DC Quantum - Volume 3

Illustrated by Maha Nawaz

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The Psychology Behind Mental Disorders condition that changes a person's thinking, feelings, or behaviour (or all three) which causes the person feelings of distress and difficulty in functioning. As with many diseases, mental illnesses are severe in some cases and mild in others - individuals who have a mental illness don't necessarily look like they are ill, especially if their disorder is vaguer. Other individuals may show more explicit symptoms such as confusion, agitation, or withdrawal.

Diagnosing mental illness is not the same as diagnosing other chronic diseases. For instance, heart disease is identified with the help of blood tests and electrocardiograms, however, diabetes, for example, is diagnosed by measuring blood glucose levels. But classifying mental illness is a more subjective endeavour. No blood tests exist for depression; no X-ray can identify a child at risk of developing a bipolar disorder; etc. On account of the new tools in genetics and neuroimaging, scientists are making progress toward deciphering the details of the underlying psychology behind mental disorders. Yet experts continue to disagree on how far we can push this biological model.

Are mental illnesses simply physical diseases that happen to strike the brain? Or do these disorders simply belong to a class all their own?

Attention Deficit-Hyperactivity Disorder: Commonly known as ADHD, it is one of the most common neurodevelopmental disorders of childhood. It is typically first diagnosed at childhood and often lasts into adulthood.

People with ADHD tend to have trouble paying attention, controlling impulsive behaviours (may act impetuously) or be overly hyperactive. Signs and symptoms can also include excessive daydreaming, zoning out, fidgeting, speaking quickly, and many more, however each symptoms’ extremity can vary from person to person. There are three main types of ADHD:

We have all had some exposure to mental illness, but many of our preconceptions about it

· Predominantly Inattentive Presentation – previously known as ADD, in this case, it is usually difficult for the individual to organize or complete a task, pay attention to details, and stay focused, particularly during conversations. · Predominantly Hyperactive Presentation – here, the person is inclined to fidget and talk a lot and finds it wearisome to sit still for long periods of time. The individual can archetypally feel like they have endless

are misleading.

A mental disorder can be defined as a health

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reaction to fraught, hazardous, or unfamiliar situations. This illness usually manifests itself as an intense, excessive, and persistent

energy and has struggles to control impulsivity. · Combined Presentation – symptoms of both of the above two types are equally present in the person.

Scientists are researching the causes and risks in an attempt to find more efficient methods of reducing and managing the chances of developing ADHD. Current causes can include genetics and scientists are studying whether brain injury, alcohol, prematurity and exposure to environmental risks are factors.

ADHD is associated with abnormally low levels of the neurotransmitters transmitting between the prefrontal cortical area and the basal ganglia of the brain. Dysfunction of the prefrontal cortex results in a lack of alertness, shortened attention span, and decreased efficiency of working or short-term memory, difficulty in initiating and sustaining activities, and being unable to distinguish and avoid unnecessary or distracting activities.

Therefore, many ADHD individuals have diminished focus.

perturbation and fear. A certain level of anxiety is expected. For instance, you may feel agitated, distressed, or even have a feeling of dread a few moments before a significant event. However, anxiety disorders are different - when you’re living with an anxiety-based condition, the amount of worry and fear you feel might be completely debilitating. This is particularly true when there’s no trigger for your anxiety. When this happens, anxious brains function in a constant state of worry and fear. Not knowing what to do, your brain releases an influx of stress hormones.

Anxiety: Anxiety disorders are the most common type of mental illness in the United States. It can hyper-activate areas in your brain that detect and respond to threats. At the same time, anxiety could also hinder activity in parts of your brain that manage your reaction to fear and stress.

Anxiety isn’t stress, however; it’s your mind and body’s

#1. Excessive Stress Hormones Are Released · When you feel anxious, your body goes on alert, prompting your brain to prepare itself for flight or fight mode. In an attempt to assist you to cease whatever has made you anxious, your brain floods your central nervous system with adrenaline and cortisol.

These hormones inform your body that something daunting is about to happen. Their

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why people with anxiety tend to feel threatened more often than someone without such a disorder.

role is to help you cope with danger. In order to do that, they sharpen your senses and make increase your reflex speed. In a non-anxious brain, when the danger is gone, the sympathetic part of your nervous system takes over and calms you down. But when you suffer from anxiety, you might be unable to reach that state of serenity. Instead, the rush of stress hormones causes your brain to release even more stress hormones until you’re simply overwhelmed.

#3.

Anxiety Could Make It Difficult for Your Brain to Reason Rationally * Anxiety debilitates the connections between the amygdala and the prefrontal cortex When the amygdala alerts the brain to danger, the prefrontal cortex should supposedly kick in and help you come up with a rational and logical response. The prefrontal cortex ensures that you’re capable of processing information analytically and can make informed decisions, as well as aiding you in problem solving situations. In anxious brains, when the amygdala alerts the prefrontal cortex of danger, the connection is weak. Consequently, the cogent, problemsolving section of the brain is unheard, which can eventually lead to irrational and farfetched thoughts and erratic logic and behaviour.

#2. Anxiety Makes Your Brain Hyperactive to Threats * Anxiety can also result in your brain becoming hyperactive towards threats. When you deal with anxiety on a consistent basis, your amygdala, a tiny almond-shaped structure located in the limbic system, grows larger.

This is in the part of your brain that deals with emotions and moods; the amygdala could be considered a brain’s watchman - alert and on the lookout for any signs of danger or threats.

When the amygdala notices potential danger, it transmits signals to the hypothalamus, which triggers a fight or flight response. In the anxious brain, the amygdala is large and hypersensitive. As a result of this, the amygdala sends an excessive number of false alarms. One may even consider a hypersensitive amygdala as a watchman who cries wolf too often. An overactive amygdala sends false alarms so often that your brain senses threats even during potentially nonthreatening situations, which is

Obsessive-Compulsive Disorder: Obsessive-compulsive disorder (OCD) is a mental health condition which enables the brain to create repetitive worries and fears.

Also referred to as obsessions, these worries, fears, and repetitive thoughts often occur suddenly and are difficult to manage. In fact, most people with OCD feel like they can’t stop worrying or thinking about “bad things.”

Some of the most common OCD obsessions include: a need to have everything in a certain order; bad thoughts becoming a reality; fear of germs and contamination; and more. These obsessions trigger compulsions or behaviours that people with OCD feel compelled to do in order to feel safe from their fears and fix their

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· Medial surface on the superior frontal gyrus - gyri are the folds or bumps in the brain. The superior frontal gyrus helps regulate and mediate cognitive functions.

Having less grey matter in this part of the brain stops people with OCD from responding methodically to obsessive notions. Diminished grey matter in this region of the brain also averts the brain from suppressing impulsive responses and habits, making people with OCD feel like they must continue their compulsions.

worries. Compulsions can include counting things over and over again; arranging things in a particular or symmetrical way; checking and rechecking and erasing, rewriting, or redoing things, to name a few.

compulsive disorder is a result of communication problems in the brain.

However, scientists are now realizing that OCD disrupts communication between the frontal cortex and another part of the brain known as the ventral striatum. While the frontal cortex regulates problem-solving, the ventral striatum plays an important role in what motivates and mentally rewards us.

Usually, the ventral striatum and frontal cortex collaborate to solve our problems in a logical way that rewards us, motivating us to continue to make logical, rational decisions.

But OCD interrupts the communication between these two parts of the brain. Instead of working together to come up with a rational solution to the problem, OCD can trick the brain into thinking that compulsions and rituals will solve the problematic obsessive thoughts instead. While this only works temporarily, the ventral striatum motivates OCD sufferers to keep trying the rituals again and again.

· Orbitofrontal Cortex - the orbitofrontal cortex helps regulate your impulses and inhibition. When this gets damaged, you may know that your choices and behaviours are unnecessary and can be excessive, but you may still find yourself continuing to perform extortionate activities, like repeatedly checking doors and locks. The orbitofrontal cortex also interacts with the amygdala which aids in controlling bodily changes associated with emotion. Unfortunately, OCD hijacks this region of the brain, triggering excessive touching, tapping, and stepping in specific ways.

While there are several contributing factors to the effects of mental disorders, it is certainly agreeable that the brain plays a large factor in influencing the actions, thoughts and fears of a person with a mental illness. It is vital that we do not forget that these symptoms and effects can vary from person to person, depending on its severity and how each individual reacts in response. As of now, there is still no scientific way to diagnose mental illnesses, however, it is clear that different parts of brain do get affected, specific to each disorder. Will it simply just be a matter of time before more welldeveloped links are discovered?

· Serotonin - scientists know that most people with OCD have low serotonin levels.

Serotonin is a chemical messenger in the brain that helps regulate your mood and aggression levels. Usually, this keeps you calm, helps you sleep well, and causes you to feel at ease. However, when obsessivecompulsive disorder affects your serotonin levels, you may feel like you’re constantly on edge and that you can never really completely calm down. Being hyper-aware of your environment can also make you more susceptible to OCD compulsions such as exorbitantly washing your hands, counting, or organizing.

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References:

4.

1. News-Medical (2017). How does ADHD

International OCD Foundation.

(2017). International OCD Foundation |

Affect the Brain? [online] News-

What Causes OCD? [online] Available at:

Medical.net. Available at:

https://iocdf.org/about-ocd/what-causes-ocd/

https://www.news-medical.net/health/How-

[Accessed 27 Jun. 2022].

does-ADHD-Affect-the-Brain.aspx

5. Eske, J. (2022). Dopamine and serotonin:

[Accessed 27 Jun. 2022].

Brain chemicals explained. [online]

2. Nami.org. (2022). Anxiety Disorders |

Medicalnewstoday.com. Available at:

NAMI: National Alliance on Mental Illness.

https://www.medicalnewstoday.com/articles

[online] Available at:

/326090 [Accessed 27 Jun. 2022].

https://www.nami.org/About-Mental-

6.

Illness/Mental-Health-Conditions/Anxiety-

CDC (2021). What is ADHD? [online]

Disorders#:~:text=Anxiety%20disor

Centers for Disease Control and Prevention.

[Accessed 27 Jun. 2022].

Available at:

3. StoneRidge: Center for Brains. (2020). How

https://www.cdc.gov/ncbddd/adhd/facts.html

Does Anxiety Affect the Brain? 4 Major

#:~:text=ADHD%20is%20one%20of%20th

Effects of Anxiety. [online] Available at:

e,)%2C%20or%20be%20overly%20active.

https://pronghornpsych.com/how-does-

[Accessed 27 Jun. 2022].

anxiety-affect-the-

Ishana Khiara 9ACL

brain/#:~:text=Anxiety%20can%20hyper%2 Dactivate%20areas,can%20help%20manage %20anxiety%20disorders. [Accessed 27 Jun. 2022].

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learning algorithm that is used to predict the probability of a binary answer occurring. For example, a way in which a logistic regression model could be applied effectively to machine learning is to determine whether a person is obese or not, or if a person is infected with Covid-19 or not. In this project, we use a logistic regression model to predict whether the patient is likely to have a UTI or not likely to have one.

The use of Machine Learning in predicting Urinary Tract Infections and minimising the use of antibiotics.

Problem statement Urinary Tract Infections are infections caused by bacteria that enter the urethra and then infect the urinary tract. These bacteria may also travel upwards and infect the kidneys [1]. Furthermore, the excessive prescription of antibiotics is the driving force to why, in present day, antibiotic resistance is surging and becoming one of the world’s greatest problems with regards to healthcare.

Many studies have proven that doctors may prescribe antibiotics based on the symptoms without consulting the results of the urine bacterial cultures. While there are many current educational courses and regulations that aim to enhance this type of prescribing behaviour, this project focuses on using a ‘logistic regression model’, a machine learning algorithm, that uses patient’s history and data extracted from electronic health records, to detect these UTIs before the doctor can prescribe medicines and treat illnesses.

Figure 1 - Depicts a classic logistic regression model to determine whether people are likely to be obese or not.

Aim of the project This project revolves around developing and evaluating a machine learning model that will predict urinary tract infections for patients in outpatient care and to also minimise the prescription and use of antibiotics.

Understanding a logistic regression model Logical regression is a supervised machine

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reduced through this machine learning algorithm.

Pre-processing of the data Patients’ data from 2015 to 2021 in a large hospital with primary, secondary and tertiary care facilities was used to undertake this project. The dataset also included adult outpatient details with at least one result of a urine bacterial culture test.

For the input features that the logistic regression model will find patterns in, we pre-processed each of the patient’s vital signs (e.g., the heart rate, temperature, oxygen level etc.) as well as ICD-10 codes, which is a way physicians classify diagnoses and symptoms into categories, and data gathered from the patient’s previous hospital encounter. The output was defined as a binary label of 0s and 1s, which indicates whether the patient had a positive or negative urine culture test result. A positive UTI test result was classified if the concentration of the urine pathogen is higher than 10,000 colony forming units per millilitre (C FU/ml).

Conclusion Through this project, we used an optimised Machine Learning model that can decrease the number of false positives and reduce the unnecessary prescription of antibiotics. This project is deemed to be very important into the future of healthcare, considering the emergence of antibiotic resistance becoming a global threat, especially when dealing with Urinary Tract Infections.

Next steps Further improve the machine learning model by fine-tuning the hyperparameters of the model and get support to apply this in hospitals.

Project Team -

Farah E Shamout (Assistant Professor, Emerging Scholar of Computer Engineering at NYU Abu Dhabi) – Mentor and Project Lead.

- Zaki Almallah – Doctor advising on the health-related side of the project - Nasir Hayat, Terrence Lee St John, Phillip Wang, Vee Nis Ling, Lelan Orquiola, Vansh Gadhia – Project Members This project was selected as one of the best abstracts and offered a podium presentation for the Faculty of Clinical Informatics Scientific Conference happening in summer of 2022 in UK.

Division of the dataset and rationale The dataset was split randomly into a training set consisting of 70% of the data, a validation set, consisting of 10% of the data, and a test set, which contains the remaining 20% of previously unseen data the algorithm has never been exposed to before to determine the true accuracy of the model.

Results After applying the logistic regression model to the dataset and based on the accuracy, we found that 80% of patients who are truly positive were also predicted by the Machine Learning model to be positive for the urinary tract infection. In addition, out of the 1,518 patients the model predicted were not likely to contract the infection, 29 of these patients were prescribed antibiotics. Furthermore, out of these 29 patients, 12 of them had a negative urine culture test result. This shows how these 12 patients were unnecessarily given antibiotics which could have been

References [1] CDC. Urinary tract infection [Internet]. Centers for Disease Control and Prevention. 2022 [cited 2022 Jun 18].

Available from: http://cdc.gov/antibiotic-use/uti.html

Vansh Gadhia 11LRU

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and some believe it would be based on the length and width of the starting rectangle; however, there is much speculation regarding this.

The Mobius Strip The mathematics

The theory of the Möbius strip goes beyond the strip itself, applying to many objects in many ways.

The Möbius band is a manifold1 named after August Ferdinand Möbius (1790-1868), who was a German mathematician and theoretical astronomer who was the second to discover it in September 1858, also named the twisted cylinder and the Moebius strip.

Another German mathematician Johann Benedict Listing started the study of surfaces, which he named topology2, and concluded the properties of the Möbius strip in July 1858 before him, published in 1862.

This calculation might be critical for future technological developments, such as the description of graphene sheets when wrapped into carbon nanotubes, the shapes of leaves and chemical film, or understanding crumpling.

The Art

At first glance, the “optical illusion” might seem simple to us, but is a mystery which has baffled scientists, artists and mathematicians alike for centuries.

A real Möbius strip rarely occurs in nature (and where it does, it is unclear and cannot be manufactured).

It is often called an “impossible shape”, although similar models can be made where we live.

It is a one-sided and one-edged strip of material with length, width and depth/height, which can be made by twisting an odd number of times a two-sided and two-edged rectangle 180° and merging the two ends, and simultaneously the inner and outer surfaces, together, creating a curved surface. It is one of the examples of a 2D plane existing in a 3D space, and even when cut in parts with a line down the middle, the shape remains the same.

The Möbius strip is not oriental3. It is made from a surface mathematicians call “developable” and a surface with a boundary compared to a true surface, which means it can be flattened without changing its unaltered shape.

It is known that after the strip is made, it will try to return to a state in which it contains the minimum amount of elastic energy possible, much like an elastic band.

The immergence of the Möbius strip in art happened entirely independent of mathematics. Swiss artist Max Bill probably thought he had invented a new geometrical shape upon sculpting “Endless Ribbon” in 1936, which he said was designed to look like "flames rising from a fire".

Musicians’, writers’, and artists’ perception of the world have been transformed, creating an immerging culture of its own, with Möbius-themed music, art, architecture (e.g. rollercoasters) and merchandise (e.g. jewellry, conveyor belts, recording tapes, printer ribbons, computer print cartridges) included.

The Möbius strip is a door to possibility, and also a door to the end.

The Thoughts

The Möbius strip can remain a fun experiment and an impossible mystery. In philosophy, it serves as a reminder that no matter how far you travel and what path you choose, you will always end up where you started, sometimes in an unrecognisable way. But in this world, like all worlds, up is down, right is left, in is out and we are all just one part of the same messedup universe.

A map on a sphere or plane only needs four colours to be coloured so no bordering countries are the same colour, hence dubbed the four-colour theorem.

However, a Möbius strip requires six colours for this rule to function, adequately named the six-colour theorem.

The strip is critical in future work.

Many scientists have tried to solve for a dimensional equation of this strip using unpublished calculations,

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A space locally resembling a Euclidean space2 near points

2A

2D or 3D space representing physical space which follows the laws of Euclidean geometry3 3the study of geometric surfaces and planes assuming axioms and theorems are true 2 the study in which objects are assumed to be equivalent if they can be altered to change into the other 3 (For a 2D object in a 3D space): the ability to name directions on an object that won’t change after alterations of movement

Moebius Strip II – Woodcut by Maurits Cornelis Escher, 1964

Photo by Max Bill

“Endless Ribbon” –

A Möbius band

Mobius Arch - Image in the public domain in the United States References:

1.

Google Books. (2013). The Handy Math Answer Book. [online] Available at: https://books.google.ae/books?id=sgRlCwAAQBAJ&pg=PA211&lpg =PA211&dq=Did+M%C3%B6bius+publish+his+findings?&source=bl &ots=hMNtLkHyXi&sig=ACfU3U1oBpFIxYXz1uGpKVfq5lk0ybRt5Q& hl=en&sa=X&ved=2ahUKEwi59sf41tr3AhWxzIUKHVt8CU4Q6AF6BA gtEAM#v=onepage&q=Did%20M%C3%B6bius%20publish%20his%2 0findings%3F&f=false [Accessed 24 Jun. 2022].

2.

Nebus, J. (2020). My All 2020 Mathematics A to Z: Möbius Strip. [online] nebusresearch.

Available at: https://nebusresearch.wordpress.com/2020/09/09/my-all-2020mathematics-a-to-z-mbius-strip/ [Accessed 24 Jun. 2022].

3.

Wonderopolis.org. (2018). What Is a Möbius Strip? [online] Available at: https://wonderopolis.org/wonder/What-Is-aM%C3%B6bius--Strip [Accessed 24 Jun. 2022].

4.

COMSOL. (2019). Möbius Strips: Where Math Meets Art. [online] Available at: https://www.comsol.com/blogs/mobiusstrips-where-math-meets-art/ [Accessed 24 Jun. 2022].

If you imagine the arrows are connected, the recycling arrows form a Möbius strip

” Mobius Strip shimmers at night” – Photo by Steve Krave, TD: “What light through a single surface breaks” Tianyue Chen 8SGA

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In the 1920s, Werner Heisenberg gave rise to the idea that the act of a person measuring the position of the particle would cause the superposition to collapse and the particle to select a definite position to be in.

Unfortunately, no components of wave equations actually indicate that a collapse occurs. While some people have accepted the idea, many physicists remain sceptical. If quantum physics is the foundation for the whole universe, how could humans have an influential role in its outcomes? While it may have some flaws, the Collapse at Measurement Theory has led to the generation of other theories, including the idea of random, spontaneous collapses in the Ghirardi-Rimini-Weber model and collapses caused by gravity in the Diósi-Penrose Model.

The Quantum Border: Where do the worlds of Quantum and Classical Physics Meet?

The quantum realm exists. It has been proven by numerous experiments conducted by physicists over time. But if that’s true, why don’t we see it all the time? Why can’t we find ourselves in many places at once? If everything on a micro scale is intrinsically uncertain, why does our world seemingly follow the rigid rules of classical physics?

First, let’s delve into the basics of quantum physics. Imagine you have an orange and two crates: Crate A and Crate B. According to our classical understanding, a single orange can only be in one of the crates at once. However, if the orange was a particle like a photon, quantum rules dictate that it actually exists in both crates at once, in a superposition of Crates A and B and many other possibilities.

It is represented by equations called wave functions, with the amplitude at each peak being the probability of the orange being at that position.

Another idea, known as decoherence theory, suggests that the particle never leaves the state of being in superposition. The particle only appears to be fixed and certain to us because, in the real world, the wave functions are entangled with the environment in such a complex mesh of probability that, when we take a measurement, we can only perceive one strand of the intricate web. This strand is what we believe to be the ‘real’ position of the particle. However, if decoherence theory is true, why aren’t we ever able to see more than one part of the web of wave functions?

That’s all very well but we never see an orange in more than one place. Even on a micro scale, when a particle is measured by a scientist, all of its quantum possibilities seem to be reduced to one certain event, like the orange being found in Crate B in an experiment. It leaves the state of being in a superposition and is forced into the ‘normal’ realm. How does the minuscule world of quantum possibility make the jarring transition into the quotidian realm? The honest answer is we don’t know – yet.

One of the wildest theories is the ‘many worlds’ interpretation, argued by Hugh Everett in 1957. It goes hand-in-hand with the concept of the multiverse. Yes, the multiverse is actually something in physics - I haven’t just been watching too many marvel movies.

It’s a theory in Cosmology that considers whether our universe is singular or if it is only one of many universes that make up the multiverse. It suggests that there was a stage, early in the development of the cosmos, when it expanded at an exponential rate. During

There are many theories.

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this period of cosmic inflation, parts of the cosmos ended their expansion at different times to other regions, forming bubble universes. In other words, if the multiverse is a bowl full of soapy water, our universe is one of the bubbles.

How does Everett’s theory link to the multiverse? He believed that the particle stays in a state of superposition and is instead determined by the universes. The idea is that, for every time you find the orange in Crate B, the orange is found in Crate A in another universe so it’s never truly in a certain place.

Every measurement branches off with different outcomes in different universes.

There are many theories that seek to explain the dilemma of the border between quantum and classical physics, each one fascinating in its own way. However, the truth of the overlap remains a mystery. While this article tries to simplify the ideas, the actual nature of the quantum realm has many parts, related by complex formulae. Perhaps, in the future, we may be able to find a definitive answer. Who knows? You could be the next physicist to provide a theory.

References:

1. Ghirardi, G. C.; Rimini, A.; Weber, T. (1986). "Unified dynamics for microscopic and macroscopic systems" 2. Diósi, L. (1989). "Models for universal reduction of macroscopic quantum fluctuations" 3. Penrose, Roger (1996). "On Gravity's role in Quantum State Reduction".

Aleeza Ahmed 10LCA

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recover the faces from the compressed images: one decoder is used to recover each face.

Finally, the face swap is done by feeding encoded images into the “wrong” decoder – for example, Person A’s face is fed into the decoder trained for Person B. Therefore, the decoder reconstructs Person B’s face with the expressions and orientation of Person A. For videos, this process must be done on each frame to make the swap look convincing.

Deepfakes: Technology and Danger Behind Them • • •

What if you were able to take someone’s face and put it over yours?

What if you could take someone’s voice?

What if you could create the face of a person that doesn’t exist?

All these questions are answered by a form of technology that has become more relevant than ever over the past few years: deepfakes.

While this new software represents major advancements in AI technology, others see them as tools that could have dangerous ramifications in our current world where misinformation is more common than ever.

Furthermore, making fake faces is done using a GAN (Generative Adversarial Network). It pits two AI algorithms against each other – the first one, known as the generator, is fed random noise which it turns into an image.

The synthetic images created are then added to a stream of real images of people which are fed into the discriminator, the second algorithm, which improves the synthetic image made. This process is repeated countless times with feedback on performance so both algorithms improve over time. This leads to the synthetic image looking nothing like a face to looking hyperrealistic.

Firstly, let’s look at how deepfakes can be created using the first example of taking someone’s face, in this case swapping the faces of two celebrities: Person A and Person B. Firstly, several face shots of the two people are run through an encoder – an AI algorithm that compares the two faces to find

While most people may have seen deepfakes used harmlessly in memes, novelty mobile applications and Kendrick Lamar’s latest music video, they have become recognised recently due to their issues. Firstly, the ethics of deepfakes are questionable as they can involve using someone’s face or voice without their consent. A prime example of

similarities, reducing them to their shared common features and compressing the images. Then, algorithms called decoders are taught to

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me too. Even with the efforts to detect them, it will get harder to spot deepfakes because the technology is constantly improving. For instance, US researchers found out deepfake faces blink abnormally in 2018 as the photos fed into the algorithms showed people with their eyes open so blinking was never learnt.

However, blinking deepfakes appeared soon after the research was published. This demonstrates “the nature of the game” [4]: weaknesses are fixed as soon as they are revealed. So, can the deepfake community make their software undetectable? Can authorities and tech firms create a truly foolproof detection system before then? It’s still a tight race and I fear of what could happen if the developers take the lead.

this was when the makers of a documentary about the late chef Anthony Bourdain got into controversy for using a deepfake of his voice in the movie to read out letters he wrote.

However, other stories have proven the extent of havoc they could cause: a few months ago, the Ukrainian TV network Ukrayina 24 was hacked and aired a deepfake video of President Zelensky “talking of surrendering to Russia” [5]. Fortunately, it wasn’t convincing enough to fool the Ukrainian people but if the software drastically improves in the next few years, people could fall for them. As a result, authorities are concerned of the grave danger deepfakes could pose to the world. For instance, the FBI put out a notification in 2021 stating that Russian and Chinese agents “are using synthetic profile images derived from GANs” [3] because the images were traced to “foreign influence campaigns” [3].

References

[1] 60 Minutes (2021). How synthetic media, or deepfakes, could soon change our world. YouTube. Available at: https://www.youtube.com/watch?v=Yb1GCjmw8_8&t=57s &ab_channel=60Minutes [Accessed 1 May 2022].

However, the issues deepfakes could cause can be prevented. For instance, according to the FBI report, there are ways to spot deepfakes using “visual indicators” [3].

These can include “flickering around the edges” [4], patchy skin tones or bad lip synching. In addition, a bill called “The DEEP FAKES Accountability Act” was passed in the United States in 2019 that regulates the use of unapproved deepfakes using irremovable digital watermarks.

Furthermore, many tech firms and universities have funded research to detect deepfakes. For example, in 2019, Microsoft, Facebook and Amazon all backed the Deepfake Detection Challenge which involved teams around the world competing to create a deepfake detection system.

[2] David, D. (2021). Council Post: Analyzing The Rise Of Deepfake Voice Technology. Forbes. [online] 10 May. Available at: https://www.forbes.com/sites/forbestechcouncil/2021/05/10 /analyzing-the-rise-of-deepfake-voicetechnology/?sh=3974db866915 [Accessed 10 May 2022].

[3]Federal Bureau of Investigation (2021) Private Industry Notification: Malicious Actors Almost Certainly Will Leverage Synthetic Content for Cyber and Foreign Influence Operations. 210310-001. Washington D.C. FBI. Available from https://www.ic3.gov/Media/News/2021/210310-2.pdf [Accessed 2 May 2022] [4] Sample, I. (2020). What are deepfakes – and how can you spot them? [online] the Guardian. Available at: https://www.theguardian.com/technology/2020/jan/13/what -are-deepfakes-and-how-can-you-spot-them [Accessed 1 May 2022].

[5] Wakefield, J. (2022). Deepfake presidents used in Russia-Ukraine war. [online] BBC News. Available at: https://www.bbc.com/news/technology-60780142 [Accessed 5 May 2022].

Personally, while what this technology can accomplish astounds me, it deeply worries

Ansh Bindroo 11CSI

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Firstly, we must realise how our eyes process colour. The human eye and brain together translate light into colour. This is done when light travels into the eye, to the retina (which is located on the very back of the eye). Since the retina is covered with millions of light receptive cells called rods and cones, these detect light and send complex signals to the brain [1]. Usually people have three cone cells and each colour can stimulate more than one cone. Therefore, the cells then produce a combined response for each colour, and distinguish them (nerve cells also help process the information at the same time) [1].

A World Without Colour

The way that colour is processed using our eyes, brain and various cells are so fascinating, and more is yet to be discovered.

Researchers estimate that the human eye can see around one million different colours if it is healthy and that it can also perceive more variations in warmer colours than cooler ones! [1]

A world without colour. Just imagine it. All of your food, the spectacular sights and nature you see when you go on holiday, your family, friends, and everything else; colourless. Colour is what gives character to our planet, evokes memories and creates emotion. Without it, the world would be achromic (having no colour except black, white, or shades of grey) [2].

However, about 8% of men and 1% of women have some kind of colour impairment [1]. This leads to them perceiving colour uniquely – usually the colours they perceive as identical have slight differences that are only visible to others. The most common impairment is red and green dichromatism which causes the colours red and green to appear indistinguishable [1]. There are impairments that affect other colour pairs as well. On the other hand, total colour blindness is very rare, but sometimes occurs due to age and extreme exposure to chemicals such as styrene.

But how do our eyes really process colour, and why are certain things certain colours?

Oddly, birds, fish and many mammals can perceive the full spectrum of colour and some insects such as bees can view ultraviolet colours that are invisible to human eyes [1].

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These abilities are very helpful in the wild where such survival skills come in handy between a predator and its prey: to camouflage and hunt.

In addition, the myth that dogs cannot see any colour is false as they possess two types of cones that discern blue and yellow (dichromatic vision) [1].

-do-we-see-color

R

Overall, there is so much to learn about colour, and a world without any of it would be quite strange. Colour is what brings life to our planet and helps creatures survive in the wild. We see colours in fascinating ways and those who can’t do so have impairments or are completely colour blind. Although we don’t always appreciate it, colour is found in art, emotions, nature, and basically everything else! It can sway thinking, change actions, and cause reactions. It can also increase blood pressure or suppress an appetite. When used in the right ways, colour can even save on energy consumption. As a powerful form of communication, colour will always be irreplaceable.

References [1] Pantone. How Do We See Color? [Internet]. Pantone.com. 2021 [cited 2022 Jun 18].

Available from: https://www.pantone.com/articles/color-fundamentals/how [2] Coelho A, Field SQ. Why is milk white? Chicago Review Press; 2013

Shaivi Kalwani 7ASY

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break down into the ratio of 2:1 Hydrogen to Oxygen atoms. Dalton’s findings were further supported by Antoine Lavoisier, when he formulated the law of conservation of mass, proving that matter could not be created or destroyed, hence atoms being indivisible.

A BRIEF HISTORY OF ATOMIC THEORY Early beginnings: In an early pursuit to understand the contents of the universe, Greek philosopher Democritus first proposed the foundations of atomic theory over 2600 years ago during 400 BCE. Democritus theorized that all matter is composed of tiny, indivisible particles, undetectable to the naked human eye. He called these particles ‘atomos’ which loosely translates to ‘unbreakable’ from Ancient Greek [2]. Democritus was often ridiculed by influential philosophers of the same era, who followed Aristotle’s theory of the four elements1 [1]. Democritus’ theory would be neglected for centuries to come, until John Dalton, a quaker teacher would make revolutionary breakthroughs in atomism, sparking new ideas for years to come.

Nearly a century later, the next major advancement in atomism took place when Physicist J.J. Thomson produced the ‘plum pudding’ model of the atom, which also proved that atoms were made up of subatomic particles [2]. By conducting a series of experiments involving a cathode ray tube, Thomson was able to determine that all atoms have subatomic particles that are negatively charged (the electron or e-). Thomson used his discovery of the electron to design the plum pudding model which stated that atoms were circles with a radius of roughly 10-10m, scattered with negatively charged electrons and other unknown subatomic particles which had positive charges to provide the atom with an overall neutral charge.

Thomson’s model was accurate to some extent; however, it didn’t account for the correct shape of the atom, and neither did it show the correct distributions of subatomic particles throughout the atom

An age of discovery: Almost 2200 years later, atomic theory was kickstarted again by quaker teacher John Dalton, who was seeking to challenge the four elements theory and further develop atomism. Democritus, although formulating a conclusive hypothesis, left his work as simply theoretical. Dalton, on the other hand, was able to find concrete evidence to support atomic theory, by proving that all amounts of the same chemical compound broke down into the same proportion of elements2 [2]. For example, all amounts of water molecules

Modern findings:

1

Aristotle and his followers believed that all matter was made up of four major elements – earth, air, fire, and water. The amount of each element used to create an object would affect its properties.

2

Elements of the periodic table. Not to be confused with Aristotle’s four elements.

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Thomson’s work was continued by two of his brightest students, Ernest Rutherford and Niels Bohr. First, Rutherford, in what is now known as the ‘Gold Foil’ experiment, concluded that atoms had a dense centre which caused waves (specifically X-Rays) to be reflected back, and less dense surroundings, which allowed the waves to be transmitted through the atom.

Rutherford was able to prove, through this experiment, that an atom contains a concentrated, positively charged centre, which accounts for the majority of the atom’s mass. He called this the ‘nuclei’ [2].

ΔE = E2-E1 = hv Bohr’s model of the atom was developed and challenged further when physicists recently proved that electrons have wave-like characteristics, such as producing vibrating oscillations causing them to move about instead of staying in a fixed orbit path around the nucleus.

Conclusion: Be it the basic building blocks of all matter, atoms are everywhere around us. What started with Democritus’ underlying predictions has evolved after two millennia of discoveries, including those of John Dalton’s atomic proof, J.J. Thomson’s electron, Ernest Rutherford’s nucleus, Niels Bohr’s electronic configurations/shells and many more, into a developed field of science that we are yet to fully grasp.

In 1913, one of the latest and most pivotal discoveries in the course of atomic theory would be made by another of Thomson’s students, Niels Bohr. Bohr, drawing on previous works from Max Planck and Albert Einstein, demonstrated that electrons existed in fixed energy levels, known as shells, orbiting the nuclei of atoms; shells were arranged in decreasing energy levels, with a shell closest to the nucleus of an atom containing the most energy [2]. Furthermore, Bohr formulated electrons may jump into different shells when gaining/losing energy.

The following equation notes that the difference in energy levels is equal to the energy absorbed or emitted by the electron [1]:

References [1] Eric, S. (2007). The Periodic Table: Its Story and Its Significance. Oxford University Press.

[2] Theresa, D. The 2400-year search for the atom.

December 2014 TED Ed. 8th (https://ed.ted.com/lessons/the-2-400-yearsearch-for-the-atom-theresa-doud)

Aarush Vir Banerjee Kharbanda 9SOR

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believed when these polymers would join and form, the water would reach a soupy consistency, from which life would reproduce and the simplest amino acids would be synthesized.

The origins of life on Earth

The Miller-Urey Experiment

It’s probably best I foreword this by saying it’s impossible to tell how life first formed on Earth. We know how humans evolved; humans evolved apes who evolved from simians and we can date this path back till LUCA (Last Universal Common Ancestor).

It is before LUCA where things get hazy. Our best guesses stem from the idea that the Earth was a carbon-dioxide-filled ball of rock, with temperatures far exceeding those of a hot summer’s day. This begs the question how something that can walk, talk and breathe evolved from a climate devoid of oxygen or water, which are essential to all life on Earth today. Despite this, scientists have their best guesses on how ‘something’ came from ‘nothing’.

This can be proven by the Miller-Urey experiment of 1953, where a simulation of the primordial soup was conducted. Prior to this, it was believed life came from ‘spontaneous generation’ where life would magically appear. A series of (fairly rudimentary) experiments quickly disproved this. In the 1800s, Pasteur coined the scientific law ‘Omne vivum ex vivo’ (Life only comes from life) and animals don’t just appear randomly. Stanley Miller of the University of Chicago aimed to prove the primordial soup theory by setting up a simulation of what the primordial soup was like. Miller put water in an apparatus, which was gently boiled, water vapour, ammonia, and methane in the space above the liquid water, and a condenser to cool the atmosphere and act like rain. Sparks were added to the atmosphere to simulate lightning, and the experiment was run for one week. The water had gone from clear to a brown-black colour, and analysis showed that complex molecules had indeed formed, including amino acids which assemble to form proteins, and life.

However, there are limitations to this experiment that have sparked debate amongst prebiotic chemists worldwide. Repetitions of Miller’s method suggest amino acids could have used the glassware of the experiment in order to catalyse reactions, due to the alkaline primordial soup eroding and dissolving silica from the walls of the glass. Furthermore, atmospheric scientists in 1983 discovered the Earth never had much ammonia or methane

The Primordial Soup One way life is thought to have come about is via the ‘primordial soup’. Don’t drink this one, because the primordial soup was monomer chains found on the edge of shorelines and in tide pools near the ocean’s edge. Millions of years ago, ammonia, carbon dioxide and methane in the atmosphere would be present in the air and the water, and when these pools would be struck by lightning, or absorb energy from powerful UV rays, or even absorb heat from underwater geothermal vents, these monomers would join to form polymers which would form the building blocks of life.

J.B.S Haldane coined the term ‘primordial soup’ in 1929, and this is because it is

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before life was around, and instead consisted of carbon dioxide and inert nitrogen. When Miller repeated his experiment with this new make-up of gases…

analysis suggests RNA far precedes DNA and protein synthesis, and RNA has been around for millions of years. RNA is thought to have been formed from ‘nothing’, usually from abiotic materials forming chemical cycles in prebiotic oceans. These formed metabolic pathways and this led to the formation of RNA molecules which gave way to life. However, scientists still deem this inconclusive because RNA is an unstable molecule and probably could not have supported itself during Earth’s hostile conditions

There was no more brown soup. No amino acids formed.

Aliens?

Francis Crick, the father of the structure of a DNA strand, suggested life could have come from outside Earth. He called it ‘directed panspermia’ which is the intentional placement of lifeforms on Earth by extraterrestrials. The paper suggests that all life forms have an abundance of molybdenum, which is an element not so common to Earth.

Crick stated that we have unusually high amounts of molybdenum even though Earth does not have much of it, and that life would not have evolved to become dependent on an element such as molybdenum given its scarcity on Earth. Hence, Crick thought life could have come from a planet rich in molybdenum who ‘planted their seed’ on Earth. However, this theory might have just been a bold speculation given its unorthodox nature and outright abandonment of prebiotic chemistry.

References: 1. Fox D. Primordial Soup’s On: Scientists Repeat Evolution’s Most Famous Experiment [Internet]. Scientific American. 2007 [cited 2022 Jun 18]. Available from: https://www.scientificamerican.com/article/primordialsoup-urey-miller-evolution-experiment-repeated/ 2. Model. Primordial Soup: Theory & Model - Video & Lesson Transcript | Study.com [Internet]. Study.com. 2021 [cited 2022 Jun 18]. Available from: https://study.com/academy/lesson/primordial-soup-theorymodelquiz.html#:~:text=The%20idea%20of%20the%20primordia l,of%20life%20would%20be%20created.

3. Wikipedia Contributors. Primordial soup [Internet].

Wikipedia. Wikimedia Foundation; 2022 [cited 2022 Jun 18]. Available from: https://en.wikipedia.org/wiki/Primordial_soup 4. Hartsfield T. What the famous Miller-Urey experiment got wrong [Internet]. Big Think. Big Think; 2021 [cited 2022 Jun 18]. Available from: https://bigthink.com/hardscience/millerurey/#:~:text=The%20simple%20amino%20acids%20did,t o%20have%20affected%20the%20results.

5. Wells J. The Miller-Urey Experiment - Chemical Evolution | BioTechSquad [Internet]. BioTechSquad |. 2017 [cited 2022 Jun 18]. Available from: https://nature.berkeley.edu/garbelottoat/?p=582#:~:text=Th e%20Miller%2DUrey%20experiment%20was,the%20theor etical%20ideas%20of%20A.I. 6. Orlic C. The Origins of Directed Panspermia [Internet].

Scientific American Blog Network. 2013 [cited 2022 Jun 18]. Available from: https://blogs.scientificamerican.com/guest-blog/the-originsof-directed-panspermia/

Still a fun one to think about.

The persists

mystery

Unfortunately, scientists still do not know how life formed on Earth. One common theory for how life evolved is by studying RNA, which has been fabricated in conditions like prehistoric Earth. Genetic

Anay Bindroo 11GCA

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Theory of Natural Selection, whereby he stated that organisms evolve by adapting to their physical environment, and that only the fittest survive and reproduce, passing on their advantageous characteristics to their offspring. What if humans evolved from having soft tissues, to harder ones, by natural selection?

Though there is currently no evidence in support of this, there is equally no evidence against it!

Still, this begs the question: if dinosaurs died from an asteroid, how could natural selection protect humans? As of now, there is no concrete evidence that directly explains the extinction of dinosaurs. Besides the theory that they were killed by an asteroid or a comet, some believe it was simply due to an insufficient number of plankton, making it difficult to sustain the food cycle.

If this were the case, can it be that the human population itself was very small, thus reducing the competition for food, hence their survival, and not the dinosaurs’, assuming both species had different food sources? While all this may sound quite far-fetched and hypothetical, it’s important to note that it is based solely on theories we currently use and rely on in scientific research and development. Therefore, while there is no evidence that proves it to be completely factual, there is also no evidence that suggests its impossibility. So, ask yourself again; what if humans and dinosaurs did coexist once upon a time?

Coexistence of humans and dinosaurs Growing up, it was fed to us that dinosaurs walked the Earth hundreds of millions of years before us, but has anyone ever stopped and pondered upon whether this was completely true or not? Recent cutting-edge research in archeology has allowed us to reach a thorough understanding of our history, as well as that of species who we share, or once did share, the Earth with.

Fossils, namely, have made monumental impacts in the field, acting as a direct lineage to our planet’s past. However, scientists have discovered that not all organisms leave fossils. Soft tissues of dead organisms decay rapidly, meaning the animal cannot be preserved. This is why some animals like bats and rodents, amongst others, are not preserved as fossils (American Geosciences Institute, 2022). This unleashes a myriad of questions in a domino effect. Could there be species who lived before us that we don’t know about? Is our knowledge of the timeline of different species on Earth entirely accurate? Is it, in any way, possible that humans, 233 million years ago, had soft tissues and thus did not leave any proof of their existence? Thus, is it possible that humans, once upon a time, coexisted with dinosaurs? Is it possible that we have

completely missed out a critical part of the Earth’s history? In the mid19th century, Charles

Leann Qadan 12KNO

Darwin, an English naturalist, established his

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Nutritional Biochemistry Astrobiology

Signs of life on other planets A research project during early 2022 by Dylan C. Gagler, Bradley Karas, professors at Arizona State University, researched enzyme function to discover a new ‘biochemical universality’. With the use of genomic datasets, they presented how enzyme functions form classes with their similar properties – proving previous organism classification methods valid. By comparing their predictions with a consensus model for the last universal common ancestor (LUCA), their results establish the existence of a new kind of biochemical universality, independent of the properties of Earth’s molecular chemistry [3]. If by tracing all organisms’ one common ancestor from over 4 billion years ago, we can find abnormalities in samples taken from space – ones that do not match up with any substances on Earth.

This is essentially one of the first steps towards finding new properties of life outside our known planet.

&

Biochemistry is the area of science that explores the chemical processes within living organisms – essentially bringing together biology and chemistry, as the name implies, to apply chemistry to the research of living organisms. Biochemistry is particularly useful in space exploration to explore the nutritional biochemistry of astronauts as well as the universal query of ‘is there life beyond Earth?’.

Nutritional Biochemistry The physiological effects of ‘weightlessness’ that occurs while in zero gravity is profound.

However, research in how space travel affects nutritional issues including absorption, metabolism, and excretion, is still in its early stages [1]. Mildly simple issues such as muscle and bone loss due to a deficit in calorie intake while on the ISS (International Space Station) have been found refined solutions due to research in nutritional biochemistry.

Furthermore, gravity level alternation causes a significant impact on your muscles and bones as they weaken, primarily in the legs and lower back.

Gravity always acts on you while on Earth, contrasting to microgravity in space where your muscles that are no longer used as much to hold your body up For example, if your leg muscles don’t hold your body weight up by standing for months at a time, they become used to this and weaken. While space station research in nutrition helps us understand how to prevent and treat muscle atrophy and bone loss, optimizing countermeasures for astronauts is particularly important as space exploration takes on new gravity levels such as on Mars [2].

Astrobiology in extra-terrestrial life The Drake equation, formulated in 1961 by astrophysicist Frank Drake, is used to estimate the number of communicating civilizations in our galaxy, or the chances of finding intelligent life in the Milky Way. Recent discoveries of numerous planets in the Milky Way have raised the chances significantly.

The Drake equation goes in order from easiest to hardest, as said by astrophysicist Kaitlin Rasmussen [4]. While variables like L remain purely speculative, scientists can now answer with some certainty things such as average star formation rates in the Milky Way. A key issue with this formula is that any attempt to solve it requires guesswork for many of the variables, leading to wildly different results.

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Credit: University of Rochester.

onal_biochemistry_of_space_flight_-fpdis.pdf [Accessed 19 Jun. 2022].

[2] Johnson, M. (2020). Bone and Muscle Loss in Microgravity. [online] NASA. Available at: https://www.nasa.gov/mission_pages/station/research/statio n-science-101/bone-muscle-loss-in-microgravity/.

It would take a long time before scientists could even begin to put rough estimates into the equation, but progress has been made so far. In 1995, Michel Mayor and Didier Queloz from the University of Geneva detected the first exoplanet orbiting a sunsimilar star outside our solar system. Now known as 51 Pegasi b, it is found 50 lightyears from Earth in the constellation of Pegasus. Its orbit is so close to its sun that its "year" is only four days long, or 102 hours long and its surface temperature close to 1093°C or 2000° F. Since then, we have discovered 4,940 new exoplanets as of March 2022. Out of those, a project done at the University of Puerto Rico expects 53 planets that "optimistically" could be suitable for life, and among those, 13 that are more likely to be habitable [5].

[3] The Planetary Society. (n.d.). The Fermi paradox and Drake equation: Where are all the aliens? [online] Available at: https://www.planetary.org/articles/fermiparadox-drake-equation.

[4] ScienceDaily. (n.d.). Scaling laws in enzymes may help predict life ‘as we don’t know it’. [online] Available at: https://www.sciencedaily.com/releases/2022/02/220228161 618.htm [Accessed 19 Jun. 2022].

[5] https://www.facebook.com/spacecom (2018). Drake Equation: Estimating the Odds of Finding E.T. [online] Space.com. Available at: https://www.space.com/25219drake-equation.html.

Karma Bridgman 10AAG

References [1] SPACE SCIENCE, EXPLORATION AND POLICIES SERIES NUTRITIONAL BIOCHEMISTRY OF SPACE FLIGHT. (n.d.). [online] Available at: https://www.nasa.gov/sites/default/files/atoms/files/nutriti

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threats – exogenous (eg. exposure to radiation) and endogenous (DNA duplication errors). These mutations to the genetic code, causes instructions to be unclear, impeding the cell’s ability to function properly and leading to disease, including cancer.

WHY DO WE AGE? Aging is universal: it’s a part of everyone’s life.

Human cells and therefore humans are not built to last forever. Molecular changes at cellular level, causes progressive decline in physiological organ functions leading to disease, disability and finally death.

2. Epigenetic Alterations

On a cellular level there are nine hallmarks or main biological processes which are considered to be the core reasons behind ageing:

In addition to the DNA code, cells get information from the epigenome that controls gene expression (turns them "on" or "off") thereby determining how genes function [2].

These hallmarks are divided into three groups: •

•

Though all cells have the same DNA, genes are expressed differently, creating different cell types: epigenetics ensures that a skin cell is different from say a brain or a muscle cell. But as we age, genes start to get expressed when they shouldn't be, or get silenced by mistake, leading to disease [2]. For instance if the gene suppressing tumors is silenced, cells could uncontrollably grow becoming cancerous.

Primary hallmarks damage cellular functions and are the foundational causes of age associated damage. Antagonistic hallmarks are responses to the damage by primary hallmarks. They are beneficial at low levels but at high levels become deleterious.

Integrative hallmarks are the consequence of the damage wrecked by primary and hallmarks, and lead to organ decline and functional decline of the body.

Primary

3 .Telomere Attrition [2] Telomeres are structures at the tips of chromosomes which do not contain critical genetic data.

When a cell divides and its DNA is copied, it cannot replicate the entire length of the DNA strand resulting in a portion of the DNA being lost [3]. The loss is from the telomeric region instead of the regions containing genes essential for life.

Telomeres also act like markers of the end of DNA strands keeping chromosome ends from fraying and sticking to each other [3].

Hallmarks:

1. Genomic [1]

Instability

DNA is the cell’s instruction manual, containing all of the information needed to synthesize the proteins essential for life.

The stability of DNA is constantly endangered by

Every time a cell divides, the telomeres

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become shorter. When they get too short the cell stops dividing and either becomes senescent (inactive) or undergoes apoptosis (programmed cell death) [2]. The shortening of telomeres can lead to diseases particularly cancer and to ageing.

must therefore be able to store nutrients when they are abundant and access these stores when nutrients are scarce. Furthermore, nutrient levels in our bloodstream need to stay within certain safe ranges.

4. Loss of Proteostasis [2]

Any imbalance with the cell's ability to sense or process nutrients, causes problems primarily, insulin resistance. Cells become less accurate at detecting glucose or fat resulting in them not being properly metabolized. This is why agerelated diabetes is fairly common.

Proteins are critical for proper functioning of cells, tissues and organs. Proteostasis is essentially the overall ‘management’ and balancing of proteins, including their synthesis, maintenance and degradation when they become damaged.

Integrative hallmarks With ageing, proteostatis starts failing, resulting in unusable proteins not being eliminated. This protein accumulation leads to a range of illnesses including Alzheimer’s and Parkinson’s.

1. Stem Cell Exhaustion [2] Stem cells have the ability to evolve into any type of cell. They act as an internal repair and renewal system for tissues and are important for immune function, blood production, and other functions. With age, there is a decline in stem cells numbers, their ability to regenerate and their quality. Consequently, tissues and organs lose their ability to recover from damage and begin to fail.

Antagonistic hallmarks 1. Cellular Senescence [2] As cells age and become damaged, they stop dividing and die. However, sometimes cells become “senescent” - resistant to death.

Senescent cells generate chemicals which can affect nearby cells prompting them to also turn senescent.

Senescent cells contribute to inflammaging, a state of chronic ongoing inflammation. Inflammation is the key factor in ageing and age-related chronic diseases including cancer, atherosclerosis, neurodegenerative diseases and diabetes.

2. Altered Intercellular Communication [2] Our cells are in constant communication with each other, transmitting billions of signals. This intercellular communication is necessary in order to coordinate immune responses to a threat, control metabolic activities and all the other myriad processes that keep our bodies functioning properly.

2. Mitochondrial Dysfunction [2] The mitochondria are the cell’s “powerhouse” generating the energy needed for cells to function. They get dysfunctional with age, impairing their ability to power the cell. This energy deficit affects cellular function, triggers chronic inflammation and other age related metabolic and neurodegenerative diseases.

As cells age, and inflammatory responses increase, communication pathways break down leading to weakened immune systems and changes in endocrine, neuroendocrine, or neuronal pathways

3. De-regulated Nutrient Sensing [2]

Aging is a series of interconnected processes: there is a cause-and-effect relationship between many of the hallmarks. To reverse ageing, it is critical to understand what ties together all of the

In Conclusion

Cells require a constant supply of nutrients to provide the energy they need to function. Cells

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2018 [cited 2022 Jun 23]. Available from: https://www.businessinsider.com/biology-of-aging-whybodies-get-old-2018-8#telomeres-may-shorten-3

processes that cause our bodies to unravel [4]. Biological ageing is also clearly impacted by our lifestyles.

Living a healthy lifestyle with adequate exercise, a balanced diet, reduced stress levels, emotional stability and good social support will delay ageing.

[4] Young S. Council Post: Will You Live To 200? Five Levels Of Breakthroughs In Longevity Research You Must Know About. Forbes [Internet]. 2021 Dec 10 [cited 2022 Jun 23]; Available from: https://www.forbes.com/sites/forbestechcouncil/2021/05/03 /will-you-live-to-200-five-levels-of-breakthroughs-inlongevity-research-you-must-knowabout/?sh=2147c648263d

References [1] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013 Jun;153(6):1194–217.

[2] What are the Hallmarks of Aging? - American Federation for Aging Research [Internet]. American Federation for Aging Research. 2021 [cited 2022 Jun 23].

Available from: https://www.afar.org/hallmarksofaging

Philip Manipadam 10BST

[3] Hu C. Biology of aging: 9 things that happen in the body as we get older [Internet]. Business Insider. Insider;

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your bloodstream and tissues to protect you from germs.

How do white blood cells fight diseases?

In order to fight diseases, white blood cells have to fight a variety of things. For instance, when you nick your skin, bacteria can get in, or you could be rubbing your eyes and not realizing that the doorknob you touched could be infected with a cold virus or that you ate something that wasn't cooked or cleaned properly [1]. However, your immune system releases white blood cells and other chemicals that can eliminate this threat. The white blood cells in your body fight it off by sneezing. You make more white blood cells constantly, despite their short lives, which can vary from a few days to a few weeks [1]. There are several types, and all are geared towards fighting infection. What are the ways white blood cells kill germs? In our body, white blood cells will latch onto the germs, absorbing them or destroying them. They produce antibodies that keep the germs at bay.

Basophils are one of the numerous kinds of white blood cells you have. Those blood cells make up much less than 1% of all of your circulating white blood cells [3]. Basophils are a part of your immune system and are created inside of your bone marrow. Basophils have been first diagnosed in 1879 with the aid of researcher Paul Ehrlich [3]. Due to the fact basophils aren’t as plentiful as other blood cells in people, scientists at the time idea that they didn’t have an awful lot of importance. but, around 100 years later, it became referred to that there are a few different functions of basophils. Basophils have a quick existence span, normally simply one or two days. because of this, research on basophils is frequently limited.

A strong immune system comes from experience.

When your body first comes into contact with a certain type of germ, your immune response may be slow. To get rid of your infection, you may need several days of making and using all the germ-fighting parts necessary. Hacking germ codes and destroying them takes time.

To conclude, white blood cells are a totally essential component as they are able to battle off diseases around your body, whilst you contact something with the aid of no longer understanding, it'd have many germs but white blood cells kill them off.

A type of white blood cell is referred to as a monocyte, it resides in your blood and tissues and is responsible for finding and killing germs (viruses, bacteria, fungi and protozoa) and eliminating those cells that are infected

References [1] Rachel Reiff Ellis. How Your Immune System Fights Infection [Internet]. WebMD. WebMD; 2015 [cited 2022 Jun 18]. Available from: https://www.webmd.com/coldand-flu/immune-system-fightinfection#091e9c5e812c5621-1-3 [2] White blood cells [Internet]. Healthdirect.gov.au.

Healthdirect Australia; 2020 [cited 2022 Jun 18]. Available from: https://www.healthdirect.gov.au/white-blood-cells

with them [2]. Furthermore, monocytes can treat injuries and prevent infections. They are your cells' firefighters. Their lifecycle begins in the bone marrow (soft tissue inside of the bones), where they grow and train to protect your body [1]. Upon maturation, they enter

[3] WebMD Editorial Contributors. What Are Basophils?

[Internet]. WebMD. WebMD; 2021 [cited 2022 Jun 18].

Available from: https://www.webmd.com/a-to-zguides/what-are-basophils

Hashim Yousaf 7MWD

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59 megajoules of energy over five seconds (11 megawatts of power) which is more than double what was achieved in similar tests back in 1997 [2]. Dr Joe Milnes, the head of operations at the reactor lab, said “We’ve demonstrated that we can create a mini star inside of our machine and hold it there for five seconds and get high performance, which really takes us into a new realm.” [2]

Nuclear fusion: Meme or dream?

Fusion is a nuclear reaction in which atomic nuclei of low atomic number fuse to form a heavier nucleus with the release of energy (which will be utilized to power homes and industrial processes). The struggle with reaching nuclear fusion is that it requires extremely high energy and temperature to happen. This is because low atomic nuclei such as hydrogen have positive charges. Therefore, for the two nuclei to fuse, the electrostatic force of repulsion (like charges repelling) needs to be overcome. In the core of the Sun, huge gravitational pressures allow this to happen at temperatures of around 50 million Celsius [1]. At the much lower pressures that are possible on Earth, temperatures to produce fusion need to be much higher - above 100 million Celsius.

Due to these unfathomable high levels of energy required to start the reaction, our current state of resources and technology are not able to start a nuclear fusion reaction sustainably. However, in the near future, innovation from scientists such as Joint European Torus, the ITER project and the UK-based JET laboratory may change the global source of energy for the better. If nuclear fusion can be successfully recreated on Earth it holds out the potential for virtually unlimited supplies of low-carbon, low-radiation energy.

Additionally, the ITER facility in southern France is said to be the last step in proving nuclear fusion can become a reliable energy provider as it experiments with the 4th state of matter plasma to gradually reach the high temperatures necessary during the second half of this century [2]. This means that those of you reading this will have a nuclear fusion reactor in your lifetime powering industrial processes, appliances, and your homes all without spikes in CO2 emissions and holes in the ozone layer.

References [1] Nuclear Fusion : WNA - World Nuclear Association [Internet]. World-nuclear.org. 2021 [cited 2022 Jun 23].

Available from: https://world-nuclear.org/informationlibrary/current-and-future-generation/nuclear-fusionpower.aspx [2] Gibney E. Nuclear-fusion reactor smashes energy record. Nature [Internet]. 2022 Feb 9 [cited 2022 Jun 23];602(7897):371–1. Available from: https://www.nature.com/articles/d41586-022-003911?utm_medium=Social&utm_campaign=nature&utm_sour ce=Twitter#Echobox=1644409150 [3] Nuclear Fusion | IAEA [Internet]. Iaea.org. 2018 [cited 2022 Jun 23]. Available from: https://www.iaea.org/publications/nuclear-fusion

A glimpse of hope for fusion power has stemmed from the UK-based JET lab which beat by a landslide its own world record for the amount of energy it can extract by squeezing together two forms of hydrogen. The experiments produced

Maha Nawaz 10MHA

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The Early Years

Go Big or Go Home.

In the years leading up to the 1960s, America had begun to put serious funding and development into their space program. Spurred on by the everpresent risk of technological domination posed by the Soviet Union, progress soon reached breakneck pace.

It’s a Saturday, and you’re on a boat with a few friends. You haven’t fared well on the trip over, and you lean over the side of the boat to hurl. You stare at yourself in the glassy surface, and smile to yourself despite the circumstances. Today’s going to be fun. A few ripples shift across the surface, gradually growing in amplitude. A low, almost guttural noise sounds across the bay, and the tame ripples grow into small waves. The boat begins rocking, and that noise ascends to a crackling hymn. On the horizon, you see a stick of black riding atop a column of fire, smoke and water. It climbs into the atmosphere, then the stratosphere. The air becomes filled with the excited chatter of your friends.

Yet, for all the recent advances in the frontiers of aerospace research, the price of putting a kilogram into orbit really hadn’t changed. Rather than creating a sustainable, economically viable industry, governments instead focused on grabbing bragging rights for propaganda. The two superpowers pumped what would eventually be billions into the space race to soar higher and claim firsts, but, as a result, all the gains in performance and efficiency in the air just didn’t translate into reductions on the spreadsheets.

“Woah,” someone says.

Something Huge.

Despite this, many scientists believed that the key to affordable spaceflight lay in highly efficient engines – if you own a car, isn’t it a good thing if you pay less for fuel? – and those major advancements lay just around the corner.

It holds the respectable title of being the largest rocket ever designed. And that’s no mean feat in a world where every billionaire with a couple of spare hundos laying around is start ing a rocket company. In 1962, one Robert Truax took a simple idea to the heart [1]. As it soon became obvious, he truly believed that bigger was better. And so, working at Aerojet, Truax set about designing what was to be the largest rocket ever designed: the Sea Dragon.

“Yes,” said “But you’re the

Truax. missing point.

We’re throwing away these rockets every time we use them. There’s no point in paying less for gas in a 50,000-dollar car if an old hack will get the job done for a fifth of the price.”

The Solution Essentially, Truax believed in simplicity of design. He recognized that minimizing complexity and moving parts would bring benefits two-fold.

Firstly, in

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submarine manufacturer – Todd Shipyards – to minimize costs, the rocket was the epitome of brute force engineering [1]. Rather than precisely machining the body to perfectly distribute loads and stresses, builders would add excess steel plating to protect against mechanical failures.

This would have meant quicker and cheaper production, driving down the price of kilo-toorbit.

development: using tried-and-tested principles would mean the team could avoid repeating mistakes of earlier rocket designs – as famously not seen in the fuel injector of the F1 engine of the Saturn V – and would lower the overall time and therefore cost of the design stage. It turns out a lot of rockets are actually relatively cheap once the final specification is decided upon – it’s just that getting to that point takes a lot more money than usually expected.

The engine operated in a fashion not too dissimilar to that of a can of silly string: pressurized gas (in this case, nitrogen) forced the propellants out of the tanks and into the engine.

[1] The fuel and oxidizer ignited, and the gases were expelled out the back, generating thrust.

As opposed to nearly all large rockets at the time, there were no fancy pre-burners or turbopumps.

Secondly, a simpler design would mean manufacturing and materials would again be cheaper than those associated with highly efficient and complex rockets, which would otherwise require exotic alloys and intricate machining to withstand extreme temperatures and pressures. Truax believed that simplicity was the key to the Sea Dragon’s success.

And now, the name.

The Design

With so much material spewing out the back, the raw power of the Sea Dragon’s engine would have completely obliterated any launch infrastructure used to get the rocket into the air – the equivalent of destroying

It’s hard not be amused by the sheer audacity of the Sea Dragon’s original specifications. Rising taller than the pyramids of Giza and made by a

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a garage every time you go to the store.

Saturn vs. Sea Dragon’s main engine.

To counter this, the rocket’s launch pad was the sea: the launch pad could essentially be replaced each launch with no extra charge. The rocket was designed to be floated out from a shipyard, ballasted to vertical and then ignited with its bell 200-300 underwater, all 36 million kilograms of thrust directed into the open ocean [2].

Obviously, there were going to be some major hurdles in overcoming combustion instability. In other words, the engine was going to blow up.

The original budget also left little room for working out the intricacies of the steel body.

When compared with the developmental issues of SpaceX’s Starship (also made of steel), the hidden complexity and costs of the project begin to show themselves in a new light.

And the final issue is that of the launch site. A rocket launch is not exactly gentle, and the shockwaves generated by the 36 million kilos of thrust would kill any marine life within a 30kilometer radius. The whole area would be turned into a seafood chowder.

Another proposal floated around was that the fuel for the second stage – hydrogen – could be produced from sea water via electrolysis. The power source for electrolysis? A nuclear aircraft carrier sitting nearby.

Conclusion The Sea Dragon was the ultimate epitome of brute force engineering. Looking at the raw performance, tonnage to orbit and proposed price savings, it’s hard to ignore the allure of the whole thing. Yet the design overlooked fundamental issues bound to surface later in development that would have likely been extraordinarily difficult to overcome, ramping up costs and ultimately countering the whole philosophy of the concept.

Nowadays, it's not difficult to imagine a world where this beast got to fly. The things we could have accomplished with the capabilities of this beast would achieve and then exceed the dreams of early science-fiction writers. But in this reality? We’re not going to be seeing it any time soon.

Early concept art for the Sea Dragon.

A Few Issues Truax’s logic and design was fundamentally flawed by no other than the laws of physics itself.

Now, remember how I said the F1 engine had a few issues with a fuel injector? Well, it turns out that was a result of the size of the engine. The Saturn V had five of those F1 engines, and was considerably smaller than the Sea Dragon. The Sea Dragon was going to have one engine.

Oh well. At least we have Starship. Watch a simulated Sea Dragon launch here:

References

Ten times the size of the F1.

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[1] 1.Sea Dragon [Internet]. Astronautix.com. 2019 [cited 2022 Jun 26]. Available from: http://www.astronautix.com/s/seadragon.html

[2] Avilla A. Hidden Histories: Sea Dragon [Internet].

SpaceflightHistories. 2020 [cited 2022 Jun 26]. Available from: https://www.spaceflighthistories.com/post/seadragon

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BioMed Central The growing research in Genomic Medicine has started to allow for more personalized treatment, better palliative care, and even lead to more accurate diagnostics.

Some areas of key interest in Genomics are the analysis of Phenotype Data to better aid congenital conditions, and modeling the effects of certain genes on biological processes [2].

ARTIFICIAL INTELLIGENCE IN GENOMIC MEDICINE AND DIAGNOSTICS Artificial Intelligence (AI) is a rapidly growing field in computer science that is slowly increasing its influence over diagnostics and genomic medicine.

Especially: Machine Learning (ML) and Deep Learning (DL), which are:

Artificial Intelligence Since Genomics requires a lot of data analysis, there is now a growing need for quick and accurate computational intelligence that can tackle the analysis of these large multidimensional datasets.

Offering new approaches to streamline key problems in Genomic Medicine.

PHG Foundation

In this case, multidimensional refers to datasets that have many different attributes.

Like how a facial feature is the result of thousands of smaller measurements like the genes in a cell.

Although some ML algorithms have already been written to analyze key problems in Genomic Medicine (GM) and Genomic Diagnostics (GD), and even been used for basic testing for many years now, a surge in High-Performance Computing and Biomedical Datasets (BD) have meant that AI’s relevance in Diagnostics has been slowly growing. This article will analyze the role of AI in GD, and cover the different types of AI that can be applied in this field while looking at some case studies.

This is why the field of Artificial intelligence is quickly gaining traction in Genomic Medicine.

The study of Genomics Image Credit — University of Cambridge & The PHG Foundation

Genomics is the study of the entire genetic material of an organism [1]. Genomic medicine makes use of an individual’s genomic information to guide their clinical care and deliver more personalized strategies for diagnostic or therapeutic decision making.

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Applications of intelligence in Genomics

Artificial

Computer Vision Computer vision is a generic field in AI that tackles analyzing images and video. These algorithms can — with enough training data — learn to recognize almost anything, from the silhouette of a dog to the facial features that hint at down syndrome. Tying back to phenotyping, computer vision can allow us to analyze images of physical features to form suggestions and ideas on the kinds of conditions that patients might have.

Most aspects of GM and Diagnostics have been brushed by AI in some form. These programs can be classified as ‘narrow’ as they cover only a certain aspect of GM / GD, however, with increased development in these ‘narrow’ algorithms, they can prove an indispensable tool for physicians.

The fields of AI that are looked at most for GM are Computer Vision and Phenotype Analysis Algorithms, and AI is also being implemented in Variant Calling, which is a method used to identify ‘variants’ in a patient’s genome compared to the average person. These methods can allow for the early identification of diseases like Cancer and other Rare Genetic Diseases (RGD).

Rare genetic diseases have been found to include minor facial patterns, and most syndromes have direct Vision phenotypes. Computer algorithms can be trained — with extensive datasets to detect these phenotypes, and effectively pre-diagnose patients, aiding towards the effort to move towards preventive medicine, rather than reactive medicine.

Phenotyping Face2gene

In a clinical setting, phenotyping is the process of examining and reporting a patient’s physical features. This can be things like the diameter of a patient’s pupil, or the curvature of their spine, however, facial features tend to be used more often. The information gathered from phenotyping can then be surveyed

by ML algorithms to create more refined BDs. Phenotype data consists mostly of genomic factors with the environment playing a moderate factor. This makes it hard for standard forms of phenotyping to separate the genomic factors from environmental factors [3].

A rapidly growing technology — DeepGesalt — is slowly gaining traction in Phenotype-Genotype AI. It uses information from the phenotype and genotype data of 1000s of patients to suggest genetic syndromes that a patient might have, that would otherwise be hard and time-consuming to discern. When this algorithm was tested with two external BDs the syndrome that a patient had, appeared in the top 10 of the computer’s suggestions, 90% of the time [4].

Many Deep Learning algorithms are surfacing that support image recognition for rare disease phenotyping and they are showing great promise.

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classification [5]. In short, it takes a DNA sequence and converts it into an image. It then compares this image to other images from different datasets to identify variants.

This is effective because Deep Learning algorithms are particularly good at tackling problems that involve image recognition and classification.

Algorithms Like Face2Gene are Becoming More Prevalent

Conclusion

Again, this is no way near the accuracy that can even be potentially administered in a clinical setting, but it is programs like these that will slowly see improvement and growth in the many years to come.

AI has many vast and intricate aspects. Its vast types allow it to become an unforgettable part of many emerging fields in

science. GM has always been quite a science-fiction type area of study.

Being on the cutting edge of science has meant that new discoveries are commonplace. AI is providing a way to cope with this fast-paced field of study.

Applications are wide, from DNA sequencing to PhenotypeGenotype analysis to many I have not covered in this article. It provides a way of accurately diagnosing and prediagnosing patients, that can allow for huge leaps in preventive medicine.

This, however, is not without its fair share of hurdles. AI is heavily dependent on accurate BDs, some of which are extremely hard to find. And more importantly, AI is a black-box system. Even the people that write AI programs cannot fully see that AI’s thought process. This creates ethical questions…

DNA Sequencing Sequencing and analyzing DNA has been an indispensable tool for medical research in diagnosing hereditary diseases and other rare conditions. Variant calling is a method used for DNA analysis and it — in simple terms — looks at a patient’s DNA and compares it to a large database to find ‘variants’ or differences in the patient’s Genome that might underlie disease.

There are already many tools and

techniques established for variant calling, many new deep learning models are being developed with the goal of improving the accuracy and reliability of variant calls. One algorithm being developed — Google’s DeepVariant — has proved phenomenal, having outperformed many well-known methods of variant calling.

DeepVariant looks at variant calling from a slightly un-intuitive angle, image

Should a robot be able to diagnosepatients if the scientists themselves cannot understand how the

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algorithm came to a diagnosis? What if there are conflicting opinions between scientists and robots, who’s diagnosis holds more weight?

Overall, AI in GM and GD holds a promising future, a future with many different possibilities, and I genuinely hope that these complications are resolved as soon as possible to push forward medicine and Computer Science in general.

References [1] Ruane J, Sonnino A, Agostini A. Bioenergy and the potential contribution of agricultural biotechnologies in developing countries. Biomass and Bioenergy [Internet].

2010 Oct [cited 2022 Jun 26];34(10):1427–39. Available from: https://www.sciencedirect.com/topics/earth-andplanetary-sciences/genomics [2] Frey L. Artificial Intelligence and Integrated Genotype– Phenotype Identification. Genes [Internet]. 2018 Dec 28 [cited 2022 Jun 26];10(1):18. Available from: https://www.mdpi.com/2073-4425/10/1/18/htm [3] Li X, Guo T, Mu Q, Li X, Yu J. Genomic and environmental determinants and their interplay underlying phenotypic plasticity. Proceedings of the National Academy of Sciences [Internet]. 2018 Jun 11 [cited 2022 Jun 26];115(26):6679–84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042117/ [4] Gurovich Y, Hanani Y, Bar O, Nadav G, Fleischer N, Gelbman D, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nature Medicine [Internet].

2019 Jan;25(1):60–4. Available from: https://arxiv.org/pdf/1801.07637.pdf?

[5] DeepVariant Blog. DeepVariant Blog [Internet].

DeepVariant Blog. 2022 [cited 2022 Jun 26]. Available from: https://google.github.io/deepvariant/

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The Evolution of Sulfonylureas as Hypoglycaemic Drugs over time, their Mechanisms and how they Treat Symptoms of Type II Diabetes Mellitus.

liver cells. When there is a deficiency or resistance of insulin it leads to hyperglycaemia (high blood glucose levels), due to the reduced ability to convert glucose into glycogen. This would lead to symptoms such as vomiting, dehydration, confusion, increased thirst, and blurred vision to name a few.

Physiology behind insulin secretion and structure To understand the pharmacology of the sulfonylurea compounds, one must first understand the physiology behind the secretion of insulin.

As stated above, insulin is a peptide hormone, so it is made from a polypeptide chain. Transcription of the insulin gene (found on chromosome 11) occurs and the resulting mRNA strands are translated to produce two peptide chains. These chains are held together in a quaternary structure by two disulfide bonds to form the hormone insulin (Brange & Langkjoer, 1993).

Insulin secretion must be tightly controlled to maintain efficient glucose homeostasis. To do so, the secretion of insulin is regulated precisely to meet its demand. The β-cells of the pancreas contain glucose transporter 2, a carrier protein that allows facilitated diffusion of glucose molecules across a cell membrane. These transporters allow glucose to be detected and enter the β-cells. Upon cytoplasmic glucose levels rising, the pancreatic β-cells respond by increasing oxidative metabolism, leading to increased ATP in the cytoplasm (Fridlyand & Philipson, 2010). The ATP in the cytoplasm of the βcells, can bind to ATP sensitive K+ channels on the cell membrane, causing them to close. This leads to a build up of K+ ions within the cell as they are unable to leave the cell, leading to the depolarisation of the cell. The increasing positive membrane potential, leads to the opening of voltage gated Ca2+ channels, leading to an influx of Ca2+ ions. This further depolarises the cell, which triggers the release of insulin from the cell, packaged in secretory vesicles, by exocytosis (Fu, et al., 2013).

Introduction Type 2 diabetes mellitus can be a difficult disease to live with and can severely affect one’s quality of life.

Diabetes mellitus is a chronic condition in which your body cannot regulate your blood glucose levels, the two main types being type 1 and type 2. These are due to either an inability to produce insulin (type 1) or when the insulin produced is ineffective (type 2). Type 2 diabetes, or non-insulin dependent diabetes mellitus, can occur as a result of lifestyle factors, such as diet and obesity. These lead to insulin resistance or the inability to produce enough insulin as necessary. Currently, there are 4.1 million people in the UK with diabetes, with 90% of these cases due to type 2 diabetes. It is estimated that 1 in 10 adults will develop type 2 diabetes by 2030 (Lacobucci, 2021) One treatment for type 2 diabetes is the use of sulfonylureas - a group of oral drugs with hypoglycaemic effects (ability to lower blood glucose levels). Since their discovery in the 1940’s, medicinal chemists have changed the structure of these drugs, to make them more effective for clinical use. These modifications have led to more favourable properties in metabolism, potency, efficacy and safety, which have made the drugs a more effective, safe and convenient treatment for type 2 diabetes mellitus. These will be discussed later on in the article.

This article will explain the chemistry of sulfonylureas, the pharmacology behind them and how they have changed over time to make them more effective in the treatment of type 2 diabetes mellitus.

Type 2 Diabetes mellitus cause Type 2 diabetes occurs when there is a deficiency in insulin secretion by the β-cells in the pancreas, or when cells develop a resistance to insulin action (Galicia-Garcia, et al., 2020). This is usually due to obesity and an unhealthy lifestyle, including lack of exercise, and a high fatty and sugar diet. Insulin is a peptide hormone that is secreted by β-cells in the pancreas. It is responsible for lowering blood glucose levels by stimulating the conversion of glucose in the blood into glycogen to be stored in muscle, fat, and

Pharmacology of sulfonylureas Sulfonylurea’s act inside the pancreatic β-cells. On the ATP sensitive K+ channel, there are sulfonylurea receptors to which the drug binds, causing them to close. The cascade of events that follows leads to the release of insulin by the pancreatic β-cell. This mimics the activity that occurs when glucose is taken into the cell, as mentioned earlier. (Panten, et al., 1996). (possibly delete this instead as it is repeated) 37

This process allows more insulin to be released, to lower blood glucose levels when insufficient insulin is produced naturally. Sulfonylureas are only effective in type 2 diabetes, since insulin production is not impaired (as in type 1 diabetes), rather the release of or resistance to insulin is affected.

Common chemistry of all sulfonylureas All the sulfonylurea drugs are characterised by their common sulfonylurea group. This functional group allows this unique group of compounds to bind to SUR on ATP sensitive K+ channels, giving it its hypoglycaemic properties. The common structure of sulfonylureas is shown in figure 1 (Fvasconcellos, 2011), with the blue R groups indicating replaceable side chains, which fluctuates between each drug development over time giving slightly different properties between the drugs. Over time, scientists have improved the drugs efficacy by changing the side compounds. Additionally, scientific research has led to development of other drugs from the same pharmacological group, but with altered side chains (again, giving them different properties) which have also improved the efficacy of the drug. These changes have altered properties of the drug such as potency, metabolism, half-life, tolerance and safety, to make the drug more effective for clinical use.

dogs and found that the drug was ineffective in the fully pancreatectomized ones but effective in the partially pancreatectomized ones. This later lead to his conclusion that the drugs’ hypoglycaemic property was due to its ability to stimulate insulin secretion directly in the pancreatic β-cells (Loubatières-Mariani, 2007).

Carbutamide The first sulfonylurea to be marketed as a drug for diabetes was Carbutamide. It was synthesised in East Germany by Ernst Carstens and in the early 1950’s, clinical trials for this sulfanilamide derivative Carbutamide were carried out, by Hellmuth Kleinsorge, for the treatment of urinary tract infections. However, during treatment, side effects of hypoglycaemia were also noted (Kleinsorge, 1998) – similar to those experienced by patients treated with IPTD for typhoid in 1942.

These findings were presented to Erich Haak, of the East German Ministry of Health, in 1952, which ultimately culminated in the ban of the drug. Haak later moved to West Germany where he patented the drug to be tested for antibacterial use, without disclosing the side effects of hypoglycaemia. Karl Joachim Fuchs, a doctor who was part of this drug testing, noticed symptoms of ravenous hunger and euphoria upon taking the drug himself, which were found to be due to hypoglycaemia. Following this, studies were undertaken, and a general conclusion was that Carbutamide was most effective in people over 45 years of age, who had had diabetes for less than 5–10 years and had not used insulin for more than 1–2 years (Tattersall, 2008). The use of Carbutamide was short lived as it was found to have fatal side effects in a small number of people, including toxic effects on bone marrow (National Center for Biotechnology, 2005).

The structure of Carbutamide is shown in figure 2 (Anon., 2021). It can be seen, attached to the benzene ring on the left-hand side of the sulfonylurea functional group, can be seen an amine group.

Attached to a second amine group on the right side of the functional group is a four-carbon chain. As mentioned previously, it is the sulfonylurea functional group that gives rise to the drugs hypoglycaemic effects. This is the first drug to contain the sulfonylurea functional group (seen in figure 1) and the beginning of many discoveries into

Figure 1 Sulfonylurea functional group

History and development of the drugs and their chemical structure Sulfanilamide and IPTD In 1935, a French research term discovered the active chemical in the antibiotic prontosil, known as sulfanilamide (Sorkhy & Ghemrawi, 2020).

Sulfanilamide was found to be a poor antibiotic and so derivatives of it were synthesised and tested.

These compounds, such as such as p-aminosulfonamide-isopropylthiodiazole (IPTD), which was used as an antibiotic for the treatment of typhoid in 1942, revealed unexpected hypoglycaemic side effects. These were discovered by French physician, Marcel Janbon (Quianzon & Cheikh, 2012).

However, scientists could not identify how these side effects were caused.

In 1946, Auguste Loubatières, investigated the effect of IPTD on dogs. He administrated the drug to fully pancreatectomized and partially pancreatectomized 38

et al., 2015). This meant that Chlorpropamide could not be administered for the safe treatment of type 2 diabetes.

the treatment of non-insulin dependent diabetes mellitus.

Figure 4 Structure of Chlorpropamide

Figure 2 Structure of Carbutamide

Glibenclamide Glibenclamide is the first of what is known as the second-generation sulfonylureas. Introduced for use in 1984, these mainly replaced the first-generation drugs (Carbutamide, Tolbutamide, Chlorpropamide etc) in routine use to treat type 2 diabetes. Due to their increased potency and shorter half-lives, lower doses of these drugs could be administered and only had to be taken once a day (Tran, 2020). These second-generation sulfonylureas have a more hydrophobic right-hand side, which results in an increase in their hypoglycaemic potency (Skillman & Feldman, 1981). In Glibenclamide, the left-hand side of the drug changed drastically from chlorpropamide, as seen in figure 5 (Anon., 2021).

This suggested to medicinal chemists, an innumerable number of possible changes that could be made to the drug, simply by changing the left and right-hand sides, resulting in better potency, safety, efficacy and convenience (Monash University, 2021). Consequently, the metabolism of the drug varied between patients, and this in addition to increased hypoglycaemia and increased incidence of Cardiovascular events (Scheen, 2021), meant that the drug is not a first choice in recommendation to treat type 2 diabetes.

Tolbutamide After the discovery of the fatal side effects of Carbutamide, the next sulfonylurea drug to be synthesised was Tolbutamide; it was one of the first sulfonylureas to be marketed for controlling of type 2 diabetes, in 1956 in Germany (Quianzon & Cheikh, 2012). There were minimal changes to the chemical structure in this next development of the sulfonylureas. The amine group on the left hand side of Carbutamide was swapped for a methyl group to give Tolbutamide, shown in figure 3 (Anon., 2021), which helped reduce the toxicity of the drug.

However, as a result tolbutamide was subsequently being metabolised too quickly (Monash University, 2021), which led to low levels of the (active) drug in the blood. The drugs efficacy was therefore lower than expected, resulting in it having to be administered twice a day, which was an inconvenience for patients.

Figure 3 Structure of Tolbutamide

Figure 5 Structure of Glibenclamide

Chlorpropamide It was soon discovered that the methyl group attached to the benzene ring in Tolbutamide was the site of its metabolism (Monash University, 2021) and so it was replaced by medicinal chemists with a chlorine atom in the next drug, Chlorpropamide (see figure 4 ), (Anon., 2021). This helped reduce metabolism, giving the drug a longer half-life, so it was not cleared as quickly from the body. Indeed, a University of Michigan study found that chlorpropamide serum concentration declined from about 21 mg/100ml at 15 min to about 18 mg/100ml at 6 hours, whereas the tolbutamide serum concentration fell more rapidly from about 20 mg mg/100ml at 15 min to about 8 mg/100ml at 6 hours. Therefore, it could be seen that under experimental conditions, tolbutamide disappeared from the blood approximately 8 times faster than chlorpropamide (Knauff, et al., 1959). This would mean less frequent dosing with chlorpropamide, which would make the drug much more convenient for patients to treat type 2 diabetes. However, further research subsequently revealed that, due to the longer half-life of chlorpropamide, the hypoglycaemic effects were compounded and lasted longer than previously expected (Sola,

Glipizide Glipizide, figure 6 (Anon., 2021), shares the same hydrophobic structure on the right-hand side as Glibenclamide, however a few changes have been made to the lefthand group, resulting in faster metabolism. Although it has similar potency to that of Glibenclamide; however, the duration of its effects was found to be much shorter (Brogden, et al., 1979). Glipizide has the lowest elimination half-life of all the sulfonylureas, reducing the risk of the long-lasting hypoglycaemic side effects found in previous developments (Anon., 2022).

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disadvantages in potency and safety. The discovery of the ability to modify the left and right sides of the drug’s common structure has led to many new forms within this class, with varying properties in potency, metabolism, efficacy, and safety. The experimentation of the chemical structures over time has led to the production of more effective treatments for the disease. Currently, Glipizide and Gliclazide are the two most commonly prescribed sulfonylureas, due to their high potencies and suitable half-lives, while maintaining minimal side effects. These now provide an effective treatment in helping reduce the symptoms of type 2 diabet es and thus improving quality of life for those suffering with the disease.

Figure 6 Structure of Glipizide

Gliclazide Gliclazide is the most common sulfonylurea used in current medicine for the treatment of non-insulin dependent diabetes mellitus; it is part of the World Health Organisation’s most recent list of essential medicines (World Health Organisation, 2021). The chemical structure of Gliclazide can be seen in figure 7 (Anon., 2021). Fascinatingly, medicinal chemists returned to the use of a methyl group on the left-hand side of the drug, which was last seen in Tolbutamide. As mentioned before, the lefthand group on the drug, attached to the benzene ring, is responsible for the metabolism of the compound.

Returning to the use of a methyl group, allows for a faster metabolism of the drug, which helped to remove the unwanted longer hypoglycaemic side effects, especially for use with elderly patients (Monash University, 2021). The right-hand group of gliclazide is comprised of two hydrophobic rings which, as mentioned previously, are responsible for its increased potency. Gliclazide has also been shown to be one of the most effective sulfonylureas.

According to Harrower, three studies carried out concluded that gliclazide is a potent hypoglycaemic agent, which compares favourably with others of its type (Harrower, 1991).

References Anon., 2021. Carbutamide. [Online] Available at: https://www.drugfuture.com/chemdata/carbutamide.html [Accessed 27 March 2022].

Anon., 2021. Chlorpropamide. [Online] Available at: https://www.drugfuture.com/chemdata/chlorpropamide.html [Accessed 29 March 2022].

Anon., 2021. Gliclazide. [Online] Available at: https://www.drugfuture.com/chemdata/gliclazide.html [Accessed 30 March 2022].

Anon., 2021. Glipizide. [Online] Available at: https://www.drugfuture.com/chemdata/glipizide.html [Accessed 29 March 2022].

Anon., 2021. Glyburide. [Online] Available at: https://www.drugfuture.com/chemdata/glyburide.html [Accessed 29 March 2022].

Anon., 2021. Tolbutamide. [Online] Available at: https://www.drugfuture.com/chemdata/tolbutamide.html [Accessed 29 March 2022].

Figure 7 Structure of Gliclazide

Conclusion Sulfonylureas are one of several groups of drugs used to treat type 2 diabetes. Through research and trials, they have developed significantly over time, to become one of the most prescribed medications in the effective treatment of type 2 diabetes.

The sulfonylureas discussed above represent significant developments in physiology and pharmacology of the group, since their initial discovery. Other sulfonylurea drugs have been synthesised and tested over the years, such as tolazamide and acetohexamide, however these are less commonly prescribed because of their

Anon., 2022. Glipizide. [Online] Available at: https://pharmaoffer.com/api-excipientsupplier/glipizide#:~:text=About%20Glipizide&text=It%20was%20fi rst%20introduced%20in,glucose%2Dlowering%20therapy%20follow ing%20metformin.

[Accessed 29 March 2022].

Brange, J. & Langkjoer, L., 1993. Insulin structure and stability, Bagsvaerd: Novo Research Institute.

Brogden, R. N. et al., 1979. Glipizide: a review of its pharmacological properties and therapeutic use. Drugs , 18(5), pp.

329-353.

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Illustrated by Maha Nawaz