JAK-STAT pathway: hacking protein regulation

So the JAK-STAT pathway, as with all pathways, have different functional effects. It is associated with cancer, immunodeficiency, growth retardation and many more.

different ligands induce the phosphorylation of different STAT residues. This increases provides a regulatory mechanism on the downstream signals. It is fascinating to see the different ways in which cells regulates proteins.

It would be interesting to utilise the cells method in controlling and understanding cellular function. This can be extrapolated to obtain therapeutic methods for the diseases associated with the JAK-STAT pathway or it can be used to counter bacterial infections.

I would like to know the differences between the phenotype and genotype between JAK-STAT caused diseases and those diseases with other causes.

Review: http://www.annualreviews.org/doi/full/10.1146/annurev-med-051113-024537

Protein structure of the JAK-STAT receptor. Image obtained from http://www.niams.nih.gov/Research/JAK-STAT_Meeting/

The importance of fly hearts

The drosophila (fly) had been, and still is, an important model organism in science.

There are developmental similarities between drosophila and vertebrate heart development. From lineage tracing and genetic testing, there are homologues to the drosophila gene found in the human genome responsible for heart development. Since it is relatively easy to view and manage drosophila in the lab. The drosophila could be induced to model a specific cardiac disease and taking into account age-related or nutrition-dependent effects.

During the third instar of drosophila development, the heart is innervated and has its own pacemaker. At this stage the heart can be extracted and utilised to test the physiological conditions.

An interesting paper (Zhou et al. 2009), discovered that cardiomyocyte are derived from epicardial progenitors. The implications of this study suggest it could be utilised in cardiac repair and regeneration.

The next experiment should determine whether the epicardial cells can be induced in foetal mice hearts as a regenerative mechanism or whether the epicardial cells are necessary for cardiomyocyte development.

Review: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551295/#R181
Primary paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574791/

Wt1-derived cells differentiate into cardiomyocytes. image obtained from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574791/

Get rid of background noise!

Sir Tim Hunt explained the complexity that arises in biological organisms in the most eloquent ways. His statement was based on the evolution of species. The previous basic pathways used to perform the task is 'replaced' efficient pathways of performing specific tasks. The basic task is actually not replaced, it is just not used, it fades into the background. But, nevertheless, it is always there. This is what make the cell a complex structure. 

As a researcher you need to know how to focus on the pathways that matter and not to be deterred by the background pathways. Going along this logic, I believe this same mindset should be used when determining the auto-immune diseases. (I have not yet checked the literature to assume that this mindset has not been used). 

The immune system is already a complex one, if we are able to extract the essential proteins involved in the disease then I believe it would lead to a quicker understanding of what goes wrong in autoimmune diseases such as myasthenia gravis. 

Image obtained from http://www.outofthewoodsnutrition.com/blog/2015/7/15/10-things-you-need-to-know-about-autoimmune-disease

Kill cancer cells?

Targeted apoptosis of cancer cells.

Tumour necrosis factor is a ligand the binds to the TNF receptors and activates downstream signalling pathways.

An interesting characteristic about the TNF signalling pathway is that they activate inflammatory-genes and it also induces apoptosis.

This might be a potential therapeutic target for cancer. By directing the gene or protein to specific tumour cells. It will be more specific than chemotherapy and more effective. The transmission method could be through retrovirus or a mechanism that pathogens utilise to enter the cell.

Function of TNF. Image obtained from http://www.sciencedirect.com/science/article/pii/S0165614710002105

review - http://www.nature.com/cdd/journal/v10/n1/full/4401189a.html

Zebrafish Regeneration

Zebrafish are model organism used in Biomedical Science. One of the used is to observe how the cellular and molecular processes influence their regeneration.

An interesting thing is that the fin can regenerate. Epithelial cells are the first type of cells to cover the wound and then other cells differentiate into the fin structures.

It also regenerate its heart. The implications are great. If we can induce pluripotency in differentiated cells. then we can induce regeneration in heart cells, especially in humans. But first, we need to understand the molecular cascades that are responsible for regeneration.

The beauty of biology is that the cascades to achieve an effect are similar. Consequently, when we deduce how regeneration is induced in the heart. It will make regeneration of nerve cells relatively simpler.

There is an interesting paper that looked at heart regeneration. They genetically ablated muscle cells. This is really impressive because there is no injury induced on the surrounding cells, as seen in lesions. This increases the specificity of the ablation. They also labeled the surrounding cells, in order to trace the origin of the regenerated cells. Regeneration was observed by fluorescence and electrophysiology.

They should experiment genetic ablation in mammals, to see whether it would induce a slight regeneration. I think KO experiment of known genes should be done in conjunction with the ablation studies to determine which genes are responsible or influence regeneration.

Review: http://www.sciencedirect.com/science/article/pii/S0168952513001133
Primary paper: http://dev.biologists.org/content/138/16/3421

Rapid regeneration of ventricular cardiomyocytes after ablation-induced injury. Figure obtained from http://dev.biologists.org/content/138/16/3421

Aims and objectives

My Aim is to at least have one post per week about science and an idea. The idea will be a hybrid of two different concepts.

The objective of the project is to:

• develop creative and innovative thinking
• being up-to date with current research
• develop an interest
• improve my critical thinking of papers
• enhance my writing skills

Well, let's start this journey, innit?

Nanotechnology and the body

TEDMED talk by Anita Goel: How will nanotechnology be used in the body?

Theme: the interaction between biomedical science, physics and nanotechnology

It comes from an understanding of nanotechnology, physics and, the cellular environment; and being able to manipulate these factors. They found that the degree of stretch of a DNA strand affects the direction of polymerase of a double stranded DNA.

apparently our current pathogen identification and detection systems are not useful in diagnosing unknown pathogens. How were they able to extract the DNA/RNA without the need for culturing and skipping the bioinformatics stage?

My idea
1. Instead of waiting and checking a patient until they are sick. why not design a nanobot that is attached to the internal environment in the body. Thus, whenever there are slight changes in the body temperature or if a pathogen is detected. It can be easily translated to the patient before they can feel the symptoms.

2. Use DNA to store information instead of USB or hard-drive. It takes up less physical space and has a much more efficient tools [enzymes] that protects it from being damaged.

Lecture: GFP and RNA analysis

Todays' lecture was about non-genetic analysis involving GFP and RNA formation.

What I found interesting was the amount of regulation and variety that is achieved from RNAs! it's so fascinating! With the example of the drosophila, how sex is determined by how the same gene is spliced. If it is spliced in one way, the embryo is male and if it is spliced in another, it is female. There are other regulatory pathways involved that promotes a specific form of splicing. Another interesting phenomenon that is seen in biology is the use of a single molecule to promote different behaviour ex. cytoplasmic iron levels and the formation of ferratin or transferrin.

I implemented the idea that I would write cue words along throughout the lecture and then constantly review them. This worked and help in recall and I realized that when I recalled I actually thought I covered everything. However, when I check, I realize that there are lots of details I missed. This is helped me become more aware of the details that is needed in BMS. I found that it is way more effective to listen to what the lecturer was saying, then read the slide and then write. This helps compact the information into what I understand and I remember it for a long time. My rate limiting step is my typing speed. Thus, this needs improving. My aim is to reach 60 wpm. I am aiming to achieve this before the next lecture. Another area of improvement is my sleep cycle, I need to maintain a strict sleep cycle otherwise I wake up late and my mind is not optimally active. The last area of improvement is seeing the connections within the topic and cross-modular.

The future
This is my favorite part because I get to see the relevance of the information to a bigger picture.
GFP is something that is used in anything and everything. Is there a way of introducing spliced eIF-4G in cancerous cells, inhibting them from producing growth factors etc. According to a study by Bauer et al. 2002, eIF-4G overexpression is associated with cancerous cells. There are other eukaryotic transcription factors that are associated with cancer. They could also be used as a diagnostic tool.


Bauer et al. 2002: http://www.ncbi.nlm.nih.gov/pubmed/11857405
Veremieva et al. 2014: http://www.ncbi.nlm.nih.gov/pubmed/25472873

Personal tutorial

Well, I just came out of a personal tutorial meeting. We talked about S1 grades. It was really interesting, this was the first time that I felt comfortable, where I felt like myself. I felt confident on talking about what I want.

I felt different, I don't know whether it is a result of being a chair... I suspect it is.

I talked about how I could have improved my grades and he gave me a contact of a person who got admitted into medicine.

What I found interesting about me was that I didn't mention my other activities this semester... It is interesting because we were talking about what I could do to get my CV up to the standard. I mentioned the SURE scheme and the volunteering at the Sheffield Royal Society for the Blind. However, I did not mention the fact that I am a chair, or that I got on the eMentoring course or that I got on the research course. Why? I think one of my fears comes up again. I don't know how I will be viewed. I was afraid of being told to drop the things I am doing. It is interesting. But, what I do is okay; it's not too much. At least in my mind.

This is something I need to assess.

Well, regarding the S1 results; there are lots of room for improvement. The next step is to determine how I will go about it. This is exciting. In my second year, I learnt that the best way to pass is by reflective writing. I learnt a lot from that process than by reading multiple books on self-improvement; and, the best part is that I am learning more about myself in the process.

Lecture: tyrosine kinase receptor and cellular analysis

There were two different lectures today, that interestingly overlapped. They were both talking about processes that were taking place in the same location. However, the first lecture was more general and the second lecture had a specific example.

Lecture 1:
This lecture described genetic and non-genetic analysis. The information discussed in this lecture was taught to us lat year, but, the lecturer categorised them. The categorisation helps during recall. Topics: different types of mutations (their effect on transcription factors), detection mechanisms of proteins using in situ. the interesting thing is that, it was way more detailed than what we learnt last year; there was more detail regarding the vectors and promotor sequences.

During this lecture I could have improved on my note taking skills. I realized that there were some points that I misspelled or didn't read the slide notes. It was because I was rushing through trying to get everything down instead of trying to understand it. for the next lecture, I need to make sure that the lecturer is the type that puts up the slides online, read prior to the lecture and just take my time to understand what he says. What I found helped me was trying to recall the points he mentioned at the beginning of the lecture and consciously trying to see how everything connects in a lecture. What I found difficult with this process was that I missed out some details and point. Next time, I will write down the main point in one word in my note book, so that when I try to recall I can check against it.

Lecture 2:
This was similar to the TGF beta, the tyrosine kinase receptor had a similar structure. What I found fascinating was the specificity in the docking proteins and their signalling cascades. The concept of  -morphic mutations were introduced in the TKR. It was interesting to find out that the extracellular matrix (HSPGs) play an important role in signalling pathways. There is just a lot of layers of regulation within a cell that's mind boggling.

Lecture: DNA control of gene expression and the brain

Well, there were 2 lectures today. One was about the control that we and other species have of DNA expression and it stressed mainly on processed that affect transcription. The other lecture was about the external features of the brain.

Lecture 1
I was more awake during this lecture and I could organize my notes. I think this was because the lecturer was talking slowly. The good thing about this lecture was that everything here was repeated. So it was all familiar and this was more like a revision. With todays lecture I listened and read before writing. I managed to get everything written down.

An area of improvement was I think the lecturer could have had better time management, he ended up rushing in the end(to be fair he was substituting for another lecturer). I realized that aiming to do the recommended reading in the morning is not working at this moment because I wake up late. Therefore, I should switch to doing the reading the night before, it should take 15-30mins. Maybe I should have a 'time-line' of the whole cellular events, so with each lecture, I will update it.

Lecture 2
I felt like I what we were covering was familiar. What I learnt about myself that, I can memorize the names during the lecture by association such as 'falx cerebri' <-- that actually took me a while... I need to find a more effective method of memorising in lectures. I learned that during lectures I need to mentally review what we went through from the time it started.

My problem is quick recall. Recalling the information is difficult. What can I do about it? What has worked for me in the past? Well, going over the objectives really helped. I feel like I need to dedicate a day of the week to gather information and commit to memory the information so far. The best day would be after the lab lessons or on friday afternoon. In the lecture, I think it would be more effective to have a mind-map rather than taking linear notes because a lot of things overlap.

The future
I just find it fascinating that the brain; something so small, so light, is in charge of our life. It's just really interesting. I would really like to know the organization of the brain. The relationship between structure and function. Is there a possibility of regenerating ones' brain? I want to have a holistic approach with the brain, how it is in charge of all the processes going on in the body. I think I will need to review my past lecture notes but this time with interest. Why don't lecturers start their lectures with an interesting way their concept can be implemented in the real world.
What is the future of brains? That is my question.

The beauty of control of gene expression is that we have an idea of what is happening in the nucleus, however, can we mimic this process? when will it be used?

RNA and mesoderm segmentation

There were two different lectures today; one regarding the pathway of RNA in the cell and the other regarding mesoderm formation.

I found them really interesting, the degree of detail and complexity was fascinating! One can't help but wonder how this strict organisation within the body is achieved and how is it conserved in so many people.

The lectures were okay. In the RNA lecture, I felt that he could have had someone volunteer to demonstrate the super-coiling. Also it would have been useful if there was an animation when explaining how the RNA is spliced. The good aspect about it is that the information was covered last year. I didn't ask any questions for this lecture, even though I had some. I felt nervous getting up and asking a question. I still don't understand myself; why do I feel this way. Another skill to develop. The second lecture, was delivered really well. There were some videos that could have been slower to help us grasp the concept but nonetheless it was understandable. It still astounds me how the clockwork mechanism works and the interaction between the clockwork and dividing front (need to recheck the terminology.

RNA: it helps understand viruses, potential areas for anti-bacterial drug development

Mesoderm segmentation: the disease that affects vertebrae symmetry, will it help in regeneration when one understands the molecules involved?

Next time:
I would have helped to read the material beforehand. Read the lecture slides and understand how the molecules interact with each other. It was interesting that the lecturer stated the clockwork formation as a story, it help stick in my mind, the background of its discovery.

New leaf

From now on this blog will be used as a reflective journal, where I will putting up my reflection regarding a set of lectures I undertook on the day.

Enjoy!

Parkinson's Disease drug target

Parkinson's disease is associated with the degeneration of dopaminergic neurons.
There are neurotrophic factors (molecules that induce neuronal growth) associated with the formation of dopaminergic neurons in the mid-brain.
It is called Glial Derived Neurotrophic Factor(GDNF).
Since, Parkinson drugs target the dopamine pathway; the have side-effect of inducing psychosis. another drug target could be increasing cAMP, or stimulating the MAPK pathway in those cells.

However, it is important to note that the research done on GDNF occurred in developing neurons and not targeted at regeneration.

Visual system; photoreceptors

The interesting thing is how light energy is turned into electrical energy using a single cell. It is amazing how the photoreceptors accumulate and work together to create a detailed 'picture' of the world.

the power of transduction. this is a useful mechanism that will be really useful in producing electricity. Where light shined on a protein, changes the electrical potential of a cell, making it more positive or negative. Imagine if we could make a single cell, like in the thick ascending limb cells, where there is a concentration gradient set up with the proteins, allowing a one-way movement of ions. However, this requires a high concentration of the ion outside the cell otherwise it wouldn't work... but an interesting thought!

The case of disease

Diseases scare us, the moment we think about them, we think death. We are afraid of death, yet it is inevitable. However, the way you die might be totally unexpected.

Cadavers provide an interesting model for understanding the body. An interesting phenomenon is that the cadavers tend to have other pathologies or problems going on with them that weren't the cause of their death. A hypothetical example (for the sake of confidentiality) is, the cause of death was throat cancer, however, when looking at the cadaver; there were other illnesses such as liver damage.

It is interesting to see what other things are wrong with the body; very very interesting!

Inspiration from Nature

Today, I had a lecture regarding the Basal Ganglia (BG). It is a structure in the brain that chooses where to move the limbs (ex. to get the water or to finish H/W). As a result of this system, vertebrates show complex behaviour. The interesting thing is that, the micro-architecture of the BG is identical; however, the BG is separated into different units that perform specific function (ex. hunger, threat response etc.).

This aspect of Nature, where complex functions occur as a result of simple repeating structures is conserved throughout the body. It is seen in cell movement with microtubule assembly and spinal cord development where it involves a small number of transcription factors.

The same approach should be used when manufacturing items/units. We should try to uncover the most simplest and generic structure that can be used across the boards.

Simplicity is the key!

artherosclerosis

Atherosclerosis is the build up of fatty substances on the inner blood vessel lining. This later causes the blood vessel to become clogged up and the fat can detach and block smaller vessels.

Problem:
Smaller blood vessel, especially the coronary arteries, when blocked have large consequences on the BP and transport of oxygen to tissues. A possible solution could be to put a nano-tracer, that circulates the blood vessels and maps out the diameter of the vessels. Any abnormal diameters or changes in it, will be detected and lead to a better diagnosis of heart attack.

The related problem is to develop a nano-tracer, that will do such a thing!

Rheumatoid arthritis

Rheumatoid arthritis is an auto-immune disease, where the body views and attacks the cartilage as a pathogen. It is really harmful and there are no distinct causes, however, there are genetic correlations. There is no solution to treating this disease. The patient will be given drugs that reduce the increase of immune cells in joints.

A possible solution could be to cover the MHC (a protein identifies a cell of an individual) with other accepted MHC. this would reduce the target of the immune cells and at the same time drugs should be given to reduce the effect.

water

This is a short one, but very far fetched (at least I think so)

Will it be possible to obtain water from air...this would solve lots of problem (obviously)...