|
|
Post by Admin on Feb 18, 2021 19:38:03 GMT
Almost one in five people lack the protein α-aktinin-3 in their muscle fiber. Researchers at Karolinska Institutet in Sweden now show that more of the skeletal muscle of these individuals comprises slow-twitch muscle fibers, which are more durable and energy-efficient and provide better tolerance to low temperatures than fast-twitch muscle fibers. The results are published in the scientific journal The American Journal of Human Genetics. Skeletal muscle comprises fast-twitch (white) fibers that fatigue quickly and slow-twitch (red) fibers that are more resistant to fatigue. The protein α-aktinin-3, which is found only in fast-twitch fibers, is absent in almost 20 percent of people – almost 1.5 billion individuals – due to a mutation in the gene that codes for it. In evolutionary terms, the presence of the mutated gene increased when humans migrated from Africa to the colder climates of central and northern Europe. “This suggests that people lacking α-aktinin-3 are better at keeping warm and, energy-wise, at enduring a tougher climate, but there hasn’t been any direct experimental evidence for this before,” says Håkan Westerblad, professor of cellular muscle physiology at the Department of Physiology and Pharmacology, Karolinska Institutet. “We can now show that the loss of this protein gives a greater resilience to cold and we’ve also found a possible mechanism for this.” For the study, 42 healthy men between the ages of 18 and 40 were asked to sit in cold water (14 °C) until their body temperature had dropped to 35.5 °C. During cold water immersion, researchers measured muscle electrical activity with electromyography (EMG) and took muscle biopsies to study the protein content and fiber-type composition.  The results showed that the skeletal muscle of people lacking α-aktinin-3 contains a larger proportion of slow-twitch fibres. On cooling, these individuals were able to maintain their body temperature in a more energy-efficient way. Rather than activating fast-twitch fibres, which results in overt shivering, they increased the activation of slow-twitch fibers that produce heat by increasing baseline contraction (tonus). “The mutation probably gave an evolutionary advantage during the migration to a colder climate, but in today’s modern society this energy-saving ability might instead increase the risk of diseases of affluence, which is something we now want to turn our attention to,” says Professor Westerblad. Another interesting question is how the lack of α-aktinin-3 affects the body’s response to physical exercise. “People who lack α-aktinin-3 rarely succeed in sports requiring strength and explosiveness, while a tendency towards greater capacity has been observed in these people in endurance sports,” he explains. One limitation of the study is that it is harder to study mechanisms in human studies at the same level of detail as in animal and cell experiments. The physiological mechanism presented has not been verified with experiments at, for example, the molecular level. Reference: “Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation” by Victoria L. Wyckelsma, Tomas Venckunas, Peter J. Houweling, Maja Schlittler, Volker M Lauschke, Chrystal F. Tiong, Harrison D. Wood, Niklas Ivarsson, Henrikas Paulauskas, Nerijus Eimantas, Daniel C. Andersson, Kathryn N. North, Marius Brazaitis, Håkan Westerblad, 17 February 2021, American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2021.01.013. The study was a collaboration with research groups at the Lithuanian Sports University in Kaunas, Lithuania, and the University of Melbourne in Australia. It was supported by grants from the Swedish Research Council, the Swedish National Centre for Research in Sports, the Research Council of Lithuania, the Swedish Society for Medical Research, the Jeansson Foundations, the Swedish Heart and Lung Foundation and Australia’s National Health and Medical Research Council. Co-author Volker Lauschke is the founding CEO and shareholder of HepaPredict AB and has been a consultant for EnginZyme AB. |
|
|
|
Post by Admin on Feb 28, 2021 3:57:29 GMT
Coronavirus affects people differently – some infected develop life-threatening disease, while others remain asymptomatic. And a year aftere COVID-19 emerged, it’s still unclear why. To try and answer this question, researchers have started looking at the genetics of people who get COVID-19, and identifying links between developing the disease and variations in specific parts of our DNA. This raises the possibility that some of what makes people susceptible to COVID-19 lies in their genes. This wouldn’t be surprising. Genetic variation plays a role in susceptibility to a number of diseases, from HIV to malaria to TB. Researchers know this because they hunt for variations of interest by comparing people’s entire DNA sequences – their genomes – to see whether certain variations coincide with certain disease outcomes. Such analyses are called genome-wide association studies. For COVID-19, these studies have uncovered two stretches of DNA with variations of interest: one on chromosome 9 and one on chromosome 3.  Blood types are a mystery The region on chromosome 9 is the ABO gene locus, which determines our blood type. Following the first wave of COVID-19 in spring 2020, studies began to investigate whether blood type was linked to disease susceptibility, particularly in patients with O or AB blood groups1. However, the early evidence was contradictory. While some studies suggested a possible link, others stated that once infected, a person’s blood type doesn’t affect their disease outcomes at all2. Since then, a more consistent pattern has started to emerge: people with blood type A now seem to be more at risk than those with blood type O3. More recent research suggests a lower risk of severe disease for blood type O, even going as far as to suggest that this blood group has a protective effect4. Additional studies have postulated5,6 that blood type A increases risk of infection (though some of these are pre-prints, meaning they have yet to be scrutinised by other scientists). This conflict between older and newer evidence is most likely due to the relatively small number of cases analysed. As the number increases, we’ll have more confidence in any findings. Blood type has also been associated with COVID-related respiratory failure. A study7 of 1,600 Spanish and Italian COVID-19 patients found that people with blood type O had a lower chance of respiratory failure compared with those who had other blood types. When compared with everyone else, people with blood type A had 1.5 times the chance of respiratory failure. This finding is supported by a paper8 that analysed the results of seven separate studies, which together looked at data from nearly three million people – including more than 7,500 COVID-19 patients. It found that COVID-positive people are more likely to have blood group A, whereas with blood group O the risk of COVID-19 infection is reduced. This conclusion was backed up by a further study9. Lastly, there’s also a large Canadian study10 that found that people with blood type O are at lower risk of infection. The difference was only slightly lower, with the risk of COVID-19 infection being 12% lower for blood type O when compared against all other types. The study also showed that people with blood type O had a 13% lower risk of severe disease or death compared to everyone else. So why might blood type be having an effect on COVID-19? This research recalls studies11 from the 2002–2004 Sars outbreak – also caused by a coronavirus – which hinted at a possible reduced risk for type O12. This earlier research theorised that antibodies – proteins in our blood that help fight infections – present in type O blood may inhibit the Sars virus from getting inside cells. But this hasn’t been proven. Similarly, whether blood type definitely provides some protection against COVID-19 – and if so, whether antibodies in certain blood types are behind this – remains unclear. It does look like there is an association between blood type and disease susceptibility, but more research is needed to know exactly how the two are related. 1. academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1150/58806002. www.ncbi.nlm.nih.gov/pmc/articles/PMC7379446/3. link.springer.com/article/10.1007/s00277-020-04169-14. www.nejm.org/doi/full/10.1056/NEJMoa20202835. www.medrxiv.org/content/10.1101/2020.04.15.20063107v1.full.pdf6. www.frontiersin.org/articles/10.3389/fcimb.2020.00404/full7. www.nejm.org/doi/full/10.1056/NEJMoa20202838. journals.plos.org/plosone/article?id=10.1371/journal.pone.02395089. www.ncbi.nlm.nih.gov/pmc/articles/PMC7391292/10. www.acpjournals.org/doi/10.7326/M20-451111. pubmed.ncbi.nlm.nih.gov/15784866/12. pubmed.ncbi.nlm.nih.gov/18818423/ |
|
|
|
Post by Admin on Feb 28, 2021 20:40:17 GMT
An ancient inheritance The picture is a bit clearer for chromosome 3. The genome-wide association study1 mentioned earlier, involving Spanish and Italian patients, also found an association between severe disease and variation in a small region on this chromosome called 3p21.31.  One of the genes in this region, SLC6A20,2 contains the instructions for building a protein that interacts with ACE2, the molecule the virus uses to get inside cells. Other genes here are for chemokine receptors, which are involved in inflammation3. Given that ACE2 and inflammation are both at the heart of severe COVID-19, this could offer clues as to why variation in this particular section of DNA appears to be associated with worse disease. The variation in this region that increases COVID-19 susceptibility may have been inherited from Neanderthals. To date, 3p21.31 is the only genetic region significantly associated with severe COVID-19.4 Having certain genetic variations in this region can therefore be considered a risk factor. As the pandemic continues, research will continue to move at a rapid pace to develop our understanding of COVID-19 and how we can combat the pandemic. This will include further understanding of how our genes and coronavirus interact – and it may be that other genetic risk factors are discovered. 1. www.nejm.org/doi/full/10.1056/NEJMoa20202832. pubmed.ncbi.nlm.nih.gov/25534429/3. pubmed.ncbi.nlm.nih.gov/17291188/4. pubmed.ncbi.nlm.nih.gov/32998156/ |
|
|
|
Post by Admin on Mar 5, 2021 5:03:45 GMT
A new study provides further evidence that people with certain blood types may be more likely to contract COVID-19.
Specifically, it found that the new coronavirus (SARS-CoV-2) is particularly attracted to the blood group A antigen found on respiratory cells.
The researchers focused on a protein on the surface of the SARS-CoV-2 virus called the receptor binding domain (RBD), which is the part of the virus that attaches to the host cells. That makes it an important target for scientists trying to learn how the virus infects people.
In this laboratory study, the team assessed how the SARS-CoV-2 RBD interacted with respiratory and red blood cells in A, B and O blood types.
The results showed that the SARS-CoV-2 RBD had a strong preference for binding to blood group A found on respiratory cells, but had no preference for blood group A red blood cells, or other blood groups found on respiratory or red cells.
The SARS-CoV-2 RBD's preference to recognize and attach to the blood type A antigen found in the lungs of people with blood type A may provide insight into the potential link between blood group A and COVID-19 infection, according to the authors of the study. It was published March 3 in the journal Blood Advances.
"It is interesting that the viral RBD only really prefers the type of blood group A antigens that are on respiratory cells, which are presumably how the virus is entering most patients and infecting them," said study author Dr. Sean Stowell, from Brigham and Women's Hospital in Boston.
"Blood type is a challenge because it is inherited and not something we can change," Stowell said in a journal news release. "But if we can better understand how the virus interacts with blood groups in people, we may be able to find new medicines or methods of prevention."
These findings alone can't fully describe or predict how coronaviruses would affect patients of various blood types, the researchers noted.
"Our observation is not the only mechanism responsible for what we are seeing clinically, but it could explain some of the influence of blood type on COVID-19 infection," Stowell and his team said.
More information
Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
Wanbo Tai, Lei He, Xiujuan Zhang, Jing Pu, Denis Voronin, Shibo Jiang, Yusen Zhou & Lanying Du
Cellular & Molecular Immunology volume 17, pages613–620(2020)
Abstract
The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
|
|
|
|
Post by Admin on Mar 5, 2021 20:40:54 GMT
The SARS-CoV-2 receptor-binding domain preferentially recognizes blood group A Shang-Chuen Wu , Connie M. Arthur , Jianmei Wang , Hans Verkerke , Cassandra D. Josephson , Daniel Kalman , John D. Roback , Richard D. Cummings , Sean R. Stowell Blood Adv (2021) 5 (5): 1305–1309. doi.org/10.1182/bloodadvances.2020003259 Introduction Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the cause of COVID-19, has resulted in a global pandemic, overwhelming modern health care systems and reshaping the world economy. Despite the devastating consequences of SARS-CoV-2, not all individuals seem to be equally susceptible to contracting the virus. Recent genome-wide association studies identified the locus responsible for ABO(H) blood group expression, the first polymorphism described in the human population well over a century ago, as one of the most significant genetic predictors of SARS-CoV-2 infection risk.1 Although previous and subsequent studies corroborate these results,2-6 additional data have failed to observe a similar association between ABO(H) blood group status and SARS-CoV-2 infection.7 Although differences in study population numbers and other variables may influence these outcomes, these collective studies in general warrant a direct examination of a possible association between ABO(H) blood group antigens and SARS-CoV-2. ABO(H) blood groups are not only the first polymorphisms described in the human population, they are also the most well-recognized. Naturally occurring antibodies against the blood group ABO(H) antigens in individuals who do not express these same polymorphic structures can cause potentially fatal hemolytic transfusion reactions after transfusion and severe acute graft rejection after transplantation.8 It is possible that anti–blood group antibodies may also influence SARS-CoV-2 infection through engagement of putative ABO(H) blood group antigens on the surface of the virus.9 However, these antibodies can be found in individuals of multiple blood types (eg, anti–blood group B antibodies are present in both blood group A and blood group O individuals) and thus may not fully account for the propensity of blood group A individuals, in particular, to exhibit an increased risk for SARS-CoV-2 infection. Furthermore, although ABO(H) antigens may influence disease progression,10 early studies suggested that increased risk was primarily associated with the likelihood of initial infection.2-5,11 In this regard, the mechanism by which ABO(H) antigens, and particularly those of blood group A, influence the likelihood of infection is still unknown. Methods Each SARS-CoV receptor-binding domain (RBD), which is responsible for infection,12 was cloned and purified as previously outlined.13,14 The SARS-COV-2 RBD was incubated with HEK293 T cells, HEK293 T cells expressing angiotensin-converting enzyme 2(ACE2), or red blood cells (RBCs), followed by detection with anti-His antibody (Anti-His-Tag mAb-Alexa Fluor 647) and flow cytometric analysis. Anti-A antibody was similarly used to detect the A antigen on blood group A RBCs. For array analysis, the SARS-CoV-2 and SARS-CoV RBDs were incubated in phosphate-buffered saline containing 0.05% Tween 20 and 1% bovine serum albumin for 1 hour at room temperature on a glycan array populated with ABO(H) glycans synthesized and printed as outlined previously.15,16 RBD binding to glycan arrays was detected by anti-His antibody (Anti-His-Tag mAb-Alexa Fluor 647),15 followed by image generation by microarray scanner (ScanArray Express, PerkinElmer Life Sciences) and array analysis using ImaGene software (BioDiscovery). See supplemental Methods for additional details. |
|
