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Category: Health and Medicine

Rabies pathobiology and its RNA virus agent – Lyssavirus

Having a dog as a pet presents myriad of benefits. One of them is having a companion reputed for being charismatic and loyal. Dogs, apparently, render a “cure” when melancholy “strikes“. However, there are repercussions to avoid or deal with when handling a dog. One of the most important concerns when domesticating a dog is preventing dog bites. Getting bitten by a dog is, in fact, how microbes could find their way through the skin.  Dogs, inopportunely, can be agents of medically-important diseases like rabies.

dog rabies
Dog infected with rabies

Rabies transmission

Rabies is a viral disease that is almost always deadly. It can be acquired chiefly through a single bite by an infective dog. One could also get it when a broken skin is exposed to infected saliva. Other potential routes include eyes, mouth, and nose. Nonetheless, not all dogs carry the virus causing the disease. Also, dogs are not the only ones that can transmit rabies virus. Most warm-blooded vertebrates (e.g. monkeys, raccoons, cattle, cats, bats, etc.) can carry the virus and transmit it to a human host. The virus has further adapted, and hence, could grow as well as in cold-blooded vertebrates.[1] However, because of the widespread domestication of dogs in human households dogs have consequently incited most rabies cases in humans.[2]  

Lyssavirus – the viral agent

The virus of rabies disease is a Lyssavirus, a type of RNA virus belonging to the family Rhabdoviridae, order Mononegavirales. It has a bullet shape. It carries a single negative-strand RNA as its genome, enough to code for proteins[3] — namely, nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA polymerase — to establish within the host cell.

Lyssavirus rabies virus
A coloured transmission electron micrograph of Australian bat lyssavirus (finger-like projections and the one that bud off from a host cell). Credit: Electron Microscopy Unit AAHL, CSIRO, CC 3.0 Unported license

In particular, the virus makes its way inside the host cell (e.g. muscle cell or nerve cell) through receptor binding and membrane fusion by way of endosome using its glycoprotein G. The virus transcribes its genome by its polymerase inside the endosome. Then, it fuses to the endosome to release its newly transcribed proteins and RNA into the cytosol.

The matrix protein regulates both transcription and replication of the virus. From transcribing, the polymerase shifts into replicating its genome. The nucleoprotein tightly binds to the newly replicated genome, thus, forming ribonucleoprotein complex. This, in turn, can now form new viruses.[4]

The virus performs transcription and replication processes via a specialized inclusion body referred to as the Negri body. In fact, the presence of Negri bodies in the cytoplasm of the host cell indicates histological proof of Lyssavirus infection.

Rabies – two types

Early symptoms of rabies disease include fever, discomfort, and paraesthesia (burning sensation at the bite site). Eventually, the symptoms progress to behavioral changes when the virus spreads to the central nervous system.

Lyssavirus enters and hijacks muscle cells to replicate. From the muscle tissue, it travels to the nervous system through the neuromuscular junctions.[5] The virus enters the peripheral nervous system directly and then spreads to the central nervous system where it can cause fatal inflammation in the brain and spinal cord.

Depending on the symptoms, the rabies may be described as “furious” or “paralytic“. The furious rabies — the more common form (80% [5]) — is characterized by hyperactivity, confusion, abnormal behavior, paranoia, terror, hallucinations, and hydrophobia (“fear of water“). The paralytic rabies, as the name implies, causes paralysis starting from the site of bite (or entry). Both of these types may lead to coma and eventually to death of the patient. However, patients with the furious type have higher risks, due to the likely cardio-respiratory arrest.[2]  Without an early and a proper medical intervention, death may ensue typically two to ten days after these symptoms manifest.

Rabies – pathobiology

How rabies causes behavioural changes baffles scientists. In 1980s and 1990s, researchers explicated how the virus caused paralysis. Accordingly, the glycoprotein at the cell surface of the Lyssavirus competes against acetylcholine in terms of binding affinities to specific muscle receptors (e.g. nicotinic acetylcholine receptors).[6] Lately, researchers conjectured that the virus could also be doing the same with the similar receptors found in the brain. Furthermore, they presumed that the interaction could have affected how the brain cells normally communicate, and thereby induced changes in the behavior of the host.[6] 

Further research

Recently, researchers from the Ohio State University College of Medicine and The Ohio State University Wexner Medical Center conducted a study aimed at identifying dog breeds and physical traits that pose high risk of biting with severe injury.[7] Their data could provide empirical basis when deciding which dogs to own. Still, further studies on rabies are necessary since the disease is marked as fatal as soon as the clinical symptoms set in.[2]  Although vaccine-preventable, rabies, especially via a dog bite, remains a significant cause of annual deaths in humans, both young and old. Novel treatments and vaccines that are effective and economical could preclude death. At present, the staggering cost of treatment remains a major health-care restraint. Without the proper and early treatment, death from rabies, unfortunately, is almost always certain.

— written by Maria Victoria Gonzaga

References:

1 Campbell, J. B. & Charlton, K.M. (1988). Developments in Veterinary Virology: Rabies. Springer. p. 48. ISBN 978-0-89838-390-4.

2 World Health Organization (WHO). (2019, May 21). Rabies. Retrieved from Who.int website: [Link]

3  Finke, S. & Conzelmann, K. K. (August 2005). “Replication strategies of rabies virus”. Virus Res111 (2): 120–131. doi:10.1016/j.virusres.2005.04.004  

4 Albertini, A. A., Schoehn, G., Weissenhorn, W., & Ruigrok, R. W. (January 2008). “Structural aspects of rabies virus replication”. Cell. Mol. Life Sci65 (2): 282–294. doi:10.1007/s00018-007-7298-1

5 Newman, T. (2017, November 15). Rabies: Symptoms, causes, treatment, and prevention. Retrieved May 23, 2019, from Medical News Today website: https://www.medicalnewstoday.com/articles/181980.php

6 University of Alaska Fairbanks. (2017, October 11). How rabies can induce frenzied behavior: Researchers better understand the disease that kills 59,000 people annually. ScienceDaily. Retrieved from website: [Link]

7 The Ohio State University Wexner Medical Center. (2019, May 22). Study identifies dog breeds, physical traits that pose highest risk of biting children. ScienceDaily. Retrieved from website: [Link]

FAAH-OUT mutation for a life of no pain – No FAAH, no pain

A Scottish woman claims that she has not experienced pain over some supposedly painful conditions, like a severe joint degeneration or a post-operation she underwent for her hand due to osteoarthritis. Accordingly, she never needed painkillers and her case astounded doctors.

A baffling case

Doctors were baffled when the 71-year old Scottish woman, Jo Cameron, came to seek treatment for her hip problem six years ago (at age 65). Astonished, the doctors found out that her joint severely degenerated and by that they expected her to experience excruciating pain just as a typical person would. However, she showed no signs of discomfort over it. Furthermore, she said that at age 66 she underwent a supposedly painful operation on her hand due to osteoarthritis yet felt no pain after. According to the news1, Cameron was not aware at first for feeling virtually no pain over such situations. Purportedly, she thought that what she felt (i.e. lack of a thwarting pain) was normal. She later learned about her lack of pain and the plausible reason only recently.

FAAH-OUT

Researchers went on to see what caused Cameron’s bizarre lack of pain. They suspected that her genes could shed light to her case. Hence, they analyzed her genes. Subsequently, they found mutations, thereby, affirming their hunch. According to their genetic analyses2, Cameron had two mutations: (1) a microdeletion in a pseudogene and (2) a mutation in a nearby gene controlling the enzyme fatty acid amide hydrolase (FAAH).2

The pseudogene was only partly annotated in the medical literature. Thus, researchers describing the gene and subsequently calling it FAAH-OUT was a first. Previously thought of as a “junk gene”, FAAH-OUT could probably be more than that. It likely regulates FAAH expression as postulated by the research team.2 Consequently, they now look upon how it works.

FAAH gene

With regard to the FAAH gene, researchers know this gene encodes for the FAAH enzyme involved in endocannabinoid signaling. In essence, FAAH normally degrades anandamide (a fatty acid neurotransmitter) into free arachidonic acid and ethanolamine. Thus, without FAAH, the levels of anandamide would increase significantly. This, in turn, leads to a reduced pain sensation, as observed in FAAH knockout mice.3 FAAH knockout mice demonstrated not only the absence of pain but reduced anxiety and faster wound healing as well.2,3

Likewise, Cameron purportedly exhibits similar traits. According to her, she never panics (even in dangerous situations), has no fears, and is immune to anxiety. She would also have bouts of cuts and burns in which she would not notice sometimes albeit her injuries would heal very quickly.2 The tests revealed that she had elevated levels of anandamide – an indication of a lack of FAAH function.2

Novel pain treatment targets

FAAH-OUT gene mutation
Mutation in FAAH-OUT gene resulted in more anandamides, which in turn leads to feeling of no pain, reduced anxiety, and quick wound healing. [Photo by juan mendez from Pexels]

One of the lead researchers of the study, Dr. James Cox, said that Cameron has a genotype that reduced gene activity. Cox and his research team are optimistic that their discovery could possibly lead to novel pain and anxiety treatments that target this newly-identified gene.2 Their findings might lead to novel strategies that would eventually help patients suffering from severe pain despite receiving advance pain killer medications.

— written by Maria Victoria Gonzaga

References:

1 Hunt, K. (2019 March 28). “Woman who feels no pain could help scientists develop new painkillers”. Retrieved from CNN website [Link]

2  University College London. (2019 March 27). “Woman with novel gene mutation lives almost pain-free”. Retrieved from Eureka website [Link].

3 Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R., & Lichtman, A.H. (2001). “Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase”. Proceedings of the National Academy of Sciences of the United States of America, 98 (16): 9371–6. 

Regeneration in humans – Finding the gene switch

Regeneration in humans is much more limited compared in other animals. Say for instance when one lost a limb, much as well say goodbye to it for the rest of one’s life. Perhaps, it would be nice if we have higher capacity to regenerate many of our indispensable body parts, like head, limbs, and many other “regeneration-incapables”. Then probably, we might not have to worry much about losing any of them knowing that they will eventually re-grow in due time.

 

 

Regeneration vs. Healing

Humans have the capacity to regenerate. However, we have a very limited capabiltiy to restoring parts of our skin, hair, nails, fingertips, and liver. At the tissue level, surely we have dedicated cells to replace lost and damaged cells. For instance, our non-injured bone eventually replenishes into a full new bone but in a span of ten years. Our skin naturally renews but give it two weeks. The story swerves differently though in the case of an injury.

 

Rather than expending energy into having it replaced with a new one, our body directs its efforts into healing it. So when our skin is deeply damaged, our body fixes it with a scar. Tissue repair mechanisms such as wound healing aren’t really a snag. They forestall pathogenic microbes from using an injured body part as an easy gateway into our body. (Besides, we do have ample microbiota naturally thriving inside of us already) The main goal is to fix it efficaciously, with relatively less effort.

 

 

 

Natural regeneration in humans

In humans, the only tissue that regenerates naturally, consistently, and completely is the endometrium.1 After it slough-offs during a woman’s menstrual period, it grows back by re-epithelialization until the next period. Humans can also regenerate an injured liver provided that the restoration involves as little as 25% of the original liver mass. The liver can grow back to its original size but may not to its original shape. Damaged tubular parts of the kidney can also re-grow. The surviving epithelial cells undergo migration, dedifferentiation, proliferation, and re-differentiation to set a new epithelial lining of the tubule.

 

 

 

Animals with higher regeneration capacities

 

axolotl regeneration
Axolotl (Ambystoma mexicanum) is one of the animals dubbed as masters of regeneration. It can grow back its limbs, even a heart, without a scar. [Photo credit: Mike Licht, Flickr]
 

 

Some animals have higher capacity to re-grow lost body parts. Sharks, skates, and rays can regenerate their kidneys. They can regrow an entire nephron, which humans cannot. A lizard would drop its tail as a mode of escape; its tail will be fully restored over time anyway. Sharks do not have qualms about losing teeth. They can replace any of them more than a hundred times in their lifetime. Axolotl can replace its broken heart. A starfish will once again be stellar upon the return of a lost arm. In fact, even its lost arm can fully regenerate into an entire starfish as long as the central nerve ring remains intact.2 A decapitated planarian worm needs not worry about losing its head; it can grow back, together with its brain, including the memories.2 Without a doubt, many of these animals are simply masters of their craft – regeneration.

 

 

Regeneration genes

Researchers from Harvard University published their new findings on whole-body regeneration capacity of the three-banded panther worm.3 They uncovered DNA switches that seemed to regulate genes that have a role in the regeneration process. Accordingly, they found a section of a non-coding DNA that controlled the activation of a master gene in which they called the “early growth response” (EGR) gene. When active, the EGR gene seemed like a power switch that turns on and off certain genes in the coding region during regeneration. On the contrary, when deactivated, no regeneration occurred.

 

Surprisingly, humans have EGR gene, too.  So why doesn’t it lead to greater regeneration capacities as it does in the three-banded panther worm? The researchers explained that while it works in the worm, it doesn’t work the same way in humans. The wiring may be different. The worm’s EGR gene may have germane connections that are absent in humans.

 

 

 

Switching the gene on

Regeneration in humans
Regeneration in humans is limited. If only we knew the switch that could amplify our regeneration capacity then we might not have to worry much about losing a body part. [Photo credit: Pete Johnson, Pexels]
 

 

Induced regeneration in humans is one of the goals of regenerative medicine. This field of medicine seeks new ways to give our regenerative capacity a boost. One of the ways is to look “molecularly”. Researchers are looking into the gene “Lin28a“. When active, this gene can reprogram somatic cells into embryonic-like stem cells. Accordingly, it has a role in tissue regeneration and recovery. However, the gene is naturally turned off in adults. Research in boosting our regenerative capacities is ongoing. Switching our organs from being regeneration-incapable to regeneration-capable may just be a matter of discovering the gene switch that could enhance regeneration capacity of humans.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Min, S., Wang, S. W., & Orr, W. (2006). “Graphic general pathology: 2.2 complete regeneration”Pathology. pathol.med.stu.edu.cn. Retrieved from [Link]

2  Langley, L. (2013, August 28). “Pictures: 5 Animals That Regrow Body Parts”. National Geographic News. Retrieved from [Link] ‌

 

Measles vaccine hesitancy leads to outbreaks, deaths of unvaccinated

Many people are afraid of getting measles vaccine these days. The fear arises from the allegedly adverse effects of it, such as autism. However, this fear comes along with the resurgence of the dreaded measles outbreak. Consequently, measles once again takes many lives, especially of the children, who ought not die from such a preventable disease.

 

 

 

Measles vaccine being linked to autism

In 1998, a team of scientists headed by Andrew Wakefield published a paper in refutable science journals. Accordingly, MMR vaccine — a cocktail of vaccine that protects against measles, mumps, and rubella— seems to have a causal link to autism in children.[1] He and his colleagues reported twelve children that displayed delay in growth development; eight of them had autism a month following MMR vaccine. However, the paper was later retracted. Accordingly, “several elements” of a 1998 paper Lancet1998;351[9103]:637–41 “are incorrect, contrary to the findings of an earlier investigation”[2]. The retraction clearly indicated data misconception. However, that did not end there. Wakefield and his team published yet another study. Again, they implicated measles virus to autism.

 

 

 

Second study, still questionable

In 2002, Wakefield and his team biopsied samples from the intestines of two groups of children: with autism and control (without autism). They tested the presence of measles virus genome via reverse-transcriptase PCR and in situ hybridization. They reported 75 of 91 children with autism tested positive for measles virus genome. In the control group, only five of 70 were positive.[3]  Accordingly, their findings corresponded to their earlier conjecture linking measles virus to autism in children. However, critics still found critical flaws.[4] For instance, the authors failed to stipulate with proof the origin of the measles virus genome in the patients — whether from nature or from the vaccine.

 

 

 

Studies refuting the link

Two independent large-scale studies (one in California, USA and another in England, UK) denied the link between MMR vaccine and autism. Truly, the number of children with autism dramatically increased. However, the percentage of children receiving MMR vaccine remained constant. The empirical data on a larger scale of population indicated the absence of causal relationship between measles vaccine and autism.[4]

 

 

 

Impact

The side effects associated with MMR vaccine are mild symptoms of measles, mumps, and rubella. And not all children administered with it will show symptoms. As for measles, the common symptoms include swelling and redness at the site of injection, fever, and rash. Rare symptoms include anaphylaxis, bruise-like spots, and fits.[5] No categorical study has fully established that MMR vaccine causes autism in children. Nevertheless, many people remain hesitant despite the many years of proven efficacy of measles vaccine. Their worries were aggravated by the likes of Wakefield studies linking MMR vaccine to autism in children.

 

Dubbed as anti-vaxxers, these people utterly lost their confidence on vaccines so much that they secluded and kept their children from getting vaccinated. The main reason arises from their fear that vaccines would cause more harm than good. Some of them even took a legal step against vaccine manufacturers for allegedly having identified the culprit of their child’s developmental delay. And despite the disavowal of Wakefield’s paper and having been repudiated by ensuing studies dissociating autism from MMR vaccine, many people including autism advocacy groups have not abandoned their skepticism. Some of them even came up with a “conspiracy theory” that vaccine manufacturers may be conspired into hiding the “truth”, i.e. MMR vaccine causes autism.[2]

 

 

 

Pathobiology of measles

The genus Morbillivirus, a single-stranded, negative-sense RNA virus, is the causative agent of measles, the highly contagious airborne disease. Humans are the only known host of the virus. The video below describes how the measles virus infects the host cell.

 

[Video credit: Folks from Osmosis, Doc James; Source: Wikipedia, CC-BY-SA 4.0 ]

 

In summary,  the virus infects the epithelial cells lining the trachea or the bronchi upon reaching the mucosa. The virus gains entry into the host cell via its surface protein, hemagglutinin (H protein). The H-protein binds to the receptor (e.g. CD46, CD150, or nectin-4) on the surface of the target host cell. After binding, the virus fuses with the cell membrane to get inside the cell. Then, it makes use of the cell’s RNA polymerase to transcribe its RNA into mRNA strand. After which, the mRNA is translated into viral proteins in which the host cell’s lipid will envelope them for their subsequent release outside the cell. They spread to lymph nodes,  and then to other tissues (e.g. brain and intestines).[6] Soon, the disease manifests as fever, cough, runny nose, inflamed eyes, and rash. Common complications include pneumonia, seizures, encephalitis, and subacute sclerosing panencephalitis.

 

 

 

Measles vaccine

 

measles-vaccine
A child getting measles vaccine during the launch of a campaign to immunize children at the Beerta Muuri Camp for internally displaced persons in Baidoa, Somalia on April 24, 2017.

[Credit: UN Photo. Credit: UNSOM Somalia, Flickr]

 

The vaccine that prevented the disease was first made available in 1963. It may be administered solely or in combinations, like in MMR vaccine. MMR vaccine renders protection against measles, mumps, and rubella viruses. The World Health Organization (WHO) recommends that measles vaccine be administered to infants at nine or twelve months of age. A person needs only two doses during childhood for lifelong immunity.

 

 

 

How vaccines work

Measles vaccine contains live but weakened strain of measles virus. Vaccines work by triggering an immune response from the white blood cells. These cells recognize them through the surface proteins of the virus. White blood cells, such as B cells, produce multifarious antibodies. One of the antibodies can fit to the surface protein. This will trigger the B cell to produce clones, called memory B cells, which, in turn, will produce large amounts of antibodies specific to the identified pathogen.

 

A re-encounter with the virus having the same surface protein would enable the antibodies to respond quickly by binding with and disabling the virus. They can also make it “palatable” to macrophages and other phagocytic cells that engulf and kill pathogens. How come the measles vaccine remain effective for so many years? The surface proteins of the measles virus are not prone to changes as presumed, and any mutation on them may render them dysfunctional.[7] Thus,  the immune system will always recognize the measles virus. And the immune response would be so quick that most of the time the vaccinated individual would no longer be ill.

 

 

Herd immunity

One of the benefits of a rabid immunization program is that the immune protection extends to those who have not received the vaccine yet. Referred to as herd immunity, the community becomes protected from measles when a huge percentage of the population got the vaccine. In a study published in the journal Frontiers in Public Health, measles vaccination in a sequence recommended by WHO apparently helped reduce child mortality.[8] But in order to prevent and ultimately eliminate measles, WHO seeks global immunization coverage of at least 95%.[9]

 

 

 

Recent measles outbreak

 

measles
The Philippines, especially the NCR, currently experiences a large measles outbreak. CDC’s Jim Goodson took this photo of a child stricken with the disease during his visit in Manila to respond to the outbreak.

[Credit: CDC Global, Flicker, CC BY-SA 2.0]

 

Failure to reach the idyllic 95% global coverage leads to the inevitable measles outbreak. For several years, global coverage with the first dose of measles vaccine has stood at only 85% whereas the second dose, at 67%. Thus, measles outbreaks occurred in all regions with over a hundred thousands of fatalities mainly due to serious complications. In 2000, about 21 millions of lives have been saved due to measles vaccine. However, measles cases around the globe surged by more than 30% from 2016.[9]

 

Dr. Seth Berkley of Gavi, the Vaccine Alliance, elucidated the reasons of the alarming resurgence of measles of recent. He said, “Complacency about the disease and the spread of falsehoods about the vaccine in Europe, a collapsing health system in Venezuela and pockets of fragility and low immunization coverage in Africa are combining to bring about a global resurgence of measles after years of progress. Existing strategies need to change: more effort needs to go into increasing routine immunization coverage and strengthening health systems. Otherwise we will continue chasing one outbreak after another.”[9]

 

 

 

Concluding remarks

Measles vaccine has indubitably protected millions of lives. However, because of the escalating apprehensions and the reluctance towards measles vaccination, we fell short from achieving the goal of eliminating the disease. If only we could stick by the goal and support local immunization program efforts, we might have already won it over once and for all.  Measles is a preventable disease and measles vaccine has already been tried and tested for over so many years. I hope it would not reach to the point whereby an immunization mandate would be the inevitable recourse when in essence we can simply heed the call.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Wakefield, A.J., Murch, S.H., Anthony, A., et al. (1998). Ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet, 351: 637-641.

2  Eggertson, L. (2010). Lancet retracts 12-year-old article linking autism to MMR vaccines. Canadian Medical Association Journal182(4), E199–E200. [Link]

3 Uhlmann, V., et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Journal of Clinical Pathology: Molecular Pathology 55:1-6, 2002. [Link]

4 Offit, P.A. (n.d.). Vaccines and Autism. [PDF]

5 NHS Choices. (2019). Vaccinations. Retrieved from [Link]

6 Moss, W.J. & Griffin, D.E. (14 January 2012). “Measles”. Lancet379 (9811): 153–64. [doi:Link]

7 Cell Press. (2015, May 21). Why you need one vaccine for measles and many for the flu. ScienceDaily. Retrieved from [Link]

8 Frontiers. (2018, February 12). Measles vaccine increases child survival beyond protecting against measles: New study shows all-cause mortality is significantly lower when a child’s most recent immunization is a measles vaccine. ScienceDaily. Retrieved from [Link]

9 World Health Organization. (2018, November 29). Measles cases spike globally due to gaps in vaccination coverage. Retrieved from [Link]

Fasting boosts human metabolism, has anti-aging effects

In the advent of 2019, we are inspired to set new goals, pursue life-long dreams, or simply make better choices. Perhaps, one of the most common reveries we wish to realize is to be able to adopt a healthier kind of lifestyle. With this in mind, some of us look for ways to feel dutifully healthier, such as by managing our weight. So, many would turn to fad diets and caloric restrictions that promise to help. One of them is intermittent fasting. Based on studies, intermittent fasting does not only help trim weight but it seems to offer further health benefits as well.

 

 

 

Intermittent fasting – overview

 

intermittent fasting
Scientists found that fasting boosted human metabolism. This could mean that fasting may slow aging in humans. [Image credit: Zeyus Media]
 

 

 

In May 2018, I wrote the article: Intermittent Fasting – benefits and caution. There, I tackled briefly about intermittent fasting, its benefits, and potential risk. In essence, intermittent fasting is a cyclic pattern of a period of fasting and a subsequent period of non-fasting. The most common forms are: (1) whole-day fasting and (2) time-restricted eating. Whole-day fasting entails one-full day of “no eating”, done twice a week (thus, referred to as “5:2 plan“). In time-restricted eating, there is an interval of fasting and non-fasting on a daily basis. It could be half a day of fasting, and then the remaining half as the non-fasting period.  With intermittent fasting, it’s not so much about “what to eat…” or “how much…” Rather, it’s more about a question of when.

 

 

 

Intermittent fasting became popular because it does not only help curb weight but it also implicates other health benefits. It apparently slows aging and boosts the immune defense.[1] However, as I pointed out in that article, caution should still be taken. Intermittent fasting is not for everyone, especially those who are immunocompromised and underweight.[2]

 

 

 

Rejuvenating effects of fasting

Previously, I mentioned that studies confirming the health benefits of fasting were done on non-human subjects (e.g. rodent models). Without much scientific proofs of efficacy on humans, what would, therefore, be definite is doubt.  However, on January 29 of this year, a team of scientists from Okinawa Institute of Science and Technology Graduate University (OIST) and Kyoto University reported rejuvenating effects of fasting on human subjects. They published their findings in Scientific Reports.[3] Accordingly, they analyzed the blood samples from four fasting individuals. They also monitored the levels of metabolites involved in growth and energy metabolism. What they found was quite interesting and promising.

 

 

 

Dr. Takayuki Teruya, one of the researchers of the team, said that their results implicated the rejuvenating effects of fasting. They found that many metabolites increased significantly, about 1.5- to 60-fold, in just 58 hours of fasting. In their previous study, they identified some of these metabolites (e.g. leucine, isoleucine, and ophthalmic acid), that typically deplete with age. According to Dr. Teruya, they found that the amount of these metabolites increased again in individuals who fasted. Also, they conjectured that fasting could possibly promote muscle maintenance and antioxidant activity based on the metabolites they found. Hence, fasting may probably promote longevity as well. Dr. Teruya further said that this was not yet known until now since most studies that have said so used animal models.[4]

 

 

 

Fasting increased metabolism

During fasting, the body turns to alternate energy stores when carbohydrates are not available. Thus, the less-common metabolites from alternative metabolic pathways superseded the typical metabolites from carbohydrate metabolism. They identified butyrates, carnitines, and branched-chain amino acids as some of the metabolites that accumulated during fasting. [4] Apart from this, the researchers also found an increase in Citric acid cycle intermediates. This means that aside from prompting alternate metabolic pathways, fasting has also augmented the common metabolic activities. The metabolism of purine and pyrimidine seemed also heightened, indicating an increase in gene expression and protein synthesis. Because of this, the researchers also saw a boost in antioxidants (e.g. ergothioneine and carnosine) that protect cells from the free radicals produced by metabolism. The researchers assume to be the first to provide evidence of antioxidants as a fasting marker. [4]

 

 

 

This new-found proof infers that fasting seems to have some anti-aging effects, this time, on human subjects. Their next step is to see if they could duplicate the results in a larger-scale study. For now, let us remain cautious, look for indubitable substantiation, and weigh in the benefits and risks of all available options.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1  Cohut, M. (2018). Intermittent fasting may have ‘profound health benefits’. Retrieved from [Link]

2  Longo, V. D., & Mattson, M. P. (2014). Fasting: Molecular Mechanisms and Clinical Applications. Cell Metabolism, 19 (2), 181–192. [Link]

3 Teruya, T., Chaleckis, R., Takada, J., Yanagida, M. & Kondoh, H. (2019). Diverse metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood. ”Scientific Reports, 9”(1) DOI: 10.1038/s41598-018-36674-9.

4  ‌ Okinawa Institute of Science and Technology (OIST) Graduate University. (2019, January 31). Fasting ramps up human metabolism, study shows. ScienceDaily. Retrieved from [Link]

Lurking beneath the ice

Scientists found dead tardigrades beneath the Antarctica based on their report published of recent.[1] It was a surprising discovery since tardigrades have acquired the mark as the tiny infinities. They are so resistant to extreme conditions that they are thought of as some sort of “immortals“. Nonetheless, scientists found remains of tardigrades, together with crustaceans in deep, frozen Antarctic lake.[1]

 

 

Antarctic Realm – The Cold Realm

 

Antarctic realm
The Antarctic biogeographic realm – the smallest of all realms.

 

The Antarctic is a region located in the southern-most tip of the Earth. The biogeographic realm that includes the Antarctic is called the Antarctic realm. A biogeographic realm refers to an area of land where similar organisms thrived and then evolved through periods of time in relative isolation.[2] It rouses extensive research with the paramount objective of understanding the extent of biodiversity, especially the distributional patterns of residing organisms and the biological evolutionary history incurred.

 

 

The Antarctic biogeographic realm is the smallest of all realms. It spans a total area of about 0.12 million square miles. Its components include the land area, the Antarctic tectonic plate, the ice in the waters, and the ocean itself. [2]  Because of the cold temperature, few floral species are able to persist and thrive. At present, around 250 lichens, 100 mosses, 25-30 livertworts, 700 algal species, and two flowering plant species (i.e. Antarctic hair grass and Antarctic pearlwort) inhabit the region. As for fauna, animal species include the penguinsseals, and whales.[2]

 

 

An Icy Surprise

 

tardigrade
Tardigrades . [Credit: Willow Gabriel, Goldstein Lab – https://www.flickr.com/photos/waterbears/1614095719/]
 

The discovery of the remains of tardigrades was unexpected, according to David Harnwood, a micropaleontologist. Late last year, Harnwood and his research team drilled a hole in the subglacial Lake Mercer. This frozen lake had been undisturbed for millennia.  Thus, their research project SALSA (Subglacial Antarctic Lakes Scientific Access) was the first to conduct direct sampling. They were absolutely surprised to find these water bears –frozen and dead.

 

Astounded, the animal ecologist, Byron Adams, conjectured that these tardigrades might have come from the Transantarctic Mountains, and then carried down to Lake Mercer. [1] Further, he said, “What was sort of stunning about the stuff from Lake Mercer is it’s not super, super-old. They’ve not been dead that long.”

 

 

Chilly Giants

mollivirus
“Mollivirus sibericum” found in Siberian permafrost.
[Credit: © IGS CNRS/AMU]
 

In September 2015, Jean-Michel Claverie and others reported two giant viruses (i.e. ”Pithovirus sibericum” and ”Mollivirus sibericum”) that they revived from a 30,000-year-old permafrost in Siberia.[3,5] Once revived, the viruses quickly became infectious to their natural hosts, the amoebae. [5] Luckily, these chilly giants do not prefer humans as hosts. Nonetheless, the melting of these frozen habitats could implicate danger to the public health when pathogens that can infect humans escape the icy trap.

 

 

A frozen Pandora’s Box

The frozen regions of the Earth hold so many astonishing surprises waiting to be “thawed”. In August 2016, a 12-year old boy from the Yamalo-Nenets region of Siberia died from anthrax. Reports included a few number of locals and thousands of grazing reindeer as well.[6] Prior to the anthrax outbreak, a summer heatwave caused the melting of the permafrost in the Yamal Peninsula in the Arctic Circle. The thawing of the frozen soil unleashed anthrax bacteria presumed to have come from the carcass of their reindeer host that died over 75 years ago. Their release apparently reached the nearby soil, water, the food supply, and eventually their new hosts.[5] The anthrax bacteria survived because they form spores that can protect them during their dormancy.

 

 

 

A Hotter Earth

Global warming supposedly increases the average temperature of the Earth’s surface enough to cause climate change. Accordingly, the global surface temperature increased 0.74 ± 0.18 °C (1.33 ± 0.32 °F) during the last century. The temperature rise brings threat as it could lead to environmental changes that could cause adverse effects of massive magnitude. One of which is the destruction of habitats due to the subsequent rise of water level from the melting of ice. Deadly pathogens could rise again from their cold slumber and plausibly cause another major mass extinction in no time. So, while we try to explore the deeper mysteries lurking beneath the ice, we should also make sure that we remain a step ahead. Claverie[5] excellently put it:

The possibility that we could catch a virus from a long-extinct Neanderthal suggests that the idea that a virus could be ‘eradicated’ from the planet is wrong, and gives us a false sense of security. This is why stocks of vaccine should be kept, just in case.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1  Berman, R. (2019, January 18). Dead – yes, dead – tardigrade found beneath Antarctica. Retrieved from [link]

2  Pariona, A. (2018, May 18). What Are The Eight Biogeographic Realms? Retrieved from [link]

3 CNRS. (2015, September 9). New giant virus discovered in Siberia’s permafrost. ScienceDaily. Retrieved from [link]

4  ‌ Wikipedia Contributors. (2018, November 10). Antarctic realm. Retrieved from [link]

5  Fox-Skelly, J. (2017, January 1). There are diseases hidden in ice, and they are waking up. Retrieved from [link]

6  Russia anthrax outbreak affects dozens in north Siberia. (2016, August 2). BBC News. Retrieved from [link]

7  Biology-Online Editors. (2014, May 12). Biology Online. Retrieved from [link]

Aerobic exercise modifies fine particle exposures to young adults

Aerobic exercise contributes to the prevention and treatment of various chronic diseases as well as helps improves endothelial function. It is also beneficial in adaptation of the cardio-pulmonary system and infection resistant. Moreover, aerobic exercise attributes to the release of vasoconstrictor substances and increased nitric oxide availability. However, exposure to fine particles in ambient condition linked to some adverse health effects. This includes oxidative stress, pulmonary systemic inflammation, increased blood coagulation and vascular imbalance. Aerobic exercise in polluted environments increased inhalation of air pollutants due to increased respiratory rate and reduction of nasal resistance. Also, long-term exercise aggravates air pollutant which causes associated respiratory impairment.

 

Air pollutant exposure during aerobic exercise

There were 20 healthy non-smoking male subjects on this study and aerobic exercise frequencies have been recorded. Wherein indices measured including fractional exhaled nitric oxide, blood pressures; cytokines exhaled breath condensate and pulse-wave analysis. However, the biomarkers of eosinophilic airway inflammation were positively associated with air pollution exposure. Also, the fractional exhaled nitric oxide concentrations were greater in high exercise frequency. Thus, explain that high strength exercise might be at higher risk of particle-mediated respiratory symptoms.

 

Aerobic exercise is associated with the exposure to air pollutant which caused respiratory inflammation and arterial stiffness. In terms of cardiovascular responses the increased in aortic augmentation pressure indicate higher pulse-wave velocity. Furthermore, aerobic exercise at moderate frequency had a greater protective effect against cardiopulmonary health risk than low or excessive exercise.

 

Therefore, long-term habitual aerobic exercise in severely polluted areas may strengthen the resistance of the cardiovascular system. But increase the risk of pollutant-related airway inflammation. In addition, surrogate biomarkers of atherosclerosis, arterial wall thickness have been decreased following the long-term aerobic exercise. And also low cardiopulmonary fitness is the key indicators for cardiovascular mortality and coronary heart disease.

 

Source: Prepared by Joan Tura from BMC Environmental Health

Volume 17:88 December 13, 2018

Pathobiology of allergy and its most severe form, anaphylaxis

When allergy season looms, some people with serious hypersensitivity to allergens tend to be apprehensive of what may come. Some would rather stay indoors than risking the odds of sucking up triggers that could instigate severe allergic reactions. Apart from triggers from the environment, other common factors for allergy include food, medication, certain toxins, venom from insect stings or bites, stress, and heredity. How does an allergy manifest? Which cells are involved in forming an allergic reaction?

 

 

 

The immune system

allergy
How does an allergy occur? The pathobiological mechanism involves several white blood cells that play a role in mounting an allergic reaction.

 

The immune system protects the body from foreign substances (generally referred to as antigens) that could pose a threat to our well-being.  It prevents harmful bacteria, viruses, parasites, etc. from invading and causing harm. The white blood cells (also called leukocytes) constantly scout for antigens in order to destroy or disable them. The white blood cells include lymphocytes, neutrophils, basophils, eosinophils, monocytes, macrophages, mast cells, and dendritic cells.

 

 

 

Allergy – overview

 

allergy pathway
The allergy pathway.
Image (by Sari Sabban) distributed under the CC 3.0 Unported license.

 

An allergy is a state of hypersensitivity of the immune system in response to an allergen (i.e. a substance capable of inciting an allergic reaction). In this regard, several white blood cells play a role in mounting an allergic reaction.

In summary, the entry of an allergen into the body triggers an antigen-presenting cell, such as a dendritic cell. The dendritic cell takes up the allergen, process it, and then present its epitopes through its MHC II receptor on its cell surface. It, then, migrates to a nearby lymph node, waiting for a T lymphocyte to recognize it.

Upon recognition, the T lymphocyte may differentiate into a Th2 cell (type 2 helper T cells), which is capable of activating B lymphocyte. B lymphocyte, when activated, matures into a plasma cell that could synthesize and release IgE antibody in the bloodstream. Some of the circulating IgE may bind to mast cell and basophil. Thus, re-entry of such allergen could incite the IgE on mast cells and basophils to recognize its epitope. In effect, this activates the mast cell or basophil to release inflammatory substances (e.g. histamine, cytokines, proteases, chemotactic factors) into the bloodstream.

 

 

 

Anaphylaxis – a dreadful allergic reaction

The allergic reaction mounted by the immune system is supposed to protect the body. However, the allergens perceived by the body as a threat are generally harmless. The body tends to overly react to the allergens, and so leads to symptoms. Histamine, for instance, brings about the common symptoms of allergy: pain, heat, swelling, erythema, and itchiness.

 

Anaphylaxis is the most severe form of allergic reaction. It can occur rapidly and it affects more than one body system, such as respiratory, cardiovascular, cutaneous, and gastrointestinal systems. It occurs as a result of the release of inflammatory substances from mast cells and basophils upon exposure to an allergen. Within minutes to an hour, symptoms could manifest as a red rash, swelling, wheezing, lowered blood pressure, and in severe cases, anaphylactic shock.

 

In the presence of breathing difficulties, racing heart, weak pulse, and/or a change in voice, the situation is precarious. It calls for an immediate medical attention.

 

Why does anaphylaxis occur? IgE-mediated anaphylaxis is the common form of anaphylaxis. Initial exposure to an allergen leads to the release of IgE so that re-exposure to the allergen leads to its identification and the eventual activation of mast cells and basophils.  Apart from immunologic factors, though, other causes of anaphylaxis are non-immunologic. For example, temperature (hot or cold), exercise, and vibration may cause anaphylaxis. In this case, IgE is not involved. Rather, these agents directly cause the mast cells and the basophils to degranulate.

 

 

 

Novel mechanism identified

Recently, a team of researchers1,2 found a novel mechanism that could explicate the hasty allergic reaction during anaphylaxis. They were first to uncover a mechanism involving the dendritic cells. Accordingly, a set of dendritic cells seem to “fish” allergens from the blood vessel using their dendrites. The dendritic cell near the blood vessel takes up the blood-borne allergen. Rather than initially processing it, and then presenting the epitope on its surface, it hands over the allergen inside a micro-vesicle to the adjacent mast cells.

 

Mast cells, unlike basophils that are in the bloodstream, are located in tissues, such as connective tissue. Thus, the question as to how the mast cells detect blood-borne allergen could be answered by the recent findings.

 

Rather than being internalized by the dendritic cells for processing, the allergen was merely taken into a micro-vesicle that budded off from the surface of dendritic cells. This, thus, saves time. It cuts the process, leading to a much rapid allergic reaction.

 

However, these findings were observed in mouse models. Therefore, the researchers have yet to observe if this novel mechanism also holds true on humans. If so, this could lead to possible therapeutic regulation of allergies, especially the most dreadful form, anaphylaxis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Choi, H.W., Suwanpradid, J. Il, Kim, H., Staats, H. F., Haniffa, M., MacLeod, A.S., & Abraham, S. N.. (2018). Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesiclesScience 362 (6415): eaao0666 DOI: 1126/science.aao0666
2 Duke University Medical Center. (2018, November 8). Using mice, researchers identify how allergic shock occurs so quickly: A newly identified immune cell mines the blood for allergens to directly trigger inflammation. ScienceDaily. Retrieved November 22, 2018 from www.sciencedaily.com/releases/2018/11/181108142440.htm

 

First time! Human blood cell turned into a young sex cell

In essence, our body consists of two major types of cells – one group involved directly in reproducing sexually (called sex cells) and another group that are not (called somatic cells). In particular, the female sex cell is referred to as the ovum (also called egg cell) whereas the male sex cell, the sperm cell. The somatic cells, in turn, are the cells in the body that have varying functions, such as nourishing the sex cells as well as keeping the body thriving and functional.

 

 

 

Origin of sex cells

Our body produces sex cells through the process called gametogenesis. The process is essentially a step-by-step process of meiosis. Oogenesis (i.e. gametogenesis in females) takes place in the ovaries to produce ova or egg cells. In brevity, the oogonium (the female primordial germ cell) undergoes meiosis to produce four haploid egg cells. Conversely, spermatogenesis (i.e. gametogenesis in males) occurs in the testes to yield sperm cells. Quintessentially, the spermatogonium (the male primordial germ cell) will go through meiosis to give rise to four haploid sperm cells.

 

 

 

Sex cells vs somatic cells

In humans, a sex cell may be identified from a somatic cell in being a haploid cell. That means a sex cell would have half the number of chromosomes as that of a somatic cell. Hence, an egg cell or a sperm cell would have 23 chromosomes whereas a somatic cell would have 46. Haploidy in sex cells is important in order to maintain the chromosomal integrity in humans across generations.

 

At fertilization, the sperm cell and the egg cell unite to form a diploid cell (called zygote). The zygote, then, divides mitotically, giving rise to pluripotent stem cells. A pluripotent stem cell is a cell capable of giving rise to various precursors that eventually will acquire specific identity and physiological function via a process called differentiation. A differentiated cell means that the cell has matured and acquired a more specific role, for instance as a skin cell, a blood cell, a liver cell, etc.

 

 

 

Somatic cell converted to sex cell

sex cell
Soon, a somatic cell could be converted into human sex cells.
[Image credit: Karl-Ludwig Poggemann, Flicker.com, CC by 2.0]

 

Intrinsically, a human somatic cell that has “differentiated” could never become a sex cell just as a sex cell could neither become nor give rise to a somatic cell. However, this may no longer hold true in the years to come.

 

Japanese researchers have, for the first time, successfully converted a somatic cell into a sex cell precursor.1 In particular, they had successfully created an oogonium from a human blood cell. They turned blood cells into “induced pluripotent stem cells” (iPS).2 Essentially, the blood cells – turned iPS – appeared to have undergone “molecular amnesia”. It means they forget their initial identity. As a result, they could become any type of cell, even as a sex cell.

 

The researchers transformed human blood cells into oogonia (plural of oogonium). They did so by incubating them for four months in artificial ovaries derived from embryonic mouse cells. They retrieved promising results. Admittedly though, they acknowledged they are still in the early steps of a rather long journey of research. The oogonia, indeed precursors to egg cells, are, at this point, still young, and thereby, unfit for fertilization. The researchers have yet to induce them to become mature, fully differentiated egg cells. Nevertheless, they remain optimistic in having reached this point, and, undeniably, pioneered an important milestone.

 

 

 

 

Ethical issues

If, in the future, research on the conversion of a somatic cell into a sex cell pushes through to completion, it could lead to significant resolves to infertility issues. However, ethical concerns shall, likely, surface as well. For instance, a possibility could occur in time. A mere hair cell or a skin cell from an unsuspecting person could be turned into an egg or a sperm cell. And from there, an offspring could come into existence.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Yamashiro, C., Sasaki, K., Yabuta, Y., Kojima, Y., Nakamura, T., Okamoto, I., Yokobayashi, S., Murase, Y., Ishikura, Y., Shirane, K., Sasaki, H., Yamamoto, T., & Saitou, M. (2018 Oct 19).Generation of human oogonia from induced pluripotent stem cells in vitro. Science, 362(6412):356-360. doi: 10.1126/science.aat1674.

 

2 Solly, M. (2018 Sept. 24). Scientists create immature Human Eggs Out of Blood Cells For the First Time. Retrieved from [link]

 

“Mutualism factor” could explain why body does not attack normal flora

When sadness reeks in and you feel as if you are all by yourself, think again. That is because you are never alone. As a matter of fact, millions of microorganisms reside in our body day in and out. They are the normal flora. Our body is a world of microscopic living entities that inhabit our body without essentially causing a disease. Rather, they live in us in harmonious mutualism. Thus, our body is not ours alone. Hence, we can say we are not absolutely sterile from the moment we are born.

 

 

 

Normal flora

Typically, the body has about 1013 cells and harbors about 1014 bacteria.1 The multifarious yet specific genera of bacteria that predominate the body is referred to as the normal flora. In essence, the normal flora thrives in a host in a mutualistic lifestyle. The microbes take advantage from living stably in the body. In return, they confer benefits to the human host. For instance, their presence helps prevent other more harmful microbes from colonizing the host. Some of them biosynthesize products that the human body can use. Nevertheless, an immunocompromised host could suffer in cases when these bacteria became overwhelming in number, and thereby cause detectable harm, like infections or diseases.

 

 

 

Normal flora in the gut

normal flora in the gut
Escherichia coli, one of the many bacterial species of the normal flora in the human gut

 

Microbes that normally thrive in the gut are greater in density and diversity compared with those in other body parts. Nevertheless, they vary in density depending on the location in the gastrointestinal tract. For instance, the stomach harbors about 103 to 106/g of contents whereas the large bowel of the large intestine has about 109 to 1011/g of contents. The normal flora in the stomach has fewer normal microbial inhabitants due to its acidity. The ileum of the small intestine contains a moderate microbial number, i.e. 106 to 108/g of contents.1

 

Some of the various bacterial species of the normal gut flora includes the anaerobes, Enterococcus sp., Escherichia coli, Klebsiella sp., Lactobacillus sp., Candida sp., Streptococcus anginosus and other Streptococcus sp.. Some of these bacteria aid in the production of bile acid, vitamin K, and ammonia since they possess the necessary enzymes.

 

 

 

Coexistence

Certain normal gut bacteria can become pathogenic. They could cause a disease when opportunity presents such as when changes in their microbiota favor their growth. Be that as it may, a healthy individual would not be usually harmed by their presence. Thus, question arises — why our immune armies do not, by and large, act against the normal flora as aggressively as they would in the presence of more harmful pathogens.

 

Karen Guillemin, a professor of biology and one of the authors of a paper that appeared in a special edition of the journal eLife, was quoted3: “One of the major questions about how we coexist with our microbial inhabitants is why we don’t have a massive inflammatory response to the trillions of the bacteria inhabiting our guts.

 

 

 

“Mutualism factor”

Guillemin and her team of scientists reported that they uncovered a novel anti-inflammatory bacterial protein they referred to as Aeromonas immune modulator (AimA).  Accordingly, AimA is a protein produced by a common gut bacterium, Aeromonas sp., in the animal model, zebrafish.  The researchers found that AimA alleviated intestinal inflammation and extended the lifespan of the zebrafish from septic shock.2 Furthermore, they described it as an immune modulator that confers benefits to both bacteria and the zebrafish host.

 

The newly-discovered protein seems to be the first of its kind. Nevertheless, it is structurally similar to lipocalins, a class of proteins that, in humans, modulate inflammation. Based on their findings, the removal of this protein caused more intestinal inflammation in the host and the destruction of the normal Aeromonas gut bacterium. The reintroduction of AimA reverted to “normal”, i.e. the host, relieved from inflammation and Aeromonas’ typical density, restored. AimA appears to represent a new set of bacterial effector proteins. And, Guillemin referred to them as mutualism factors.3

 

Guillemin and her team postulate that many more of these mutualism factors exist even in humans, and yet to be found. These mutualism factors may have therapeutic potential for use in modulating inflammation especially in medical conditions such as sepsis and certain metabolic syndromes.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Davis, C. P. (1996). Normal Flora. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston. Retrieved from [link]

2 Rolig, A. S., Sweeney, E. G., Kaye, L.E., DeSantis, M. D., Perkins, A., Banse, A. V., Hamilton, M.K., & Guillemin, K. (2018). A bacterial immunomodulatory protein with lipocalin-like domains facilitates host–bacteria mutualism in larval zebrafish. eLife. [link]

3 University of Oregon. (2018, November 6). Novel anti-inflammatory bacterial protein discovered: Newly discovered protein alleviates intestinal inflammation and septic shock in an animal model. ScienceDaily. Retrieved from [link]