Pathogenetics behind RASopathies

RASopathies are group of genetic syndromes cased due to mutation in genes (somatic) in RAS/MAPK pathway. The possible syndromes include Neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome (NS), Costello syndrome, autosomal dominant intellectual disability type five and many others. Commonly the RASopathoes represent developmental malformation syndrome. This article represents the short note about RASopathies and the pathogenetics behind.

RAS/MAPK Pathway

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RAS/MAPK pathway plays a pivotal role in cancer as well as in development. Genetic mutation in any of the pathway molecule may lead to different RASopathies as discussed above. Ras proteins are guanosine nucleotide-bound GTPases which is activated through multiple mechanisms including growth factors binding to receptor tyrosine kinases (RTK). This binding promotes RTK to auto-phosphorylation and interaction with growth factor receptor-bound protein 2 (GRB2). GRB2 then binds to son of sevenless (SOS) that is recruited to plasma membrane.

SOS is a guanosine nucleotide exchange factors (GEFs) that increase Ras’s GDP exchange rate for GTP. The activated Ras then lead to the activation of Raf (ARAF, BRAF and CRAF). Then a serious of phosphorylated events takes place for MEK and ERK. Finally the ERK1 and ERK2 are the ultimate effectors which functions to modulate downstream molecules.

Pathogenetics in Rasopathies

Ras signals to multiple intracellular pathways and the central pathogenetic denominator for Rasopathies is RAS/MAPK pathway activation. As mentioned before each mutations within this pathay leads to different Rasopathies as the distinct mutations affect the fundamental molecular mechanism of the pathway.

Table: Functional Characterization of genes associated with RASopathies (Follow Reference)

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Ras effecter pathways are down regulated or up regulated or sudden aberration due to different mutations generated within the pathway. Functional studies have generated enhanced pathway signalling due to the majority of mutations. Each Rasopathy is unrelated or unique. Upstream of Ras mutation causes aberrant Ras activation like mutation in PTPN11 and RasGAP; whereas downstream mutation of Ras may reflect intolerance for such mutations in development. It is important to decipher the function or aberration caused by the mutations to understand pathogenetic etiology.

Reference:

Tidylman WE, Rauen KA (2016) Pathogenetics of the RASopathies. Human Molecular Genetics. July 12, 2016.

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Ancient Civilization of Microbes who built ‘Lost City’, Not Greeks

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The formations resembling Greek ruins

Zykanthos is a Greek island in Ionian Sea and there are many stories about this lost city. It is the time when snorkelers discovered the ancient stonework and excavations in the bay off to this Greek island and government archaeologist began to investigate. The debris found might be the ruins of the city and a rare discovery in the shallow waters.

Now plucking the odd things out, archaeologists did not found shards of pottery or other valuable remnants for everyday’s existence. This would suggest that people might once have lived here and perhaps need to move away to survive, fleeing from rising water levels of sea.

After such long thoughts about the habitat, scientists finally navigated the clue. The columns and other objects found are not at all stonework but rather are the natural byproduct of breakdown methane gas. So those are ancient microbes who made it not people.

The research was published in the journal Marine and Petroleum Geology which led by the lead author Julian Andrews from University of East Anglia, England mentioned it as “cold seep” where methane in deep formations moved upward and then added sediments over sea bed. Those sediments are used by bacteria that use methane as their source of energy.

All the consumption of methane changed the chemistry of the water that lead to the saturation of sediments. The minerals precipitated and formed as rock dolomite. These dolomites cemented the sedimented particles at places forming concretions.

These concretions might have formed millions of years ago as the researchers suggested. The wonderful mystery lead by microbes are now solved which was previously misleaded.

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Say hello to Microbes! MiTalk the Radio Show

Now it is from reading to listening. A leap ahead in science communication from writing about Microbiology and now speaking about Microbiology too. It was already under future objectives of We The Microbiologist forum. Our group was under discussion about how to team up and go ahead with such an oriented Radio Show about Microbes. But finally it hit the success. The show is named MiTalk or Microbiology Talk and can be reached at www.microbiologytalk.com

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It was Mr. Varun Chakrakodi who is an active science blogger from Medical Microbiology looked at the objectives listed at WTM and contacted me. I was glad to know that I was not the only person who was thinking to launch such Podcast. Soon then we team up with Dr. Sridhar Rao, Assistant Professor in Microbiology from JJM Medical College, Karnataka, India and Mr. Sagar Aryal from Kathmandu Nepal.

Dr. Rao is the mentor of this show management and also a co-host of this show. He is well known about his medical microbiology notes he shares over his own website which is filled with wonderful knowledge database for students. Mr. Sagar Aryal was approached to be the co-host of MiTalk while we were discussing over this podcast. He has been an obvious person who can lead with the knowledge he bears about Microbiology. Mr. Aryal is well known for his notes he shares through his website and only Microbe active science communicator from Nepal.

So here is the team:

  • Mr. Varun C.N. – who is the chief-host of MiTalk and associates in recording and managing the shows with notes. He is also co-editor of the content in website.
  • Dr. Sridhar Rao – co-host and mentor of MiTalk. He guides the whole system.
  • Mr. Sagar Aryal – co-host and associates in web management. He is the chief-editor of the website and content.
  • Mr. Saumyadip Sarkar – co-host and manage the recording. I audit the recording and also communicate Scientists who can be the part of this show.

There are so much to explain about Microbiology and it can be well placed while we discuss over some mysteries which is solved, debatable or still under mystery. We try to pull those topics which is important to talk and can be communicated with general audience. It is open access and can be accessible through iTunes . So you can plug in your headphones and you can listen to MiTalk even though you are traveling.

It was published on 4th of September 2016 as the first Microbiology Radio Podcast from South-Asia. I feel many of the science lovers listen to many Microbiology Podcast but this might be little different why? Here are some reasons:

  1. General to Hard Core Science: Here we talk about general topics and even pull in research papers. So if you are a student and wish to explore more about Microbiology then you can easily understand and also make notes if needed. Researchers too can have the complete overview about the topic including research notes which are vital.
  2. Join the Show: It is much enthusiastic to know that Scientists can join for a talk in one of our show either voluntarily or even we try to contact to share his/her views over his own research field.
  3. Science apart from Microbiology: It is not just Microbiology but at the end of the show we often conclude with “Science aside Microbiology” which can be important and fun.
  4. Comments and Answers: What you suggest, comment or add is important. It is obvious you may wish to add some point about the show, add some comments, email us with possible topics, or anything about Microbiology. If it is worth sharing or could be discussed we will refer your name in the show.

You are very much welcome for Microbiology Talk. Please listen to the shows which is released twice in a month. Subscribe to get regular updates and mail us your views.

 

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I support open access research! But why?

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It has been a long debate between open access and restricted access of research. So what is open access? Simply it is free from all restrictions of copyright and licence. We often find some of the conference papers, research articles, book chapters, etc are not freely accessible and one has to pay some amount to get the full access. On the other side there are organizations who publish research opening gates of full access of all the materials. So here are important notes about why open access research is vital.

Students prospective

Students keep on looking things and search articles over internet. It is obvious that they cannot pay such hurdles to complete their school or college assignments. Open access research can expand the information which is more relevant than in restricted access which will provide just an outlook of the content. Internet is the source of education and hence pupils use the resources to go through research papers. Even to cite them you need the full access of the paper so that you can read the content.

Scientists or Researchers’ prospective

This is under the highest category. Researchers keep on searching things that is vital for their experiments. A small hint can sculpture the whole hypothesis. So it is important to read the whole matter of the content than just the overview. No researchers wish to deduce amounts from their funds to perform study. It also pours an important effect to avoid duplication of research.

Science communicators’ acts as a bridge that communicates different readers providing the importance of research materials that is full of scientific terms into simple understandable formats. Research is useless if it is not shared. So, open access research is probable of fetching more citations than restricted access which is much overlooked.

Experimental protocols also seem to be important and for different research the protocols are modified according to the type of samples or conditions they study. It is a hurdle too if there is a barrier. Most protocols cannot be standardised and require help for such protocols. So open access breaks this barrier and also helps researchers gain citation.

Why are there restricted accesses?

erik12_1383873905Restricted access is important too. Some of the confidential datasets cannot welcome public to impose threats. It is like a home with uninvited guests. But if you provide greetings to some people whom you know is better from any threat.

On publishers point of view both for profit or non-profit, by some it is mostly observed that they shuffle between open access and restricted access. So it is a kind of strategic business to run a journal.

Many researches can also be a part of social threat. Many formulas which should be enclosed to improvement of living can be used by terrorists in the negative shades. Confidential barrier allows people to know who actually wants the access of the research.

 

In conclusion, it is good to add that still in my personal motif I support open access research and it is very important for development of scientific research. It fetches a lot of solutions and exposure of scientific activity required nowadays. Confidential barrier is important too, for avoiding unwanted situations. Scientific research data is an asset and hence protecting it is also a duty.

Let me know what you think about open access and restricted access in the comment box. I will try to reply most of you. Do not forget to vote🙂

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Why vaccine run is slower than the epidemic spread of virus?

about-ebola

Ebola under SEM (Courtesy: CDC)

Are we aware? What is happening? Where are the vaccines that proved to be successful? Why Ebola vaccines are still under trial? Why are there success stories been proposed in research papers? I am sure that these questions are must and most obvious. There are several reasons why a laboratory proposed vaccine needs long time to launch in market. Here in this small note brining you forward about why vaccines are slower than the epidemic run of virus.

While we take two names those come first are Zika and Ebola. Looking at Zika three vaccine candidates have proved to be successful in monkeys and another has reached under human trials. Unfortunately the run of Zika is much higher. It has already reached 66countries after Brazilian epidemic. On the other hand looking towards Ebola, two vaccines have reached its final trial. But Ebola had been reported to halt its spread since the last update on 10th of June with 28,616 cases and 11,310 deaths. (Read Ebola 2016 update on Biomysteries). So hopes are high but vaccine run is too slow and may be the Zika virus vaccines may take a year to reach the market.

So here are some reasons why vaccines are backlogging

  1. Before Epidemics

When disease starts to spread and often it takes late to understand what it is that is spreading high. So taking example of Zika which was known to spread in Brazil early August 2015, World Health Organization (WHO) reported its alarm in February 2016. In between Zika already has reached to be pandemic. For Ebola too, it took the same time to be understood what it is that spreading. Even investigators get affected with Ebola.

  1. Shifting strains

There are different strains every time. Common example would be Influenza which have multiple strains based on the protein coat Hemagglutinin (H) and Neuraminidase (N). So it is named on the type of strains like H1N1, H2N3, H1N4, etc. Similarly for Zika there are two strains African and Asian. The recent hit is considered to be similar to Asian strain. One of the scientific reason is low processivity of Viral DNA proofreads. So it may shift in between the strain. More it shifts slower would be the run for vaccine.

  1. Risky business for companies and lack of funds

It is not about the virus but about the vaccines. Big pharmaceutical companies can invest only for research and few come forward while there is an urgent need of vaccines. WHO also needs enough support of various companies to eradicate the Viral attack. The negative side lies when vaccines does not overcome all the clinical trials and make them push towards losses. So it is a big job for pharma companies to think before they invest. Whereas, WHO also lacks enough funding and it needs support so that all from the world can collaborate.

  1. Animal models

Once Scientists make a potential vaccine it has to be tested on rodents like rat or mice specifically. But sometimes it is not enough available to undergo testing. Also, it is not always that vaccines that worked on mice will work similarly on humans. The virus also may not affect rodent’s similar way as it does on humans. Although mice holds most genetic similarity with us but it is not same as humans.

  1. Reaching Human trials

It is the ultimate goal for any researchers to push the vaccine to human trials. It is not always to take lightly but there are many vaccines that made it to human trials. Unfortunately the bad news is companies struggle to find enough volunteers to continue the trials.

 

It is just a brief story about the hurdles that most vaccines need to face. The morale of the story is although the epidemic spread runs like rabbit but the race is finally for vaccines although it runs like turtle. It needs enough support to build the bridge between the clinical trials. Scientists, organizations and companies are equally struggling to halt the spread of Zika with successful vaccine. Hope the final news hits soon.

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NorA Multidrug resistance Efflux pumps in Staphylococcus aureus

Gram positive organisms can be resistant to first line of antimicrobial agents and leading to complications in therapy. One of major reasons for these complications is efflux pumps. Apart from Drug resistance efflux pumps are used by bacteria to acquire nutrients, establish proper membrane charge and pH gradient, and to excrete out the by-products. [1] The efflux pumps are natural process that allows bacterial survival against multiple environmental challenges. There are lots of potential researches about gram positive efflux pumps and amongst those norA is much notable pump to be discussed here.

Types of efflux pumps

Efflux pumps in Gram positive bacteria are encoded by both plasmid and/or chromosomally expressed genes. For transmissible drug-specific efflux pumps are encoded by plasmids, whereas those which are multidrug resistance (MDR) are usually encoded by chromosome and not donated to other organisms. The plasmid based efflux pumps are multi copy in nature without any additional need of subsequent mutations. On the other hand, MDR occurs due to increased gene expression or occurrence of regulatory mutations.

Types of Efflux pumps in S aureus

Image: Multidrug efflux pumps in S. aureus which is categorized into four families of proteins: major facilitator super-family (MFS), the ATP-binding cassette (ABC) superfamily, the multidrug and toxin extrusion (MATE) family,and the small multidrug resistance (SMR) family.

NorA efflux pump

NorA was first identified efflux pump which is encoded by Staphylococcus aureus. As it is encoded by chromosome and can be well categorized under Multidrug resistance Efflux pumps. The function was identified when norA gene was cloned from the chromosome and based on its nucleotide sequence it was identified to encode major facilitator superfamily protein with 12 transmembrane segments.  NorA efflux pump is amongst the 8efflux pumps known. The others are NorB, NorC, MdeA, LmrS, SdrM, QacA and QacB efflux pumps. Check Figure for the classes of MDR efflux pumps in S. aureus.

Although the function was unknown until Yu et al in 2002 inhibited the protein motif force (pmf) that was necessary for norA gene to function. [3] Most of the active research was in the study of regulation. Most active regulators known are MgrA, NorR and NorG. MgrA fine tune the expression of norA gene and also norB gene and relates with the phophorylation status of the gene. NorG, a GntR-like regulatory protein found to bind the promoter of norA gene. Interestingly, disruption of norG does not affect the transcript of norA rather it provides susceptibility of S. aureus toward beta-lactam antibiotics. Thus norG has additional functions too apart from regulation of norA.

norA is highly expressed in MRSA isolates along with norB genes. Several researches have been experimented on detail role of this efflux pump and notably the promoter regulation of this gene. This is just an overview of one of the efflux pumps but there are more to this and research disclosed several pattern to disrupt the mechanism. Unfortunately there are way other mechanisms S. aureus bring forward for resistance.

Find the following video of a brief about of efflux pump


Additional Reading:

  1. Jang S. 2016. Multidrug efflux pumps in Staphylococcus aureus and their clinical implications. Journal of Microibology 54(1): 1-8
  2. Schindler, B.D; Kaatz, G.W 2016 Multidrug efflux pumps of Gram-positive bacteria. Drug Resistance Updates 27: 1-13
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Interview of Dr. Prashanth Suravajhala

Dr. Prashath Suravajhala made his recent visit in India and I am glad that he welcomed me and spent some time for a scientific interview in between at Ecological Park, Kolkata, India. Dr. Partha Sarathi Das also joined, who is a post doctoral researcher at Vidyasagar University.

Prash shared about his current research, his thoughts on current teaching process, bioinformatics research and also about Bioclues Organization as how he framed it.

Find the full interview here. The weather was windy and even in scorching he heat he didn’t complain.

Click CC after you play the video to get the subtitle.

 

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Interview of Dr. Partha Sarathi Das from Vidyasagar University

It was a general meet of scientists at a common place called Ecological Park (commonly known as Eco park) at Kolkata, India where I am glad to meet Dr. Partha Sarathi Das. It was a common welcome from Dr. Prashanth Suravajhala (Post Doctoral Scientist from Aarhus University, Denmark) for his scientific visit at Kolkata.

I am glad that I shared the screen on behalf of Bioclues Organization with Dr. Das sharing his thoughts over recent advancements in Bioinformatics research in India, share his research and also how to uplift thoughts and research processes in Bioinformatics.

Please click CC after playing the video.

Although it was windy and scorching heat, but still he shared his views without complain. Great man indeed.

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Where is Ebola now? 2016 update

about-ebola

Colorful Ebola under Transmission Electron Microscope (Image: CDC)

The Deadlier Ebola outbreak and it was one of the major pandemic known. This small neither living nor dead nanoscale object shook the world back in 2013-2014 and also after. It was a mighty fight among the researchers around the globe to bring down this Ebola virus (EBOV) outbreak. Thousands of research took place and organizations from different countries came hand to hand with World Health Organization (WHO) for immediate action. It wasn’t been easy then since multiple research does brought some light to cure but they need to go through some controversies. I published a science communication review back in 2015 under International Journal of Microbiology and Allied Sciences along with Mr. Sagar Aryal (Science Blogger at Microbiology World, Nepal) and Dr. Aftab Ahmad (President at National Academy of Young Scientists, Pakistan) highlighting the controversies and solutions 2015. Here I am highlighting the current scenario upto 8th of July 2016.

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Image: WHO

Ebola hit 2013-2015 (based on the paper Ebola outbreak controversies and solutions 2015)

Let’s rewind back in December 2013, WHO confirms on 30th with 27,049 cases at three major hit centres – Liberia, Guinea and Sierra Leone. Then soon from these three major states it starting to spread to other parts of Africa, Europe and even found cases in United States. EBOV spreads from fruit bats especially some species found in Africa. It was believed that the spread was due to consumption of bat as food. The fatality rate was too high (41.02%) and was rising exponentially. All turned to WHO for answers and WHO itself was muddled. Researchers and Companies all around the globe united to accept this challenge and successfully came with multiple possible vaccines that does work in animal models. But the controversies struck then when it comes to human trial. WHO was under huge burden of financial crisis as the budget was much higher than they require.

Check the documentary of the 2013-2015 outbreak

It was 24th of October with 10,141 confirmed cases and 4,922 deaths. Researchers from Yale University had predicted that if there are no better measures taken then it will take a record rise by mid of November 2014. Unfortunately the prediction followed and still researchers were arguing with their researched vaccines proposed still tied in the knots of controversy. With some vaccines like ZMapp (the triple antibody), GSK proposed vaccines, etc the steep rise was getting submerged now. The Nigerian government has quarantined the whole country to prevent any further spread. But EBOV does not obey such rule and it was spreading. Many scientists who were working even got affected with EBOV.

WHO still was fighting strong with much collaboration to eradicate EBOV completely. The review was written up to WHO’s report of 10th June 2015. Surprisingly the record has reached more with 27,237 confirmed cases and 11,173 deaths. It was not restricted to African countries and it had become glober concern of fear of EBOV with positive cases found in US, UK, Senegal, Spain and Italy.

Ebola 2016 update

After all these steep rise and fear of EBOV, where is it now? Are we free from the risk of EBOV completely? In the 9th of June WHO’s last update till now declares the end of EBOV outbreak in Liberia. The announcement was done after surveillance for 42days post to last confirmed Ebola patient who was tested negative for second time. Still Liberia is now under 90days trial of strict surveillance. (Read the WHO’s last press of 9th June here)

According to the final update till now there are 28,616 cases and 11,310 deaths (check the data here) as on 10th of June 2016. So how does this total expedition of hunting EBOV coming to an end? What are the vaccines those come out of the controversial trial and made success?

It is important to note that there is not yet any final vaccine for EBOV. Ebola keeps on mutating itself and change its strain. Most of the vaccines that might work on some, may not work for others. A British company GlaxoSmithKline developed a vaccine ChAd3-ZEBOV that had made to final trial during Ebola Outbreak and another from Merck, a company from US. Governments from each national took step to prevent further spread of Ebola. A combined effect may have provided a huge success to stop this outbreak. The recovery was known for some people used the trial vaccines to save their life but also some have not recovered. WHO and World Economic Forum now are having more conversation with these companies to provide possible vaccines into human trial in future to confirm the application.

Suggested readings:

  1. The Ebola outbreak is over, but the hunt for a vaccine continues. Michell Eloy, February 25, 2016. Marketplace dot org
  2. Looking, hopefully, towards an Ebola-free future. April 2016, WHO.
  3. Ebola virus disease outbreak. (total news by WHO)
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Global emergency of Polio from Hyderabad, India

On 14th of June Talengana government announced ‘global emergency’ after an active strain of wild polio virus (P2 strain) was detected in water sample collected from a drain at Ranga district.

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Image Courtesy: Times of India representative

The vaccine derived polio virus (VDPV) strain has not been seen in the country for long (around 5 years).  It has also been reported to be safe as no such positive cases been detected although the regional government wish to alarm emergency to avoid reach to neighbouring countries as well as in India. The government soon going to launch massive vaccination programme before it become pandemic.

Earlier the oral polio vaccination contained attenuated P1, P2 and P3 strains but as P2 strain not been communicated so far, the recent vaccines lack P2 strain. “In this case, the P2 strain is vaccine derived. Someone vaccinated 10 months to a year back released the strain through stool. Such rare cases happen when a child’s immunity is very low. To avoid such stray cases, that happens one in a million, the P2 strain is no longer given even in vaccines,” said Dr G Srinivasa Rao, chief programme officer, National Health Mission, Telangana was said to Times of India.

“We’ll be following WHO set standards during our programmes,” he added. As part of the special campaign, children aged between six weeks to three years will be given additional doses of the injectable polio vaccine (IPV). Booths will be set up in areas being covered in these campaigns.

Officials informed that they will not deploy teams for door to door vaccination rather will encourage people to bring their children at vaccine booth which will provide additional information and protection against all kinds of polio strains.

Source: Times of India

Additional reading: History of Polio Vaccination, WHO’s report on India’s Polio status, Polio virus wiki study

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