Lactobacillus casei: Difference between revisions
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==Description and significance== | ==Description and significance== | ||
Lactobacillus casei is a rod shaped | Lactobacillus casei is a rod-shaped Gram-positive bacteria. It is non-sporing, non-motile, and anaerobic. Consistent with other lactic acid bacteria, this species is acid tolerant. Lactobacillus casei dwells in environments such as the intestinal tracts of animals and fermented dairy products. It can be found naturally in both the human intestine and the mouth. They have a wide temperature range as well as a wide pH range. The organism is mesophilic, which means it has an optimum temperature range around 30°C to 40°C. The optimum pH is at approximately 5.5. Scientists have found it to possess beneficial properties that support human health. It is able to improve and promote digestion. Some strains of the bacteria help control diarrhea, while other strains have an anti-inflammatory effect on the gut. Other advantageous effects include reducing lactose intolerance, alleviating constipation, and even modulation of the immune system. Numerous strains have been proven to be probiotics, that is according to the World Health Organization, are "live microorganisms which when administered in adequate amounts confer a health benefit on the host." Because it is lactic acid producer, it has several applications in biotechnology and in the food industry.<ref>http://genome.jgi-psf.org/finished_microbes/lacca/lacca.home.html genome.jgi-psf.org</ref><ref>{{cite web|last=Wong|first=Alison|date=16 September 2010|title=''Lactobacillus casei''|url=http://microbewiki.kenyon.edu/index.php/Lactobacillus_casei|work=MicrobeWiki|publisher=Kenyon College|accessdate=3 November 2013}}</ref> | ||
<ref> | |||
==Genome structure== | ==Genome structure== | ||
The genome of Lactobacillus casei ATCC 334 comprise of a circular chromosome with 2,895,264 base pairs and a circular plasmid 1 with 29,061 base pairs. According to US DOE Joint Genome Institute the strain contains a total of 2,924,325 nucleotides, 2,771 protein genes, and 75 RNA genes. L. casei have a 45-47% G+C content.<ref>http://www.kegg.com/kegg-bin/show_organism?org=lca kegg.com</ref> | |||
The genome of Lactobacillus casei ATCC 334 comprise of a circular chromosome with 2,895,264 base pairs and a circular plasmid 1 with 29,061 base pairs. According to US DOE Joint Genome Institute the strain contains a total of 2,924,325 nucleotides, 2,771 | |||
==Cell structure and metabolism== | ==Cell structure and metabolism== | ||
The cell structure Lactobacillus casei is typically straight, rod-shaped, and arranged in chains. The cell size tends to be around 0.7-1.1 x 2.0-4.0 micrometer. It is also a | The cell structure of Lactobacillus casei is typically straight, rod-shaped, and arranged in chains. The cell size tends to be around 0.7-1.1 x 2.0-4.0 micrometer. It is also a facultative anaerobe. This means it is an organism that is able to grow under both aerobic and anaerobic environments but develops better and more rapidly in the presence of oxygen. The microbe is an organotroph and its metabolism is a homofermentative one. Unlike heterofermentative lactobacteria which can produce either alcohol or lactic acid from carbohydrates, L. casei participates in a homolactic fermentation process that can only result in one single major end product. It obtains most of its energy by converting glucose into lactic acid. Some varieties of Lactobacillus casei can produce lactic acid utilizing galactose, fructose, or even mannose. Stress, poor diet, and antibiotics can lead to a deficient growth of the bacteria.<ref>"Lactobacillus casei." Microbewiki, <http://microbewiki.kenyon.edu/index.php/Lactobacillus_casei></ref> | ||
==Ecology== | ==Ecology== | ||
L.casei inhabits the oral and gastrointestinal tracts of animals. The bacterium bears a resistance to both gastric acid and bile enabling it to endure the harsh conditions throughout the gastrointestinal tract. Studies have shown that this bacterium generates health-promoting effect on the host. Therefore they are best known as probiotics. Their presence helps sustain a stabilized distribution of microflora in the intestine. It fulfills this role through antimicrobial activity. The mechanism involves creating an acidic habitat that restricts the growth of other bacteria that may be detrimental or cause infections. The production of bacteriocins (a toxin) by L.casei inhibits the growth of similar or closely related bacterial strains preventing overpopulation. Another mechanism is by competition inhibition and exclusion. L. casei Shirota strain is able to directly compete with pathogens that resides in the gastrointestinal tract for adhesion sites. This reduces pathogenic bacteria from adhering to the intestinal wall. Their occupation within the intestine is significant in maintaining the homeostasis of the gut immune system as well. It is also known to produce DL-lactic acid and amylase that complements the growth of Lactobacillus acidophilus, another probiotic lactic acid bacterium. Similar to many probiotics it does not permanently stay in the host, instead it usually lives in the intestine for a duration of around 10 days after being taken.<ref>http://www.probiotics-lovethatbug.com/lactobacillus-casei.html www.probiotics-lovethatbug.com</ref><ref>http://jmm.sgmjournals.org/cgi/content/full/52/10/925 jmm.sgmjournals.org</ref> | |||
L.casei inhabits the oral and gastrointestinal tracts of animals. The bacterium bears a resistance to both gastric acid and bile enabling it to endure the harsh conditions throughout the gastrointestinal tract. Studies have shown that this | |||
==Pathology== | ==Pathology== | ||
Lactobacillus casei does not cause any diseases. Not only is it generally considered to be harmless it is well recognized as a beneficial microorganism and a nonpathogenic. | Lactobacillus casei does not cause any diseases. Not only is it generally considered to be harmless, it is well recognized as a beneficial microorganism and a nonpathogenic. | ||
==Application to Biotechnology== | ==Application to Biotechnology== | ||
L. casei strains are of industrial significance since they can be applied in a range of fermentation processes, whereas other strains are utilized for their probiotic properties. Some are used in the production of cheese, yogurt, fermented milks, fermented Sicilian green olives, and other products. The natural end product of fermentation for this microbe is lactic acid, which inhibits the development of other organisms as well as decreasing the pH level in the food or beverage product. It is also known to be used in the development of flavor for selected cheeses. | L. casei strains are of industrial significance since they can be applied in a range of fermentation processes, whereas other strains are utilized for their probiotic properties. Some are used in the production of cheese, yogurt, fermented milks, fermented Sicilian green olives, and other products. The natural end product of fermentation for this microbe is lactic acid, which inhibits the development of other organisms as well as decreasing the pH level in the food or beverage product. It is also known to be used in the development of flavor for selected cheeses. | ||
Numerous food industries use the probiotic | Numerous food industries use the probiotic bacteria in their products to promote health. '''Yogourmet''' a probiotic yogurt starter includes Lactobacillus Casei, Bifidus, and Acidophilus. Other name brand that also uses L. casei includes '''Lifeway Yogurt''' and '''Stonyfield Farm Yogurt'''. | ||
'''DANNON''' the worldwide leader in fresh dairy products, began producing a probiotic drink called DanActive. The product is contains their own particular strain of the bacteria called '''L. casei Immunitas®''', L. bulgaricus, S. thermophilus, and milk as the main ingredient. L. casei Immunitas® is also known as L. casei DN-114001. It claims that "daily consumption of DanActive with L. casei Immunitas® helps strengthen your body's defenses." <ref> | {{Image|125323959 76882662f6.jpg|right|150px|Add image caption here.}} | ||
'''DANNON''' the worldwide leader in fresh dairy products, began producing a probiotic drink called DanActive. The product is contains their own particular strain of the bacteria called '''L. casei Immunitas®''', L. bulgaricus, S. thermophilus, and milk as the main ingredient. L. casei Immunitas® is also known as L. casei DN-114001. It claims that "daily consumption of DanActive with L. casei Immunitas® helps strengthen your body's defenses."<ref>http://www.danactive.com/danactive_whatIs_casei.html</ref><ref>{{cite news|author=Staff writer|date=15 April 2010|title=Danone withdraws health claims for Actimel and Activia|url=http://news.bbc.co.uk/2/hi/8622017.stm|work=BBC News|publisher=British Broadcasting System|accessdate=3 November 2013}}</ref> | |||
Since 1955, the Lactobacillus casei Shirota strain has been used by '''Yakult Honsha''' a Japanese food company to produce a probiotic milk-like product called '''Yakult'''. It is generated from the fermentation of the bacteria with skimmed milk. It contains 6.5 billion cfu of the bacteria per 65 ml bottle.<ref> | Since 1955, the Lactobacillus casei Shirota strain has been used by '''Yakult Honsha''' a Japanese food company to produce a probiotic milk-like product called '''Yakult'''. It is generated from the fermentation of the bacteria with skimmed milk. It contains 6.5 billion cfu of the bacteria per 65 ml bottle.<ref>{{cite journal|author=EFSA Panel on Dietetic Products, Nutrition and Allergies|date=18 October 2010|title=Scientific Opinion on the substantiation of a health claim related to ''Lactobacillus casei'' strain Shirota and maintenance of the upper respiratory tract defence against pathogens by maintaining immune defences pursuant to Article 13(5) of Regulation (EC) No 1924/2006|url=http://www.efsa.europa.eu/en/efsajournal/pub/1860.htm|journal=EFSA Journal|publisher=European Food Safety Authority|volume=8|issue=10|pages=1860-1875|doi=10.2903/j.efsa.2010.1860|accessdate=3 November 2013}}</ref> | ||
==Current Research== | ==Current Research== | ||
"'''Lactobacillus casei DN-114 001 Inhibits the Ability of Adherent-Invasive Escherichia coli Isolated from Crohn's Disease Patients To Adhere to and To Invade Intestinal Epithelial Cells'''" by Isabelle Ingrassia, Antony Leplingard, and Arlette Darfeuille-Michaud | |||
Lactobacillus casei have been found to be helpful to people with a chronic inflammatory bowel disease (IBD) called Crohn's disease. This research purpose was to demonstrate the in vitro inhibitory effects of Lactobacillus casei DN-114 001 on adherent-invasive E. coli. The adherent-invasive E. coli was extracted from Crohn's disease patients. The experiment included the pre-incubation of cultured intestinal epithelial cells with L. casei DN-114 001 before infecting it with adherent-invasive E. coli LF82. Intestine-407 and Caco-2 cells are intestinal epithelial cells. The probiotic was able to inhibit the adherent-invasive ability of LF82 to undifferentiated Intestine-407 cells by 62%. It also was able to inhibit E.coli LF82 from adhering to undifferentiated Caco-2 cells by 47% and differentiated Caco-2 cells by 43%. The inhibitory effect on LF82 invasion was only found for undifferentiated cells, but the effect was slightly higher than the effect on adhesion. When the adherent-invasive E. coli and L. casei DN-114 001 were added together with intestinal epithelial cells in co-incubation, reduction in adhesions and invasions were observed as well. These results illustrates that the strain can be effectively used to inhibit the interaction of those pathogenic bacteria with intestinal epithelial cells. This suggests a new possible option for the treating Crohn's disease.<ref>http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1151832 pubmedcentral.nih.gov</ref> | |||
"'''Daily ingestion of fermented milk containing Lactobacillus casei DN114001 improves innate-defense capacity in healthy middle-aged people'''" by Parra MD, Martínez de Morentin BE, Cobo JM, Mateos A, Martínez JA at Department of Physiology and Nutrition, University of Navarra, Spain. | |||
The goal of this experiment was to examine the effects of Lactobacillus casei DN114001 intake from fermented milk on the immune response capacity in middle-age participants. This case consisted of 45 healthy subjects between the ages of 51 to 58: 24 women and 21 men. The two groups were formed randomly. One group received three cups per day of the fermented milk with the bacteria and the other group received a placebo for a period of eight weeks. The results showed no significant changes in immune cell proportions. However there was an increased in oxidative burst capacity of monocytes and an increase in tumoricidal activity of NK cells seen in the group treated with DN114001 strain. They concluded that "that daily intake of fermented milk containing Lactobacillus casei DN114001 could have a positive effect in modulating the innate immune defense in healthy-middle-age people".<ref>http://www.ncbi.nlm.nih.gov/pubmed/15457926?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel. | |||
Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed www.ncbi.nlm.nih.gov</ref> | |||
"'''Modulation of natural killer cell activity by supplementation of fermented milk containing Lactobacillus casei in habitual smokers'''" by Morimoto K, Takeshita T, Nanno M, Tokudome S, Nakayama K at Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. | |||
This research involves testing L. casei's ability in restoring natural killer cell activity in habitual smokers which tend to have a significant reduction in natural killer cell activity. The 99 habitually smoking volunteers were randomly placed in to two groups. One group received the fermented milk containing the probiotic daily and the other group received a placebo daily. This experiment was carried out for a duration of three weeks. The researchers recorded the NK cell activity in the peripheral blood mononuclear cells before and after the intake. According to the journal the natural killer cell activity in participants had an inverse relationship with the number of cigarettes smoked. The results revealed that there was no significant difference in the proportion of natural killer cells between the two groups. The averaged natural killer cell activity adjusted by the numbers of cigarettes was significantly higher for the individuals in the L. casei group than those in the placebo group. They concluded that the consumption of fermented milk with lactic acid bacteria, which in this case is Lactobacillus casei, can be effective in restoring the natural killer cell activity in habitual smokers.<ref>http://www.ncbi.nlm.nih.gov/pubmed/15749143?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel. | |||
Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed www.ncbi.nlm.nih.gov/pubmed</ref> | |||
==References== | |||
{{reflist|2}}[[Category:Suggestion Bot Tag]] | |||
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Latest revision as of 11:00, 9 September 2024
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| Lactobacillus casei |
Description and significance
Lactobacillus casei is a rod-shaped Gram-positive bacteria. It is non-sporing, non-motile, and anaerobic. Consistent with other lactic acid bacteria, this species is acid tolerant. Lactobacillus casei dwells in environments such as the intestinal tracts of animals and fermented dairy products. It can be found naturally in both the human intestine and the mouth. They have a wide temperature range as well as a wide pH range. The organism is mesophilic, which means it has an optimum temperature range around 30°C to 40°C. The optimum pH is at approximately 5.5. Scientists have found it to possess beneficial properties that support human health. It is able to improve and promote digestion. Some strains of the bacteria help control diarrhea, while other strains have an anti-inflammatory effect on the gut. Other advantageous effects include reducing lactose intolerance, alleviating constipation, and even modulation of the immune system. Numerous strains have been proven to be probiotics, that is according to the World Health Organization, are "live microorganisms which when administered in adequate amounts confer a health benefit on the host." Because it is lactic acid producer, it has several applications in biotechnology and in the food industry.[1][2]
Genome structure
The genome of Lactobacillus casei ATCC 334 comprise of a circular chromosome with 2,895,264 base pairs and a circular plasmid 1 with 29,061 base pairs. According to US DOE Joint Genome Institute the strain contains a total of 2,924,325 nucleotides, 2,771 protein genes, and 75 RNA genes. L. casei have a 45-47% G+C content.[3]
Cell structure and metabolism
The cell structure of Lactobacillus casei is typically straight, rod-shaped, and arranged in chains. The cell size tends to be around 0.7-1.1 x 2.0-4.0 micrometer. It is also a facultative anaerobe. This means it is an organism that is able to grow under both aerobic and anaerobic environments but develops better and more rapidly in the presence of oxygen. The microbe is an organotroph and its metabolism is a homofermentative one. Unlike heterofermentative lactobacteria which can produce either alcohol or lactic acid from carbohydrates, L. casei participates in a homolactic fermentation process that can only result in one single major end product. It obtains most of its energy by converting glucose into lactic acid. Some varieties of Lactobacillus casei can produce lactic acid utilizing galactose, fructose, or even mannose. Stress, poor diet, and antibiotics can lead to a deficient growth of the bacteria.[4]
Ecology
L.casei inhabits the oral and gastrointestinal tracts of animals. The bacterium bears a resistance to both gastric acid and bile enabling it to endure the harsh conditions throughout the gastrointestinal tract. Studies have shown that this bacterium generates health-promoting effect on the host. Therefore they are best known as probiotics. Their presence helps sustain a stabilized distribution of microflora in the intestine. It fulfills this role through antimicrobial activity. The mechanism involves creating an acidic habitat that restricts the growth of other bacteria that may be detrimental or cause infections. The production of bacteriocins (a toxin) by L.casei inhibits the growth of similar or closely related bacterial strains preventing overpopulation. Another mechanism is by competition inhibition and exclusion. L. casei Shirota strain is able to directly compete with pathogens that resides in the gastrointestinal tract for adhesion sites. This reduces pathogenic bacteria from adhering to the intestinal wall. Their occupation within the intestine is significant in maintaining the homeostasis of the gut immune system as well. It is also known to produce DL-lactic acid and amylase that complements the growth of Lactobacillus acidophilus, another probiotic lactic acid bacterium. Similar to many probiotics it does not permanently stay in the host, instead it usually lives in the intestine for a duration of around 10 days after being taken.[5][6]
Pathology
Lactobacillus casei does not cause any diseases. Not only is it generally considered to be harmless, it is well recognized as a beneficial microorganism and a nonpathogenic.
Application to Biotechnology
L. casei strains are of industrial significance since they can be applied in a range of fermentation processes, whereas other strains are utilized for their probiotic properties. Some are used in the production of cheese, yogurt, fermented milks, fermented Sicilian green olives, and other products. The natural end product of fermentation for this microbe is lactic acid, which inhibits the development of other organisms as well as decreasing the pH level in the food or beverage product. It is also known to be used in the development of flavor for selected cheeses.
Numerous food industries use the probiotic bacteria in their products to promote health. Yogourmet a probiotic yogurt starter includes Lactobacillus Casei, Bifidus, and Acidophilus. Other name brand that also uses L. casei includes Lifeway Yogurt and Stonyfield Farm Yogurt.
DANNON the worldwide leader in fresh dairy products, began producing a probiotic drink called DanActive. The product is contains their own particular strain of the bacteria called L. casei Immunitas®, L. bulgaricus, S. thermophilus, and milk as the main ingredient. L. casei Immunitas® is also known as L. casei DN-114001. It claims that "daily consumption of DanActive with L. casei Immunitas® helps strengthen your body's defenses."[7][8]
Since 1955, the Lactobacillus casei Shirota strain has been used by Yakult Honsha a Japanese food company to produce a probiotic milk-like product called Yakult. It is generated from the fermentation of the bacteria with skimmed milk. It contains 6.5 billion cfu of the bacteria per 65 ml bottle.[9]
Current Research
"Lactobacillus casei DN-114 001 Inhibits the Ability of Adherent-Invasive Escherichia coli Isolated from Crohn's Disease Patients To Adhere to and To Invade Intestinal Epithelial Cells" by Isabelle Ingrassia, Antony Leplingard, and Arlette Darfeuille-Michaud
Lactobacillus casei have been found to be helpful to people with a chronic inflammatory bowel disease (IBD) called Crohn's disease. This research purpose was to demonstrate the in vitro inhibitory effects of Lactobacillus casei DN-114 001 on adherent-invasive E. coli. The adherent-invasive E. coli was extracted from Crohn's disease patients. The experiment included the pre-incubation of cultured intestinal epithelial cells with L. casei DN-114 001 before infecting it with adherent-invasive E. coli LF82. Intestine-407 and Caco-2 cells are intestinal epithelial cells. The probiotic was able to inhibit the adherent-invasive ability of LF82 to undifferentiated Intestine-407 cells by 62%. It also was able to inhibit E.coli LF82 from adhering to undifferentiated Caco-2 cells by 47% and differentiated Caco-2 cells by 43%. The inhibitory effect on LF82 invasion was only found for undifferentiated cells, but the effect was slightly higher than the effect on adhesion. When the adherent-invasive E. coli and L. casei DN-114 001 were added together with intestinal epithelial cells in co-incubation, reduction in adhesions and invasions were observed as well. These results illustrates that the strain can be effectively used to inhibit the interaction of those pathogenic bacteria with intestinal epithelial cells. This suggests a new possible option for the treating Crohn's disease.[10]
"Daily ingestion of fermented milk containing Lactobacillus casei DN114001 improves innate-defense capacity in healthy middle-aged people" by Parra MD, Martínez de Morentin BE, Cobo JM, Mateos A, Martínez JA at Department of Physiology and Nutrition, University of Navarra, Spain.
The goal of this experiment was to examine the effects of Lactobacillus casei DN114001 intake from fermented milk on the immune response capacity in middle-age participants. This case consisted of 45 healthy subjects between the ages of 51 to 58: 24 women and 21 men. The two groups were formed randomly. One group received three cups per day of the fermented milk with the bacteria and the other group received a placebo for a period of eight weeks. The results showed no significant changes in immune cell proportions. However there was an increased in oxidative burst capacity of monocytes and an increase in tumoricidal activity of NK cells seen in the group treated with DN114001 strain. They concluded that "that daily intake of fermented milk containing Lactobacillus casei DN114001 could have a positive effect in modulating the innate immune defense in healthy-middle-age people".[11]
"Modulation of natural killer cell activity by supplementation of fermented milk containing Lactobacillus casei in habitual smokers" by Morimoto K, Takeshita T, Nanno M, Tokudome S, Nakayama K at Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
This research involves testing L. casei's ability in restoring natural killer cell activity in habitual smokers which tend to have a significant reduction in natural killer cell activity. The 99 habitually smoking volunteers were randomly placed in to two groups. One group received the fermented milk containing the probiotic daily and the other group received a placebo daily. This experiment was carried out for a duration of three weeks. The researchers recorded the NK cell activity in the peripheral blood mononuclear cells before and after the intake. According to the journal the natural killer cell activity in participants had an inverse relationship with the number of cigarettes smoked. The results revealed that there was no significant difference in the proportion of natural killer cells between the two groups. The averaged natural killer cell activity adjusted by the numbers of cigarettes was significantly higher for the individuals in the L. casei group than those in the placebo group. They concluded that the consumption of fermented milk with lactic acid bacteria, which in this case is Lactobacillus casei, can be effective in restoring the natural killer cell activity in habitual smokers.[12]
References
- ↑ http://genome.jgi-psf.org/finished_microbes/lacca/lacca.home.html genome.jgi-psf.org
- ↑ Wong, Alison (16 September 2010). Lactobacillus casei. MicrobeWiki. Kenyon College. Retrieved on 3 November 2013.
- ↑ http://www.kegg.com/kegg-bin/show_organism?org=lca kegg.com
- ↑ "Lactobacillus casei." Microbewiki, <http://microbewiki.kenyon.edu/index.php/Lactobacillus_casei>
- ↑ http://www.probiotics-lovethatbug.com/lactobacillus-casei.html www.probiotics-lovethatbug.com
- ↑ http://jmm.sgmjournals.org/cgi/content/full/52/10/925 jmm.sgmjournals.org
- ↑ http://www.danactive.com/danactive_whatIs_casei.html
- ↑ Staff writer. Danone withdraws health claims for Actimel and Activia, BBC News, British Broadcasting System, 15 April 2010. Retrieved on 3 November 2013.
- ↑ EFSA Panel on Dietetic Products, Nutrition and Allergies (18 October 2010). "Scientific Opinion on the substantiation of a health claim related to Lactobacillus casei strain Shirota and maintenance of the upper respiratory tract defence against pathogens by maintaining immune defences pursuant to Article 13(5) of Regulation (EC) No 1924/2006". EFSA Journal 8 (10): 1860-1875. DOI:10.2903/j.efsa.2010.1860. Retrieved on 3 November 2013. Research Blogging.
- ↑ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1151832 pubmedcentral.nih.gov
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/15457926?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel. Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed www.ncbi.nlm.nih.gov
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/15749143?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel. Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed www.ncbi.nlm.nih.gov/pubmed