapped onto the corresponding sequence.

Extended Data Fig. 8 Phosphorylation of CDK5 S159 is required for kinase activity and mitotic fidelity.

a , Structure of the CDK5-p25 complex (PDB ID: 1h41 ). CDK5 (blue) interacts with p25 (yellow). Serine 159 (S159, magenta) is in the T-loop. b , Sequence alignment of CDK5 and CDK1 shows that S159 in CDK5 is the analogous phosphosite as that of T161 in CDK1 for T-loop activation. Sequence alignment was performed by CLC Sequence Viewer ( https://www.qiagenbioinformatics.com/products/clc-sequence-viewer/ ). c , Immunoblots of indicated proteins in nocodazole-arrested mitotic (M) and asynchronous (Asy) HeLa cell lysate. d , Myc-His-tagged CDK5 S159 variants expressed in RPE-1 CDK5- as cells were immunoprecipitated from nocodazole-arrested mitotic lysate by Myc-agarose. Input from cell lysate and elution from immunoprecipitation were immunoblotted with antibodies against indicated protein. EV= empty vector. In vitro kinase activity assay of the indicated immunoprecipitated complex shown on the right panel. Data represent mean ± s.d. of four independent experiments. p -values were determined by unpaired two-tailed student’s t-test. e , Immunoblots showing RPE-1 FLAG-CDK5- as cells stably expressing Myc-His-tagged CDK5 WT and S159A, which were used in live-cell imaging and immunofluorescence experiments to characterize chromosome alignment and spindle architecture during mitosis, following inhibition of CDK5- as by 1NM-PP1, such that only the Myc-His-tagged CDK5 WT and S159A are not inhibited. Representative results are shown from three independent repeats. f , Hoechst staining showing nuclear morphology of RPE-1 CDK5- as cells expressing indicated CDK5 S159 variants following treatment with either DMSO or 1NMP-PP1 and fixation at 120 min post-release from RO-3306-induced arrest (upper panel); quantification of nuclear circularity and solidity (lower panels) g , Snapshots of live-cell imaging RPE-1 CDK5- as cells expressing indicated CDK5 S159 variant, mCherry-H2B, and GFP-α-tubulin, after release from RO-3306-induced arrest at G2/M, treated with 1NM-PP1 2 h prior to and upon after release from G2/M arrest (upper panel); quantification of cells displaying abnormal chromosome alignment in (lower panel). Representative images are shown from two independent experiments, n = 30 cells each cell line. h , Representative images of RPE-1 CDK5- as cells expressing indicated CDK5 S159 variants in metaphase, treated with DMSO or 1NM-PP1 for 2 h prior to and upon release from RO-3306-induced arrest, and then released into media containing 20 µM proTAME for 2 h, fixed and stained with tubulin and DAPI (upper panel); metaphase plate width and spindle length measurements for these representative cells were shown in the table on right; quantification of metaphase plate width and spindle length following the indicated treatments (lower panel). Data in f and h represent mean ± s.d. of at least two independent experiments from n = 486 WT, n = 561 S159A, and n = 401 EV, where n is the number of cells in f ; from n = 65 WT, n = 64 S159A, and n = 67 EV, where n is the number of cells in h . Scale bar is as indicated. Uncropped gel images are provided in Supplementary Fig. 1 .

Extended Data Fig. 9 The CDK5 co-factor-binding helix regulates CDK5 kinase activity.

a , Structure of the CDK5-p25 complex (PDB ID: 1h41 ). CDK5 (blue) interacts with p25 (yellow) at the PSSALRE helix (green). Serine 46 (S46, red) is in the PSSALRE helix. Serine 159 (S159, magenta) is in the T-loop. b , Sequence alignment of CDK5 and CDK1 shows that S46 is conserved in CDK1 and CDK5. Sequence alignment was performed by CLC Sequence Viewer ( https://www.qiagenbioinformatics.com/products/clc-sequence-viewer/ ). c , Immunoblots of CDK5 immunoprecipitation from lysate of E. coli BL21 (DE3) expressing His-tagged human CDK5 WT or CDK5 S46D, mixed with lysate of E. coli BL21 (DE3) expressing His-tagged human cyclin B1. Immunoprecipitated CDK5 alone or in the indicated complex were used in kinase activity assay, shown in Fig. 5b . Representative results are shown from three independent repeats. d , Immunoblots showing RPE-1 FLAG-CDK5- as cells stably expressing Myc-His-tagged CDK5 S46 phospho-variants, which were used in live-cell imaging and immunofluorescence experiments to characterize chromosome alignment and spindle architecture during mitosis, following inhibition of CDK5- as by 1NM-PP1, such that only the Myc-His-tagged CDK5 S46 phospho-variants are not inhibited. Representative results are shown from three independent repeats. e , Immunostaining of RPE-1 CDK5- as cells expressing Myc-His-tagged CDK5 WT or S46D with anti-PP4R3β S840 (pS840) antibody following indicated treatment (DMSO vs 1NM-PP1). Scale bar is as indicated (left). Normalized intensity level of PP4R3β S840 phosphorylation (right). Data represent mean ± s.d. of at least two independent experiments from n = 40 WT and n = 55 S46D, where n is the number of metaphase cells. p- values were determined by unpaired two-tailed student’s t-test. f , Immunoblots showing level of indicated proteins in RPE-1 CDK5- as cells expressing Myc-His-tagged CDK5 WT or S46D. Cells were treated with either DMSO or 1NM-PP1 for 2 h prior to and upon release from RO-3306 and collected and lysed at 60 min following release (left). Quantification of the intensity of PP4R3β phosphorylation at S840 (right). Data represent mean ± s.d. of four independent experiments. p -values were determined by two-tailed one sample t and Wilcoxon test. g , Representative snapshots of live-cell imaging of RPE-1 CDK5- as cells harbouring indicated CDK5 S46 variants expressing mCherry-H2B and GFP-α-tubulin, treated with 1NM-PP1, as shown in Fig. 5d , from n = 35 cells. Imaging commenced in prophase following release from RO-3306 into fresh media containing indicated chemicals. Uncropped gel images are provided in Supplementary Fig. 1 .

Extended Data Fig. 10 Localization of CDK5 S46 phospho-variants.

Immunostaining of RPE-1 CDK5- as cells stably expressing Myc-His CDK5-WT ( a ), S46A ( b ), and S46D ( c ) with antibodies against indicated protein in prophase, prometaphase, and metaphase. Data represent at least two independent experiments from n = 25 cells of each condition in each mitotic stage.

Extended Data Fig. 11 RPE-1 harbouring CDK5- as introduced by CRISPR-mediated knock-in recapitulates chromosome mis-segregation defects observed in RPE-1 overexpressing CDK5- as upon inhibition of CDK5- as by 1NM-PP1 treatment.

a , Chromatogram showing RPE-1 that harbours the homozygous CDK5- as mutation F80G introduced by CRISPR-mediated knock-in (lower panel), replacing endogenous WT CDK5 (upper panel). b , Immunoblots showing level of CDK5 expressed in parental RPE-1 and RPE-1 that harbours CDK5- as F80G mutation in place of endogenous CDK5. c , Representative images of CDK5- as knocked-in RPE-1 cells exhibiting lagging chromosomes following indicated treatments. d , Quantification of percentage of cells exhibiting lagging chromosomes following indicated treatments shown in (c). Data represent mean ± s.d. of three independent experiments from n = 252 DMSO, n = 220 1NM-PP1, where n is the number of cells. p -value was determined by two-tailed Mann Whitney U test.

Extended Data Fig. 12 CDK5 is highly expressed in post-mitotic neurons and overexpressed in cancers.

a , CDK5 RNAseq expression in tumours (left) with matched normal tissues (right). The data are analysed using 22 TCGA projects. Note that CDK5 expression is higher in many cancers compared to the matched normal tissues. BLCA, urothelial bladder carcinoma; BRCA, breast invasive carcinoma; CESC cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; THYM, thymoma; and UCEC, uterine corpus endometrial carcinoma. p -value was determined by two-sided Student’s t-test. ****: p <= 0.0001; ***: p <= 0.001; **: p <= 0.01; *: p <= 0.05; ns: not significant, p  > 0.05. b , Scatter plots showing cells of indicated cancer types that are more dependent on CDK5 and less dependent on CDK1. Each dot represents a cancer cell line. The RNAi dependency data (in DEMETER2) for CDK5 and CDK1 were obtained from the Dependency Map ( depmap.org ). The slope line represents a simple linear regression analysis for the indicated cancer type. The four indicated cancer types (Head/Neck, Ovary, CNS/Brain, and Bowel) showed a trend of more negative CDK5 RNAi effect scores (indicative of more dependency) with increasing CDK1 RNAi effect scores (indicative of less dependency). The p value represents the significance of the correlation computed from a simple linear regression analysis of the data. Red circle highlights the subset of the cells that are relatively less dependent on CDK1 but more dependent on CDK5. c , Scatter plots showing bowel cancer cells that expresses CDK5 while being less dependent on CDK1. Each dot represents a cancer cell line. The data on gene effect of CDK1 CRISPR and CDK5 mRNA level were obtained from the Dependency Map ( depmap.org ). The slope line represents a simple linear regression analysis. Red circle highlights the subset of cells that are relatively less dependent on CDK1 but expresses higher level of CDK5. For b and c , solid line represents the best-fit line from simple linear regression using GraphPad Prism. Dashed lines represent 95% confidence bands of the best-fit line. p -value is determined by the F test testing the null hypothesis that the slope is zero. d , Scatter plots showing rapidly dividing cells of indicated cancer types that are more dependent on CDK5 and less dependent on CDK1. Each dots represents a cancer cell line. The doubling time data on the x-axis were obtained from the Cell Model Passports ( cellmodelpassports.sanger.ac.uk ). The RNAi dependency data (in DEMETER2) for CDK5, or CDK1, on the y-axis were obtained from the Dependency Map ( depmap.org ). Only cell lines with doubling time of less than 72 h are displayed and included for analysis. Each slope line represents a simple linear regression analysis for each cancer type. The indicated three cancer types were analysed and displayed because they showed a trend of faster proliferation rate (lower doubling time) with more negative CDK5 RNAi effect (more dependency) but increasing CDK1 RNAi effect (less dependency) scores. The p value represents the significance of the association of the three cancer types combined, computed from a multiple linear regression analysis of the combined data, using cancer type as a covariate. Red circle depicts subset of fast dividing cells that are relatively more dependent on CDK5 (left) and less dependent on CDK1 (right). Solid lines represent the best-fit lines from individual simple linear regressions using GraphPad Prism. p -value is for the test with the null hypothesis that the effect of the doubling time is zero from the multiple linear regression RNAi ~ Intercept + Doubling Time (hours) + Lineage.

Supplementary information

Supplementary figure 1.

Full scanned images of all western blots.

Reporting Summary

Peer review file, supplementary table 1.

Phosphosite changes in 1NM-PP1-treated cells versus DMSO-treated controls as measured by LC–MS/MS.

Supplementary Table 2

Global protein changes in 1NM-PP1-treated cells versus DMSO-treated controls as measured by LC–MS/MS.

Supplementary Video 1

RPE-1 CDK5(as) cell after DMSO treatment, ×100 imaging.

Supplementary Video 2

RPE-1 CDK5(as) cell after 1NM-PP1 treatment (example 1), ×100 imaging.

Supplementary Video 3

RPE-1 CDK5(as) cell after 1NM-PP1 treatment (example 2), ×100 imaging.

Supplementary Video 4

RPE-1 CDK5(dTAG) cell after DMSO treatment, ×100 imaging.

Supplementary Video 5

RPE-1 CDK5(dTAG) cell after dTAG-13 treatment (example 1), ×100 imaging.

Supplementary Video 6

RPE-1 CDK5(dTAG) cell after dTAG-13 treatment (example 2) ×100 imaging.

Supplementary Video 7

RPE-1 CDK5(as) cells expressing MYC-CDK5(WT) after 1NM-PP1 treatment, ×20 imaging.

Supplementary Video 8

RPE-1 CDK5(as) cells expressing MYC-EV after 1NM-PP1 treatment, ×20 imaging.

Supplementary Video 9

RPE-1 CDK5(as) cells expressing MYC-CDK5(S159A) after 1NM-PP1 treatment (example 1), ×20 imaging.

Supplementary Video 10

RPE-1 CDK5(as) cells expressing MYC-CDK5(S159A) after 1NM-PP1 treatment (example 2), ×20 imaging.

Supplementary Video 11

RPE-1 CDK5(as) cells expressing MYC-CDK5(WT) after 1NM-PP1 treatment, ×100 imaging.

Supplementary Video 12

RPE-1 CDK5(as) cells expressing MYC-CDK5(S46A) after 1NM-PP1 treatment (example 1), ×100 imaging.

Supplementary Video 13

RPE-1 CDK5(as) cells expressing MYC-CDK5(S46A) after 1NM-PP1 treatment (example 2), ×100 imaging.

Supplementary Video 14

RPE-1 CDK5(as) cells expressing MYC-CDK5(S46D) after 1NM-PP1 treatment (example 1), ×100 imaging.

Supplementary Video 15

RPE-1 CDK5(as) cells expressing MYC-CDK5(S46D) after 1NM-PP1 treatment (example 2), ×100 imaging.

Supplementary Video 16

RPE-1 CDK5(as) cells expressing MYC-EV after 1NM-PP1 treatment,×100 imaging.

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Zheng, XF., Sarkar, A., Lotana, H. et al. CDK5–cyclin B1 regulates mitotic fidelity. Nature (2024). https://doi.org/10.1038/s41586-024-07888-x

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Pilihan Obat Pilek untuk Dewasa

• Rhinos SR 10 Kapsul
• Intunal F 10 Tablet
• Panadol Cold & Flu 10 Kaplet
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Rekomendasi obat flu dan pilek selanjutnya adalah Panadol Cold & Flu 10 Kaplet. Obat ini memiliki paracetamol, pseudoephedrine HCI, dan dextromethorphan HBr di dalamnya, sehingga dapat meredakan gejala flu seperti batuk tidak berdahak, demam, sakit kepala, dan hidung tersumbat. 

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Kamu juga bisa memilih obat flu dan pilek lainnya untuk dewasa, seperti  Anadex 10 Kaplet.

Anadex adalah obat flu dan pilek yang ampuh dengan kandungan paracetamol, Dextromethorphan HBr, Chlorpheniramine maleat, dan Phenylpropanolamin HCl.

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Demacolin 10 Tablet mengandung paracetamol, pseudoephedrine HCl, dan chlorpheniramine maleat. Mekanisme masing-masing obat adalah, parasetamol sebagai antipiretik dan analgesik. Sedangkan pseudoephedrine HCl sebagai dekongestan dan chlorpheniramine maleat sebagai antihistamin.

Kombinasi dari 3 senyawa di atas dapat membuat pilek dan flu kamu lebih cepat sembuh. Obat ini juga dapat menyembuhkan pilek dan flu yang disertai sakit kepala dan demam. 

Berikut adalah aturan dosis yang dapat diminum oleh anak-anak dan dewasa:

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Sebab, obat ini mengandung parasetamol sebagai penurun panas, dextromethorphan sebagai antitusif (batuk kering),  Chlorpheniramin maleat sebagai antihistamin, dan Phenylpropanolamin HCl sebagai dekongestan.

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Dosis pemberiannya antara lain:

• Dewasa dan anak usia di atas 12 tahun: 1 kaplet sebanyak 3 kali sehari.
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Kandungannya antara lain pseudoephedrin dan triprolidine. Pseudoefedrin bekerja sebagai dekongestan untuk meringankan hidung tersumbat. Sedangkan, triprolidine sebagai antagonis kompetitif untuk reseptor histamin H1 yang dapat meringankan gejala alergi yang ditimbulkan. 

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• Dewasa dan anak di atas 12 tahun: 1 sendok takar (5 ml) 3 kali sehari.
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   EXPERIMENT. AIM: To discover how various common liquids, that we consume, affect how Panadols dissolve. Hypothesis: By placing the Panadol in more acidic drinks, such as coke and juices, the quicker the panadol will dissolve. The faster the tablet dissolves, the quicker it can be observed through the stomach lining and into the bloodstream.

4. Paracetamol a curriculum resource

   Dissolve 0.3 g of a mixture containing paracetamol n a mixture of water (I o cm3) and 1 rnol dm-3 sulfuric acid (30 cm'). Boil under reflux for 1 hour, cool and dilute with water (I00 cm').

5. Dissolution of paracetamol tablets

   Water Tablet Compare the rates of dissolution of various paracetamol formulations, such as capsules and dispersible ('soluble') paracetamol. Repeat the experiment using buffer solutions that reflect pH values found in the gastrointestinal tract instead of water.

6. PDF The Royal Society of Chemistry

   The Royal Society of Chemistry

7. DISSOLUTION STUDIES OF PARACETAMOL COMMERCIAL TABLETS

   Dissolution study procedure: 1. Switch the heater of the dissolution device on and manage the temperature to reach 37C. 2. Wash the vessel (of dissolution apparatus) using water and soap then put ...

8. Results and Observations

   49min 48sec | The tablet had immediately sunk to the bottom of the cup, throughout the process of dissolving it stayed at the bottom. It broke away slowly with flakes of the Panadol surrounding the Panadol in a circle while the Panadol was in the centre of the cup. Gatorade (Refrigerated) 51min 36sec | The tablet had reacted in the same way as when placed in refrigerated water, but with the ...

9. Paracetamol synthesis

   Experimental procedure DANGER! "Carry out all experiments in fume cupboard". A) Nitration of phenol: synthesis of p-nitrophenol To a 250 ml flask, cooled with an ice bath, 15 g of sodium nitrate and 40 ml of water are added. The mixture is stirred until the solid is completely dissolved, and then 25 g (13.6 ml) of concentrated H 2 SO 4 is added little by little. Then, 9.4 g of phenol are ...

10. PDF Panadol Solubility at Body Temperature Hypothesis: Equipment

    Aim: to compare the solubility of various forms of Panadol at body temperature. Hypothesis: Slow relief will take the longest to dissolve and fast relief will dissolve the quickest.

11. Solubility of Paracetamol in Pure Solvents

    The solubility of paracetamol (4-hydroxyacetanilide) in 26 solvents in the temperature range from −5 to +30 °C is reported. Paracetamol has a very low solubility in nonpolar and chlorinated hydrocarbons such as toluene and carbon tetrachloride whereas the solubility is very high in solvents of medium polarity such as N,N-dimethylformamide, dimethyl sulfoxide, and diethylamine. Paracetamol ...

12. PDF Microsoft Word

    Furthermore, water and dichloromethane are immiscible. Therefore, the aspirin and caffeine in the filtrate can be separated by extraction either with acid, which will remove the caffeine as a water-soluble salt, or by extraction with base, which will remove the aspirin as a water-soluble salt. The latter procedure will be used in this experiment.

13. Carbonation Countdown: The Effect of Temperature on Reaction Time

    To take the tablets, they're fully dissolved in water, where they famously undergo a chemical reaction that produces lots of carbon dioxide bubbles—or fizz. Why is this?

14. Pill Dissolving Demo

    In a class demonstration, the teacher places different pill types ("chalk" pill, gel pill, and gel tablet) into separate glass beakers of vinegar, representing human stomach acid. After 20-30 minutes, the pills dissolve. Students observe which dissolve the fastest, and discuss the remnants of the various pills. What they learn contributes to their ongoing objective to answer the challenge ...

15. Method

    The independent variable in my experiment is the type of painkiller tablet. My investigation's range of tablets are Panadol, Panadol Rapid, Nurofen, Nurofen Zavance, and Advil. The dependant variable in my experiment is the time that it takes for the painkiller tablet to dissolve in water. This is what I am testing in my experiment.

16. The Effect of Temperature on the Rate of Dissolving.

    The purpose of this project is to learn how temperature affects the rate of dissolving of a certain solid in a certain liquid. More specifically I will examine the effect of temperature on the rate in which table salt or rock salt dissolves in water. Similar procedures can be used to determine the effect of temperature on the rate of dissolving ...

17. Dissolution rates of over-the-counter painkillers: a ...

    Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia.

18. PDF Introduction Activity Explain It With Atoms & Molecules

    erence in the energy of the molecules.DEMONSTRATION6. Your teacher showed you an activity comparing the amount of salt that can dissolve in hot and cold water and the. mount of sugar that can dissolve in hot and cold water. Just like in your. M&M experiment, much more sugar dissolved in hot water. Does much more s.

19. Panadol in Different Temperatures by Felivic Aserios on Prezi

    Panadol in different temperatures Title, Aim and Hypothesis Title Result Graph Aim Panadol in different temperatures To investigate wheter colder or warmer temperature of water would dissolve the panadol the fastest. Hypothesis Hot water will dissolve the panadol in the shortest

20. Dissolving time of Panadol tablets by ella parsons on Prezi

    Dissolving time of Panadol tablets Introduction and Background research Introduction In this experiment, I will be testing the effectiveness of different Panadol tablets. Panadol tablets do not contain any ibuprofen and only contain paracetamol. Panadol is a pain relief tablet

21. Panadol Extra Soluble Tablets

    How to use Panadol Extra Soluble tablets Panadol Extra Soluble tablets are easy to use. Simply dissolve the tablet (s) in at least half a glass of water and drink. See dosage instructions above, or consult the product label to determine the appropriate dosage for you.

22. Paracetamol

    Paracetamol (acetaminophen [a]) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. [13] [14] [15] It is a widely used over the counter medication.Common brand names include Tylenol and Panadol.. At a standard dose, paracetamol only slightly reduces fever; [14] [16] [17] it is inferior to ibuprofen in that respect, [18] and the benefits of its use for ...

23. Transient overturning changes cause an upper-ocean nutrient ...

    A total of four experiments were carried out using the ocean-biogeochemical model: "Control", "Wind", "Buoyancy", and "4×CO 2 ". In "Control", both surface wind and buoyancy ...

24. Structure and Dynamics of Water in Polysaccharide (Alginate) Solutions

    In both biological and engineered systems, polysaccharides offer a means of establishing structural stiffness without altering the availability of water. Notable examples include the extracellular matrix of prokaryotes and eukaryotes, artificial skin grafts, drug delivery materials, and gels for water harvesting. Proper design and modeling of these systems require detailed understanding of the ...

25. CDK5-cyclin B1 regulates mitotic fidelity

    Data in f and h represent mean ± s.d. of at least two independent experiments from n = 486 WT, n = 561 S159A, and n = 401 EV, where n is the number of cells in f; from n = 65 WT, n = 64 S159A ...

26. Ini Rekomendasi Obat Flu dan Pilek Dewasa yang Paling Ampuh

    Panadol Cold & Flu 10 Kaplet. Rekomendasi obat flu dan pilek selanjutnya adalah Panadol Cold & Flu 10 Kaplet. Obat ini memiliki paracetamol, pseudoephedrine HCI, dan dextromethorphan HBr di dalamnya, sehingga dapat meredakan gejala flu seperti batuk tidak berdahak, demam, sakit kepala, dan hidung tersumbat.

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