Wednesday, December 31, 2014

Blogger's Desk#4- Probability in Science: Why


At the end of 3 years of blogging with 130+ posts and more than 131K views in total, I want to thank those people who have constantly questioned me and sometimes have asked me questions that left me running for answers. I have been able to answer a few of them, with a large chunk of reply attributed to the rescue statement "I'm not aware of any research or text in response to your question". But the path has been rewarding though. This blog page has been a product of my appreciation of research and researcher's alike.

However, there seems to be a question that hit me which is exquisitely simple, but to convincingly tell you an answer, seems to be so difficult. But lately, I think I have an answer and let me make an attempt. Let me re frame the question like this. "Why do scientists always talk about a finding in terms of 'probability' and not certainty? This question has also come up when I was data mining regarding understanding of science (Link) and its public outreach.

Let us consider a scenario. you are mixing a chemical X with Y to yield X2Y4 under specified conditions. If I say there is a statistical chance that you will not get the same reaction 15 times out of 100 attempts despite everything being same. What is your reaction? Absurd right. But that's the way Biology works, since it has variability. That means, at least simply by fluke you end up getting a deviated result, simply by chance. It is possible to quantify this degree of uncertainty and the possibility of chance to a certain extent by using standard bio statistical models. Here's is the first point why biologists talk in terms of probability, regarding any claims.

Second point, studying biology is a complicated process. There are many a times too many variables to consider, with each variable studied one at a time. This is called a reductionist approach. The puzzle is divided into multiple parts, with each individual part solved one at a time, and then the whole thing is stitched together. However, there is a catch here. There is nothing to tell you that the puzzle is complete and hence you cannot be sure. I want to quote from Richard Dawkins (I think it was in his book, "The greatest show on earth"). You could never prove anything with absolute certainty in science. Inability to disprove is a proof of correctness. This stands in line with the standard that any theory should be testable and falsifiable (Read more here).

Let me give you an example. Shamelessly, I'm replicating this from David Eagleman from his book "Incognito". Let us consider that a person who has never known anything about radio waves gets a radio which produces music. Having never seen such a thing he decides to scientifically deduce how it works. After years of research he figures out that by arranging circuit in certain way, he is able to generate the music. As per the science hypothesis would be, he is correct. But the actual way is there is a component which he has never studied and unknown to him. The telecasting radio waves. You see, despite everything being right there was a completely hidden component in the puzzle, but there is no way of knowing there is such an extra component. Now you get the point.

This provides an additional explanation of why with better technologies we come to know better and sometimes may even overturn a standard hypothesis based on fresh new understanding. In a summary, the extreme variance in biology and the inability to predict that a problem has been solved is the reason why a responsible sane scientist always talks about his results in terms of probability.

Wish You all a Happy New Year.

Tuesday, December 30, 2014

Blogger's Desk #3- Science awareness

More recently I have discovered from the internet that there is a great set of misinformation and lack of understanding of science, how it works and what makes it important. As a person into the science myself, I see deep problems with this. So I decided I could set up a survey and try to find some answers. The survey respondent has been far less than I expected it to be. I also talked about it to people who are not in science and tried to mine some additional data. 

The most striking feature that I found from the response is what does research mean? There was a universal agreement that science enhances our understanding of basic process and has enhanced our capabilities. More than a 50% declined to comment on a difference between Translational and basic research. Rest agreed that basic leads to translation. In reality there is no such thing as basic and translation. It’s a product of the highly competitive funding system (Link).

Fig 1: Preferred mode in updating and searching for literature
On an average the active researchers looking for science papers and materials, search and update their literature once in 3.20 days. That seems fine, till you see that majority of them use “Simple Google” approach. About 38% read review articles and almost 0.72% read original articles. And the big blow, a great deal of people agreed that the soundness of work was determined by the journal in which it has been published. It was found that majority of them don’t understand the article to a large degree; forget about critically evaluating the paper. For finding research paper of interest, PubMed followed by Google was the choice. I had expected that.

Towards science communication, there is quite a mixed signal. There was equal distribution in terms of how feasible was it to explain their science to layman and should scientists communicate more? Striking enough, too few people listen to materials such as podcast by journals such as Nature, Cell, Lancet, Science, NEJM etc. Some even don’t know they exist. In fact the aim of the podcast is simplifying the material, how far is the goal met, debatable. No wonder, “Google” is the choice. And I’m talking about one’s in science.

A chief complaint by majority of the researchers is that the published work is not available to read and you have to pay for individual papers. That forms the chief drive for Open access publications. But when asked if the paper is submitted to archives, very few agreed that they do in sites such as, arXiv, biorxiv or personal websites. A majority doesn't know it is legal to submit papers to repositories and a few denied they want to. Archiving should enable access to papers. 

The story is quite different from others perspective. Google is almost exclusively used for finding anything they want to know. They avoid reading scientific papers and rely heavily on news reports or webpages that looks promising (not necessarily true information). Their major problem is that scientists don’t communicate in an understandable layman language. Except when there is a ground breaking emergency or issue there is virtually no communication by the scientists to general public. Oh yes, most are not aware of authentic materials out there on web for general public, which attempts to communicate.

Box 1: The scenario.
The Box 1 is a depiction of the current science communication reality. I can quote an example. When scientists decided that they want to do an experiment to study H7N9 the hype of gain of function was needed to be addressed to public. Instead it was in a high tier journal (Link). Press picked up on it, and the tables turned around the wrong way. Some argued that scientists plan secretly and not open enough with public. Though the intention was to communicate and not cover the problem, the mode of doing it actually brought in mistrust. As said by Adel A. F. "The scientific justification presented for doing this work is very flimsy, to put it mildly, and the claims that it will lead to anything useful are lightweight”. People including scientists forgot what Gain of function and DURC is all about. 

Second, even the science specialists themselves have a problem. The most frequently encountered is the “authenticity in communication”. For example, when scientist say there is a “probability X that event Y will happen”, it sounds less authentic than media hyping, “Scientists claim they found Y will happen”. Even if the reader gets back to original paper and tries to understand it, chances are (Probability!!!) he won’t understand a word. As I have already shown relatively inexperienced scientists can find it difficult to understand modern complex high impact factor papers.

The original idea of scientific papers was to communicate science. Science had just started growing up and hence wasn't complex, easily understood. Today in journals like Nature, a original publication is a distillation of years of hard core science for years sometimes condensed into less than 4-5 pages. Naturally, a detail that seems to be universally known is not inked in. And here’s the catch. When you are at the very peak of knowledge, details that seem to be very complex can be perceived by you as a obvious fact. For others it isn't, and needs explanation. This phenomenon is called as “Knowledge paradox”. The resulting output is a very complex paper. The idea of abstract or author’s summary is supposed to curb this problem. However, the growing complexity of science literature makes this problem worse. Journal such as Elife aims to publish as much detail as possible. Such approach may alleviate the problem.

I by no means am discrediting the hard work of scientists nor does the public. The point is science understanding is currently low. In the ages of booming of physics, there used to be public lectures for the lay audience. In the newer age Podcasts and science shows could lead similar way.

Your opinion and thoughts?

Saturday, December 20, 2014

Ebola 2014: December updates


Fig 1: Ebola deaths in key areas.
Once again it is time for some updated news on Ebola 2014. As of he official reports, the total number of Ebola cases is 18,000, a figure more than all the cases combined, ever reported in past Ebola outbreaks. Also a recent outbreak discovered in Kono by the WHO, has brought in fresh concerns. The news report is that 87 bodies have been buried by 2 teams in past 11 days. The concern is Ebola outbreak hasn't completely leveled off. As Olushayo, an official in WHO's response Ebola team puts it, "Our team met heroic doctors and nurses at their wits end, exhausted burial teams and lab techs, all doing the best they could, but they simply ran out of resources and were overrun with gravely ill people". This underlines an important point. The total number of Ebola is probably under reported, as WHO agrees in their reports.

Other than the deaths of civilians, doctors killed in outbreak is also part of the headlines. Victor Willoughby, senior doctor involved in combating the outbreak, has died just when the experimental drug ZMab (Different from Zmapp) arrived from Canada on request. ZMab is also a monoclonal antibody preparation, targetting different epitopes- 1H3, 2G4, and 4G7. These monoclonal antibodies, raised in mice immunized with a VSV-based EBOV vaccine (VSVΔG-EBOVGP), recognizing the Ebola glycoprotein. The cocktail was tested recently in a Cuban doctor Felix Baez, who successfully recovered.

With favorable results from ChAd3 Ebola vaccine, in Phase I, plans to begin a Phase II trial has been initiated and currently under review by WHO. The trials are expected to begin by February 2015. In West Africa, trial has begun to check the efficiency of plasma exchange from a Ebola recovered donor (Link). A clinical trial is also underway, using a attenuated replication competent Ebola strain. The trial in Geneva has been halted a week after inception, based on four patients complaining of joint pain. 59 people have been vaccinated so far. Though it is expected that there would be side effects of mild nature, the replication competence of virus is to be considered. Hence the careful observation. The experts suggest it would be better to try and understand the reason behind side effects.

Fig 2: Action of FX-06. Source
A team from Frankfurt University Hospital, has published the use of a experimental drug on a A 38-year-old male doctor who had contracted Ebola. One of the major problems in EBOV is the vascular hemorrhage. The patient received a 3 day treatment course with FX06. The safety and efficacy of FX06 (The fibrin Bbeta chain-derived peptide) in the treatment of vascular leak syndrome has previously been explored in animal models of lipopolysaccharide induced and dengue haemorrhagic shock. FX-06 competitively binds to vascular endothelial (VE)-cadherin, thereby inhibiting leukocyte transmigration and initiating VE-cadherin-mediated signaling, which tightens the endothelial barrier and reduces capillary leakage. The sequence of FX-06 resembles that of a physiological peptide, and the compound has been well tolerated in clinical trials. On treatment, improvement was seen from an almost fatal case to improved respiratory and vascular function, reduction in viral load in blood. The virus was not detectable after 30 days.

With currently more than 53 different treatment regimens under R&D testing, the chances of developing a good vaccine and drug to combat Ebola Outbreak, the prospects appear good.
Audet J, Wong G, Wang H, Lu G, Gao GF, Kobinger G, & Qiu X (2014). Molecular Characterization of the Monoclonal Antibodies Composing ZMAb: A Protective Cocktail Against Ebola Virus. Scientific reports, 4 PMID: 25375093

Callaway, E. (2014). How do you test an Ebola vaccine? Nature DOI: 10.1038/nature.2014.16579

Timo Wolf, Gerrit Kann, Stephan Becker, Christoph Stephan, Hans-Reinhardt Brodt, Philipp de Leuw, Thomas Grünewald, Thomas Vogl, Volkhard A J Kempf, Oliver T Keppler, Kai Zacharowski. Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. The Lancet; Published online December 19, 2014

Tuesday, December 09, 2014

One more add-on to brand of New Generation Antimalarials


I have previously blogged a few posts on efforts to fight malaria. Malaria has been a longstanding problem in tropics and efforts to control have achieved reasonable success, at least in some parts of the world. As recently noted, there is a growing need for better Anti-malarials (Link). More recently there is a headlines circulating over the web- "A new antimalarial compound". And this post is all about it.

Table 1: Drugs in development through MMV 
The original publication is based on a paper published in nature, in 2010. By using a high throughput phenotypic assay (The screening was done by identifying molecules that block the proliferation of Plasmodium falciparum strain 3D7 in co-cultures with human erythrocytes), 309474 unique compounds. The screen generated 1,134 valid hits. Of them 172 chemicals was closely evaluated. The database is available at St.Jude research. In nutshell, reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. One among the 3 series of potential chemicals was DHIQs (dihydroisoquinolones). (+)-SJ733 is a component of that class. There is a huge list of chemicals that are gaining popularity for use against plasmodium which are developed in partnership with MMV (Medicines for Malaria Venture). A list of some well known compounds is shown in Table 1.

Table 2: SJ733 
pfATP4 is a P-type cation-ATPase which serve as parasite plasma membrane protein with sequence similarities to Na+-ATPases. It is the target for many types of antimalarials such as Pyrazoleamide compounds, Spiroindolone etc. It counters the influx of Na+, thereby maintaining a low Na+ content. SJ733 or (+)-SJ557733 (both are same chemical), disrupts this action which leads changes in physical structure of RBC. The RBC is more shrunken, resembling a pattern of eryptosis. The RBC is seen as a damaged version in the reticuloendothelial system. The next step is obvious, immune system attacks the RBC thereby defeating the plasmodium inside. This is something similar to people who have G6PD deficiency. Plasmodium simply doesn't survive well cause of similar RBC elimination.

In a mouse model, the drug was administered as a single dose which cleared about 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was not detectable. And here is the most interesting part. This target molecule is a heavily conserved system and mutation has a huge fitness cost. That means resistance can develop but in low level. To quote from Kiplin Guy (Source), "Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose. These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude".

Oh of course, Clinical trials are now on the next "To Do" list.
Jiménez-Díaz M.B., Ebert D., Salinas Y., Pradhan A., Lehane A.M., Myrand-Lapierre M.E., O'Loughlin K.G., Shackleford D.M., Justino de Almeida M. & Carrillo A.K. & (2014). (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.PNAS PMID: 25453091

Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F, Jiménez-Díaz MB, Martinez MS, Wilson EB,Tripathi AK, Gut J, Sharlow ER, Bathurst I, El Mazouni F, Fowble JW, Forquer I, McGinley PL, Castro S, Angulo-Barturen I, Ferrer S, Rosenthal PJ, Derisi JL,Sullivan DJ, Lazo JS, Roos DS, Riscoe MK, Phillips MA, Rathod PK, Van Voorhis WC, Avery VM, Guy RK. Chemical genetics of Plasmodium falciparum. Nature. 2010 May 20;465(7296):311-5. PMID: 20485428

Monday, December 08, 2014

Salmonella- survival Inside Macrophage; How?


Isn't it interesting to know that that there are several regions of interest in research, that I have never talked about? Well considering that there is so much of information out there, this blog timeline is too short to have even covered the part of any. Often I get communications from readers, asking opinion on certain topics and ends with a "You need to blog it". Well the list is growing up, but I enjoy those discussions. Here is one such topic that I felt needs a share- Salmonella Typhi, etiological agent of typhoid fever.

More than the biology of Salmonella, it is the story behind it that seems to be popular. So popular that almost everyone has heard "Typhoid Mary". Perhaps only there is a handful of names where patient / carrier is famous as much as the disease. Mary Mallon ( Irish immigrant) was the first documented "healthy carrier" working as a cook in North America. She was banned from the cooking industry twice having infected more than 50 people. There is a radiolab podcast which you must listen to (Link) Salmonella is a mega group of organism, with more than 3000 members in it. Salmonella Typhi (Note, I wrote Typhi and not "typhi"). S Typhi, is in fact a serovariety. Its complete name is Salmonella enterica subsp enterica serovar typhi. You see why we should stick to the short name.

Pathogenesis of typhoid is one of the most fascinating research question. Salmonella Typhi needs to infect in a large dose (ID50 > 105). Most of the organisms are destroyed by gastric acidity. Once into intestine, Salmonella calls up macrophages near it an enjoy a free ride. In addition salmonella can use anaerobic respiration with tetrathionate as a terminal electron acceptor, which gives it a competitive advantage over other members of flora. The details are covered in splendid detail in a post by Elio (Link), in small things considered.

Fig 1: Salmonella inside host. Source

Once inside the macrophage, the bacteria can simply inject different proteins (Nearly 20 effector proteins) into host cell, two distinct type three secretion systems (T3SSs) located on Salmonella pathogenicity islands- 2. These proteins interfere with antigen presentation, Cytokine secretion and cell survival. Moreover, there is an ability to survive inside macrophages as a dormant, non replicating persister. In a earlier paper, it was shown that something stimulates PPARδ (Peroxisome proliferator-activated receptor- delta), a eukaryotic transcription factor involved in sustaining fatty acid metabolism, which increases glucose availability and enhances bacterial replication in macrophage model, and increases persistence. Another important point is once salmonella is inside a macrophage vacoule it probably messes with the pH through a mgtCBR leader sequence which senses cytosolic ATP levels, interacts with mgtCBR operon and is important in virulence.

This discussion came up when someone asked me how does salmonella survive inside a macrophage. As most of the times, as is true in science, it is very difficult to throw a complete definitive answer. That said, it makes an interesting question which I'm sure scientists are exploring.

There is a probable outbreak of salmonella in North Cumbria, with 10 laboratory confirmed cases and five probable cases. It is suspected that the origin is a food source from Penrith.
Forest CG, Ferraro E, Sabbagh SC, & Daigle F (2010). Intracellular survival of Salmonella enterica serovar Typhi in human macrophages is independent of Salmonella pathogenicity island (SPI)-2. Microbiology, 156 (Pt 12), 3689-98 PMID: 20817644

Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA, & Holden DW (2014). Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science, 343 (6167), 204-8 PMID: 24408438

Haraga A, Ohlson MB, & Miller SI (2008). Salmonellae interplay with host cells. Nature reviews Microbiology, 6 (1), 53-66 PMID: 18026123

Eisele NA, Ruby T, Jacobson A, Manzanillo PS, Cox JS, Lam L, Mukundan L, Chawla A, & Monack DM (2013). Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence. Cell host & microbe, 14 (2), 171-82 PMID: 23954156

Tuesday, December 02, 2014

Neural code for immunity


A lot of time have I talked about the connection between immune system and nervous system. However, it never occurred to me question, as to why should there be a network sharing between immune and nervous system. As a part of routine, I was browsing through articles online and almost stumbled on NEJM article, that left me venturing.

Fig 1: A model of neuronal regulation.
Source: Kao etal
The idea is that whenever there is a local inflammation peripheral nervous system communicates the information to CNS. This helps in coordinating the response. It is argued that if this code of information can be understood, we could make use of it to our benefit. As Dr. Steinberg puts it, "Timely diagnosis and intervention are essential to minimize deaths and complications. If the neurons are reading this information from an infection in the blood or the liver and we can interrogate the nervous system, we can make a diagnosis in real time". I haven't been able to get the full article to digest the complete information. However, I thought that this probably isn't the first paper in literature.

The best method of studying a very complex system as immune and neural networking is a simple nematode Caenorhabditis elegans. They have a well characterized genome and a immune system representative enough to make a case. It has been shown with a C elegans model, innate response to a variety of pathogens elicit downstream immune regulators that the neuronal system can regulate. A model of this has been explained by Kao etal (See Fig 1). To cite an example, neural circuit involving NPR-1, which encodes a G protein–coupled receptor (GPCR), functions to suppress innate immune responses.

The leading hypothesis is that GPCRs participate in neural circuits that can recognize bacterial pathogens (probably via PAMPs) or receive inputs from non-neuronal infected cells which can then integrate them allowing coordination of appropriate immune responses.

Fig 2: Two way signalling between Neurons
and Immune system.
As a matter of fact, neurons express receptors which otherwise is classically associated with immune system such as toll like receptors, nucleotide binding oligomerization domain receptor etc. On the other hand immune cells express classic neuron related molecules especially neurotransmitter receptors. Clearly its a two way signalling as I have illustrated in Fig 2.

Fig 3: Components of Immunity.
It wouldn't require to convince you more that the same applies to the adaptive immunity, just as in the case of innate. In this light, I want to postulate that we can define 3 types of immunity (in contrast with classic 2 types- cellular and humoral; In reality this isn't my idea, I have already seen a published paper which advocates). The third addition is Neural immunity.

Perhaps in one simple sentence I could sum it up.. "Probably Neural systems are not the immune privileged type, they are the regulators.." More research will tell.
Kawli T, & Tan MW (2008). Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nature immunology, 9 (12), 1415-24 PMID: 18854822

Kao, C., Los, F., & Aroian, R. (2008). Nervous about immunity: neuronal signals control innate immune system Nature Immunology, 9 (12), 1329-1330 DOI:10.1038/ni1208-1329

Styer KL, Singh V, Macosko E, Steele SE, Bargmann CI, & Aballay A (2008). Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science, 322 (5900), 460-4 PMID: 18801967

Steinberg BE, Tracey KJ, & Slutsky AS (2014). Bacteria and the neural code. The New England journal of medicine, 371 (22), 2131-3 PMID: 25427116

Andersson U, & Tracey KJ (2012). Neural reflexes in inflammation and immunity. The Journal of experimental medicine, 209 (6), 1057-68 PMID: 22665702

Tuesday, November 25, 2014

SCCmec IX- Mec C gene


One of the most common known microbe of interest to the public and scientists equally is MRSA. It has been so deeply engraved in to the medical literature that it needs no introduction. If you are connected to medical microbiology you would know that, MRSA is a genetic output of a gene called MecA gene, sitting inside a gene cassette called Sccmec element. But many probably don't know there are variants, the most well known is called MecC which also manifests as MRSA phenotype, but doesn't lend itself to easy identification in the clinical laboratory.

Table 1: Mec gene variants. 
A strain called S. aureus isolate, LGA251, was first isolated in study of bovine population which showed phenotypic resistance to cefoxitin but latex agglutination PBR2a and MecA- PCR negative, despite repeated tests. On sequencing, a novel gene which was just 69% genetically similar to MecA was identified. The new variant was referred as MecA-LGA251. Subsequently reports emerged on the presence of this strain from multiple regions and retrospective sample search identified from a Danish blood, 1975. As per the current consensus, the MecC lies in a novel cassette XI SCCmec. The first question is why not MecB? MecB is identified in Macrococcus caseolyticus as a variant from MecA. See Table 1 for list of variants known.

There is no clear evidence on origins of MecC gene. The gene has been isolated from Staphylococcus stepanovicii, Staphylcoccus scirui and a variant tentatively called MecC1 isolated from SCCmec IX-like element in Staphylococcus xylosus.

The MecC gene (Also called as Class C) contains MecA and truncated MecR1 due to insertion of a IS431 upstream of MecA, and hyper-variable region and IS431 downstream of MecA. Based on the symmetry of insertion, two distinct class C mec gene complexes are recognized. Class C1 Mec gene complex, the IS431 upstream of MecA has the same orientation as the IS431 downstream of MecA, while in the class C2 Mec gene complex, the orientation of IS431 upstream of MecA is reversed. C1 and C2 are considered to have probably evolved independently. IS431 is a member of staphylococcal insertion sequence-like element and is constantly associated with Methicillin resistance.

Fig 1: Oxacillin/ Cefoxitin sensitivity in
MecA vs MecC types.
In a study by Torok etal; of 62 MecC MRSA isolates 88.7% were susceptible to oxacillin but resistant to cefoxitin (S/R), 11.3% were resistant to both oxacillin and cefoxitin (R/R), and none were susceptible to both antimicrobials. Based on the finding it was projected that Oxacillin Susceptible/ Cefoxitin resistant profile probably represents a MecC MRSA. Considering the current data, with an expected MecC S aureus is less than 4%, the positive predictive value of identification based on antibiotic disc screening is very low (less than 50%). Hence the current recommendation is testing for Mec gene using universal Mec primers which can pick multiple Mec gene variants.

Methicillin resistance is now an old and almost a universal phenomenon in S aureus. The arrival of new varieties represents new challenges in terms of diagnostics. This blog post is just a primer to keep you thinking, how many more flavors of Mec could be out there.
García-Álvarez, L etal. Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study The Lancet Infectious Diseases, 11 (8), 595-603 DOI:10.1016/S1473-3099(11)70126-8

Ito T, Hiramatsu K, Tomasz A, de Lencastre H, Perreten V, Holden MT, Coleman DC, Goering R, Giffard PM, Skov RL, Zhang K, Westh H, O'Brien F, Tenover FC, Oliveira DC, Boyle-Vavra S, Laurent F, Kearns AM, Kreiswirth B, Ko KS, Grundmann H, Sollid JE, John JF Jr, Daum R, Soderquist B, Buist G, & International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC) (2012). Guidelines for reporting novel mecA gene homologues. Antimicrobial agents and chemotherapy, 56 (10), 4997-9 PMID: 22869575

Cartwright EJ, Paterson GK, Raven KE, Harrison EM, Gouliouris T, Kearns A, Pichon B, Edwards G, Skov RL, Larsen AR, Holmes MA, Parkhill J, Peacock SJ, & Török ME (2013). Use of Vitek 2 antimicrobial susceptibility profile to identify mecC in methicillin-resistant Staphylococcus aureus. Journal of clinical microbiology, 51 (8), 2732-4 PMID: 23720794

Paterson GK, Harrison EM, & Holmes MA (2014). The emergence of mecC methicillin-resistant Staphylococcus aureus. Trends in microbiology, 22 (1), 42-7 PMID: 24331435

Wednesday, November 19, 2014

Indian Ebola survivor- Quarantined.


    Seldom have I got the chance to talk about any topic again and again in this blog that has only attracted more readers. Oh yes, You got it right. Once again, talking about Ebola 2014. When the outbreak began, it wasn't predicted by any that this would be such a mega outbreak. As of on November 11, 2014 a total of 14,383 Ebola cases have been reported as of November 11 from three West African countries (Source). The media attention that has been received is simply great. And when a country announces they have a fresh case, its the fastest news in circulation.

    The most important news, Democratic Republic of Congo has been declared officially as "outbreak free", after not registering any new case since October 4. There are no new cases for 42 days which is the officially accepted time to declare as outbreak free. Of course the after effects are still being dealt with. And the second most, India quarantines a Ebola survivor. I have purposefully mentioned as a "survivor" and not as the first case in India. There seems to be a lot of panic in the media reports and the story has been blended in press as of to indicate India has its case. Hmmm. Let me try and tease that situation out.

    The suspect is a 26-year-old survivor, successfully treated for Ebola in Liberia and released from a health facility back in late September. He had no symptoms. He was cleared to fly after he had tested negative by standard blood tests (In fact he tested 3 times as negative). However, his semen tested positive. This discussion seems to be over to me after listening to multiple episodes of TWiV podcasts in recent shows, were this has been discussed in immense details. The basic point boils down to the fact that Ebola seems to be surviving in patients semen (Culture positive) even after they have recovered from illness for about 2- 3 months, possibly more. To the best of knowledge, there are no documented case of sexually transmitted case of Ebola. I have though seen arguments over the internet, that it could be possible and there is a documented evidence of similar scenario in a related virus- "Marburg virus". Best advice at this point is no sex after Ebola recovery for at least 90 days. There is a definitive lack of research on the possibilities of Ebola latency in body fluids.

      I totally agree with the move of health officials quarantine for the "just in case" scenario.  However, It should be considered that he has been treated, survived and cleared by blood tests. This indicates that he is no more diseased. However, to call it the first case is unwarranted. In fact technically speaking, he is not even a case. The outbreak currently seems to be currently in a decline phase and the outbreak should be officially over worldwide, hopefully in a few months.
Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, Nichol ST, Ksiazek TG, & Rollin PE (2007). Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. The Journal of infectious diseases, 196 Suppl 2 PMID: 17940942

Friday, November 14, 2014

Microbiome- Follow up post


  In my previous post, I talked about the growing field of microbiome and tried to put important concepts of virome in a snapshot pattern. I realized that I should have cited more examples and some concentrated a bit more on microbiome, to get the reader a full picture. So, this post is a follow up for my previous post.

First, let me revisit the debated question of microbiome. "Is it worth to call our microbiome a yet another organ"? This is a well discussed question with science thinkers and practitioners taking both sides of opinion and there is no consensus. However more and more of the scientific community is beginning to accept the yes part of it. The point that the microbiome is more than significantly associated with multiple physiological components is striking enough to be called as an organ. Gnotobiotic rats are maintained in such artificial conditions, shows that natural life without microbiome is probably impossible. That argument delivered, let us at least tentatively agree it as another organ (But unlike other organs, in terms of dynamic nature).

I'm pretty sure you have heard at least one example similar to the following. Two identical persons with similar exposure to environmental factors (Let's say mosquito bite), and one of them keeps getting infection. Th other appears resistant always. The earliest of the arguments was "Genetics". With more research pouring in this seems to be possible even if the genetics was much similar (Say in siblings) and genetics may not account, nor chance. Such questions have led researchers to question if there is more to it. A set of gene similarity don't mean much these days, since concepts such as epigenetics has to be considered for variability. But microbiome probably produces a gene pool that can account for a million more variation to be considered, and that is why the the hypothesis of "microbiome influence" is damn attractive.

Not convinced yet? In addition to the previous post citing articles (I have previously posted multiple blogs on the same concept, Indeed this blog site is full of such examples), here I will present a couple of examples that stress on what I have said.

Perhaps the most compelling of the evidence is microbiome influence on weight. Obesity is considered as a disease in the current era and there is enough genetic factors that lie around the whole concept. However, off late evidence has begun to accumulate that microbe gene pool is also important. Studies have been conducted on humanized mice to show that microbiome can have a significant impact on obesity. It has been demonstrated that by transferring the microbiome, from gut obesity can be influenced. Lean mice can be made obese and other way around. More recently deep sequencing from human gut has shown supportive results.

In a recent example I cited, C difficile has got an important rival C scindens, which can reduce the C diff effect (Read my previous post here). This is not the only such study. For example Ruminococcus obeum is shown to significantly effect the virulence of V cholerae. This is mediated through a inter species quorum sensing, specifically R obeum AI-2 which repress V cholerae virulence genes. There are more such examples in literature, and more on coming. You just need to look.

There are more examples. For example, microbial composition is shown to influence how frequently you will get a mosquito bite. Skin flora metabolites are the cause of odor, signatures of which can be detected by the mosquito, It has been shown that a particular pattern of microbiota composition is more attractive to mosquito. Another one, bacterial colonization in the wound is common concurrence. The type of composition has been shown to impact the healing capabilities in terms of time and quality.

The first question that has been often raised is why can't we get such data for every condition? Is it reliable. I have already discussed the dynamic nature and the technical challenge in evaluating the flora composition in previous post. Additionally understanding the pathways between every microbial entity is currently out of the technical capabilities. Working with more than a million connections is simply a challenge.

More recently the whole concept of microbiome has met with a challenge of addressing contamination. In a article published in nature, there is a lot of discussion on issue of contaminating sequences, based on papers published in BMC biology and PloS One. The point basically boils down to the fact that the reagents used in two commonly used sequencing techniques -16S rRNA and whole-genome shotgun metagenomics, contain contaminating sequences. The lack of negative control sequence has impacted the way we look into the deep sequencing technique. The point is illustrated in the statement by Walker, "We haven’t challenged anyone directly. We hope the message will stand for itself. We’re trying to nip it in the bud now before it becomes more of an issue.” Source

So what are the implications?

One of the microbiota based therapy is projected to be Fecal transplantation (FTM). The success story of treating C diff infection, by FTM has led many people to argue that probably "microbiota transfer", can be the answer to many of the conditions. In other words, there is a tendency to designate "Good" & "Bad" microbiome. My projection was that, if we can recolonize with "Good microbiota", for other conditions such as asthma, where it can be influential, that would be great. Of course we don't know at this point what is that combination in any of our normal flora system. However, A post in ASM blog (Link), has led me to rethink this. Probably, just like genes its not good or bad. Its the context that matters.

Story has just begun to uncover, and am sure I will be revisiting these concepts.
Baquero, F., & Nombela, C. (2012). The microbiome as a human organ Clinical Microbiology and Infection, 18, 2-4 DOI:10.1111/j.1469-0691.2012.03916.x

Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, & Gordon JI (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341 (6150) PMID:24009397

Hsiao A, Ahmed AM, Subramanian S, Griffin NW, Drewry LL, Petri WA, Haque R, Ahmed T, & Gordon JI (2014). Members of the human gut microbiota involved in recovery from Vibrio cholerae infection. Nature PMID: 25231861

Saturday, November 08, 2014

Microbiome- Dwelling a little deep


      Everyone is familiar with the nomenclature "Normal flora". They represent a set of microbes that inhabit us. Estimates have claimed that there are nearly 10 times more microbes in human body than the cells. Debates exist as to if this is true or an exaggeration. But it is irrelevant at this point. It is for sure however that they interact and influence our cellular machinery. Their influence is studied in terms of Immunological signatures, neurobiology, oncogenesis etc. Most of the textbooks don't acknowledge this yet, since the details are just beginning to emerge. I have blogged about these aspects a variety of time in this blog which you could check out.

Fig 1: A representation of common members
of bacteriome. Source

   I have been thinking for sometime, "Is it worth to call our microbiome a yet another organ"?. I haven't posed this question for the first time. This question has been discussed in great depth in a variety of conferences, academic papers etc. What is not realized is the human microbiome is much more than that, and its dynamic is too difficult to study. The term microbiome in itself is considered as a sloppy definition (Read ASM blog post here). For the purpose of clarity, let us stick to the definition that microbiome denote all microbes at a site. The concept of microbiome is derived from the development of deep sequencing methods with billions of reads. Even the best of microbial culture method cannot retrieve and analyse every possible species in a site. Clearly we had to await the emergence of modern technology. A massive Human microbiome project, is currently pursuing studies to understand the human microbiome. It is clear that microbiome is a signature of individual and there is a huge variation. Its uniqueness is so striking that it has been proposed as a forensic tool. Body sites presumed to be sterile in healthy humans, such as the vascular endothelium, Brain etc have been shown to be colonized without apparent signs of disease. Such publications have shaken the ground beliefs of sterile sites in body.

     Till extremely recently the word microbiome was almost exclusively studies on bacteriome. This is because, almost all bacteria have a signature identifiable sequence in one single gene- 16S ribosomal sequence. Amplify and identify all the 16S deep sequences (not as simple as said), a metagenomic approach and boom you have everything. Fungal microbiome is a little more harder and the virome is the hardest. As represented in Fig 2, expected virome content is much more than bacteriome or mycobiome. For virome, you just deep sequence everything you find and remove the known bacteriala nd other DNA matches. The rest is matched directly with known database and similar looking viral genomes from database. Often there will be "grey sequences" (casually referred as dark matter) which doesn't match with anything. 

Fig 2: A rough representation of
microbiome content.
     So much of information to bring you into a question, one of the readers had asked me after reading my previous post on "Algal virus and cognition". Is there examples of good or bad effects of human virome? And suddenly I realized that I have never talked much about the Human Virome. 

    As can be understood from above, "microbiome" is a massive subject of interest with too much grey area to even speculate on its functionality. As I have said, bacteria has been studied more in connection with a variety of conditions. But it simply seems logical to me, to extend that where there is a bacteria, viruses will tag along. But the current virome literature is in its infancy and so I chose to put up some examples taken from studies. This should help in getting the answer across allowing room for exploring.

Box 1: Projected contents of
human virome.
   For every bacterial species known, there are bacteriophages. Gut microbiome is perhaps the most heavily colonized microbiome. with more than 35000 varieties of bacteria in the site, I expect at least a million (if not billion) phages there. The best part is they form a defense layer. Innate immunity acquired via such phages are referred as, phage-mediated immunity (PMI). Study by Barr etal, had shown that our mucus membrane is heavily colonized by lytic phages, which tend to attack incoming invaders and serve as first line of defense. Due to their extreme importance in defense, there is a expected evolutionary pressure to retain these phages. It is not known as to how these phages are maintained, or if at all it is maintained by the host or the gut microbiota. As the next story will show bacteria can equip themselves with more than toxins to counter other invading pathogen. They can arm themselves with phages against others. So maybe, the microbiome maintains the phages. After all its the requirement of normal flora to stay in competition for their own benefit.

     Let me digress a little bit, to cite maintenance of virus as an armory. This is based on an article published by Lora Hooper and team. The study showed that Enterococcus faecalis has in its genome integrated genomes of two different phage elements (one gives structure to the composite, while the other helps it infect victims), which can be unleashed on demand. These phages attacks other bacteria providing a competing advantage. This strain is called V583. That's a proof of concept, and maybe PMI is replenished through similar mechanism. I however, have no data to support my idea.

     I have talked about HERV in a post almost about 2 years ago emphasizing the fact that our very existence as to humans owes a lot to these viral pieces. Just to remind, the placental formation is based on a viral protein (Syncytium beta)- HERV-W envelope glycoprotein coding gene. Read my previous post here. Many more such marvels are slowly being discovered. As explained in a previous post (Link), Inactively residing herpes in neurons may have beneficial effects.

     Just as the bacteriome influences outcome in many different conditions so does viruses. Studies are currently studying viral composition in a variety of disease conditions. One of the most cited study is by Moya etal; showed there is less viral diversity in the Crohn’s disease patients compared to healthy. Additionally they found these where mostly Retroviridae members in effected patients. My take on this there is a lack of phage varieties that effect the bacteriome. It is known that there is a significant importance of bacteriome quality and type in crohn's disease.

    The said field offers new research avenues, but comes with its own set of challenges. Microbiomes are not stagnant types in a person. At least some percentage of it vary continuously. By using a CRISPR based tagging approach, in a 11 months study it was shown that the virome can vary by anywhere between 25 and 75% between every sample. This means that it is computationally and logically difficult to characterize a virome and associate it with a condition.

   Just to add to flavor there is a realm of fungus in the microbiome. Recently published data suggests that fungus too have dynamic interaction. A study has gone as far as to characterize how fungal microbiome can dictate T cell balances (which can be done by bacteria and some helminths as well), thereby creating a risk for allergies. And then there are phages of fungus called as mycophages which am sure will be present as a part of our virome. The entire field of mycophages is currently a dark region, so forget about commenting on its effects.

  To conclude, I will say microbiome is currently a hot topic. Connection has been made with a variety of conditions and microbiome. But proving and characterizing every connection is very hard at least with current technology. Virome is a step next to it, though science will make its advance slowly.
Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM, Scott NM, Gibbons SM, Larsen P, Shogan BD, Weiss S, Metcalf JL, Ursell LK, Vázquez-Baeza Y, Van Treuren W, Hasan NA, Gibson MK, Colwell R, Dantas G, Knight R, & Gilbert JA (2014). Longitudinal analysis of microbial interaction between humans and the indoor environment. Science, 345 (6200), 1048-52 PMID:25170151

Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, & Knight R (2009). Bacterial community variation in human body habitats across space and time. Science, 326 (5960), 1694-7 PMID:19892944

Wylie KM, Weinstock GM, & Storch GA (2012). Emerging view of the human virome. Translational research : The journal of laboratory and clinical medicine, 160 (4), 283-90 PMID:22683423

Barr JJ, Youle M, & Rohwer F (2013). Innate and acquired bacteriophage-mediated immunity. Bacteriophage, 3 (3) PMID: 24228227

Pérez-Brocal V, García-López R, Vázquez-Castellanos JF, Nos P, Beltrán B, Latorre A, & Moya A (2013). Study of the viral and microbial communities associated with Crohn's disease: a metagenomic approach. Clinical and translational gastroenterology, 4 PMID: 23760301

Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, & Shibuya A (2014). Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE₂. Cell host & microbe, 15 (1), 95-102 PMID: 24439901

Friday, November 07, 2014

Algal virus and Cognition- Is there a link?


    One of the most important accepted rule in the world of pathogens is the specificity of host. This rule is especially true when it comes to viruses. Most of the viral pathogens have a very restricted range of host. With drastic mutations, the virus maybe able to infect other hosts which are closely related to the original host. But, if I will cite an example of algal virus probably sitting in human throat, that would blow your mind of. And if I add to it that it may possibly influence your neurological activity, you will probably think I have gone nuts. I was equally mesmerized when I heard of the study and headlines in internet saying "Algal virus impacts cognition". I decided to look into a little more detail.

     The virus under discussion here is ATCV-1 (Acanthocystis turfacea chlorella virus 1), a member of Chlorovirus. ACTV-1 has been previously reported to be found in human oral sample metagenomic analysis, in psychiatric patients though it was never formally tested for its importance. Being a virus of algae, it can be easily thought of as a contaminant since they are found in water reservoirs. Previous literature has evidence for detection of the viral signatures in brain biopsy samples. However, its validity couldn't be convincingly established.

Box 1: Highlights of the study.
     In this new study, the researcher's studied normal and psychiatric patients for the presence of viral signatures in the oral flora. The study was able to show that of those infected with the virus, performed 10% worse than uninfected people on standard cognitive tests. So the most important question that arises from the result is does it mean anything? This was further tested by using a mouse model. The results looks quite compelling. Other than a significant difference in cognitive tests between infected and non infected, changes in roughly 1300 genes were also shown in hippocampus. By using modern bioinformatics analysis, the genes effected were found to be involved in pathways related to dopamine receptor signaling, cyclin-dependent kinase 5 (CDK5) signaling, antigen presentation, immune cell adhesion, and eukaryotic initiation factor 2. Note that dopamine is a central component of many psychiatric conditions.

   Chloroviruses are common in inland waters throughout the world, usually in high numbers. Is the virus actively involved or is it through some non specific mechanism such as inflammation that has caused these changes. The current suggestion is. most possibly through a non specific inflammatory reaction. I had also like to take some more opinions into consideration. First, the virus was given to mice along with its host algae. Did that create an effect? Second, is it possible that the presence of ACTV-1 predisposes to some phenomenon (mostly inflammation), which accelerates the effect by some other compound. Or perhaps, does the antibodies produced against the virus induce any cross effect, such as is the case with PANDAS where culprit is Group A streptococcus.

    The current paper however, does warrant the need to look into more details. In my opinion, the study is novel and has a point. However, 10% effect and no compelling mechanism is asking for more data and studies. Its too early to claim "Algal virus impacts cognition". Remember, Association is not causation.
Yolken RH, Jones-Brando L, Dunigan DD, Kannan G, Dickerson F, Severance E, Sabunciyan S, Talbot CC Jr, Prandovszky E, Gurnon JR, Agarkova IV, Leister F, Gressitt KL, Chen O, Deuber B, Ma F, Pletnikov MV, & Van Etten JL (2014). Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice. PNAS PMID: 25349393

Wednesday, November 05, 2014

Ebola-2014: Still in news


   In less than a couple of months, Ebola has become the search term of interest and is currently the most focused component of concern. And rightly so. It has been accused by many that there are no readily approved treatment or vaccines against this infection. But it is to be understood that scientists don't work like magic. Science needs its own time to make discoveries. But then scientists are working out of their way to bring in promising results.

    The current outbreak is perplexing, given its unprecedented geographical distribution and number of cases involved. As per the estimates the total number of reported cases is more than 13500 and deaths nearing 5000. Liberia alone has 6,500 cases and 2,413 deaths reported as of Oct. 31. And then there will be a set of unreported cases. Models have estimated a very high number of total cases which includes reported and unreported cases. However, its debatable if the models are over estimating the current prevalence and incidence.

     Other than the Zmapp, and a couple of experimental drugs (Link) which in itself is under testing phase, there is not much available in the hands to counter the current outbreak. This provides the most attractive time to come up with anything novel. As I have previously discussed in this blog vaccine is perhaps the best candidate (Link). However, only a vector vaccine containing replication competent VSV (Vesicular stomatitis virus) carrying Ebola Glycoprotein has shown to be of some use. The other well explored area is use of adenovirus carrying antigens as a vaccine. In a recently published hot paper- this has been used in the form of nasal spray, promising to provide long-term immunity.

    This isn't actually a new discovery. Literature has been published on this by Maria Croyle and team in 2006 (Link), showing that nasal delivery of Adenovirus Expressing the Ebola Glycoprotein conferred protection in a mice model. The vaccine basically consists of human adenovirus serotype 5 (AdHu5) expressing the wild-type ZEBOV glycoprotein sequence from a CMV promoter. This combination is called Ad-CMVZGP. The new study by Croyle and team showed that the vaccine elicited good immune response, through Intra nasal route in comparison with other routes. The protection was demonstrated 21 weeks after immunization.

   The study offers great advantages, as one of the author in study says "The main advantage of our vaccine platform over the others in clinical testing is the long-lasting protection after a single intranasal dose. This is important since the longevity of other vaccines for Ebola that are currently being evaluated is not fully understood. Moreover, the nasal spray immunization method is more attractive than a needle vaccine given the costs associated with syringe distribution and safety." Source

   Another vaccine that has promising pre clinical data ChAd-Ebola; Chimpanzee-Adenovirus chAD3-ZEBOV. The Phase I trial is expected to be initiated at the earliest and results will be available by early 2015.

The current outbreak has exposed the unpreparedness to counter the Ebola. As I always say, basic biology needs to be done. But, then there is a great support to come up with defense mechanism that may help us be prepared at least the next time. And the question of prospects of the vaccine, only the next set of data will tell.
Croyle, M., Feldmann, H., Jones, S., Wilson, J., & Kobinger, G. (2006). 595. Nasal Delivery of Adenovirus Expressing the Ebola Glycoprotein Protects Mice Against Ebola Virus in the Presence of Preexisting Immunity to the Vaccine Carrier. Molecular Therapy, 13 DOI: 10.1016/j.ymthe.2006.08.669

Richardson JS, Yao MK, Tran KN, Croyle MA, Strong JE, Feldmann H, & Kobinger GP (2009). Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PloS one, 4 (4) PMID: 19390586

Choi, J., Jonsson-Schmunk, K., Qiu, X., Shedlock, D., Strong, J., Xu, J., Michie, K., Audet, J., Fernando, L., Myers, M., Weiner, D., Bajrovic, I., Tran, L., Wong, G., Bello, A., Kobinger, G., Schafer, S., & Croyle, M. (2014). A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection. Molecular Pharmaceutics DOI: 10.1021/mp500646d

Tuesday, October 28, 2014

Blogger's desk #2: Guest post- Science communication


I had requested Mr. Saumyadip Sarkar, a regular contributor to a variety of science activities online to contribute a guest post on his journey as a science communicator. The following is what he sent me, and am glad to host it on my blog.

Thank you Saumyadip Sarkar

Science Communication:

Thinking leads to activity, and activity leads to discovery. The getting the unknown thing into known is how all about science communication. The discovery of any research we mean it when we read the articles of great discoveries. The words, the steps of thinking and bringing the hard work into light, are all about holding the story towards the common people. It is the cable which joins the research and the people who reads it.

I am an individual Science Communicator. It is all about, picking up great stories of research, communicating scientists from different aspect of science background, taking interviews and highlighting them before readers. Sounds easy! Quite easy when you know the importance of science and how communicators do to seed the importance of it. A small research doesn’t remain too small, a big research sounds interesting and the artefacts are designed to confront the beauty of science. This is how a science communicator believes in science.

My journey of science communication was brought forward from a social networking site. Sounds crazy though, I grabbed some cool science freak guys and then planted a small group of microbiology lovers named “We The Microbiologist” []. The daily questionnaire and solving the puzzles started the game. WTM became a big early platform of discussion and then we made a science website who wished to build up science research before the readers who are actually interested to read science. Starting from magazines to events has brought forward the beauty and hope it will grow further with the interests of the readers who believes in science. Now I am a science communicator at CSIR NISCAIR’s Science Reporter Indian Magazine, Microbiology World [] and my own blog Biomysteries [].

Taking ahead of my personal walk of being a science communicator, let me highlight you why science communication is important. In the discoveries of recent research from the developing countries always remains deep just into a three to four page publication, unless people know what you are contributing for the society. Many research publications are brought into the practical field use when searched in science websites. If we think about the current youth of developing countries specifically grab their interests when they read the whole story of a research, starting from the failures to success. If you are reading this, I would request you to just have a look into the corner up or below of any science websites, you will get the name of the science communicator who brought you the story. Keep digging your thoughts into action; because you got no worries, we are watching you!

Saumyadip Sarkar
Twitter: @iamsaumyadip