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{{Taxobox
{{Taxobox
| color = purple
| color = purple
| name =  Caenorhabditis elegans
| name =  Caenorhabditis elegans
| image =  
| image = Nematode with stained nuclei.jpg
| regnum = Animalia
| regnum = Animalia
| phylum =  Nematoda
| phylum =  Nematoda
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==Description and significance==
==Description and significance==
Caenorhabditis elegan is a simple organism that is small free living nematode. It is found in various parts of the world.  A microscope is required to view a C. elegans because its length ranges up to 1 mm. The growth of C. elegans is rapid; under a standard laboratory condition it takes the entire life cycle from egg to an adult producing more eggs in just 3.5 days at 20°C.<sup>1</sup>  After the egg hatches, it undergoes four larval stages L1 to L4; the larval stages are punctuated by molts.<sup>2</sup>  After the L4 stage the C. elegan   will undergo a final molt to produce an adult.<sup>1</sup> It is an adult stage that its length is 1mm.  At a time when there is a food shortage and a high population, the C. elegans take an alternative pathway during the larval stages. At the alternative stage a dauer is formed after the molt of L2 instead of a L3.  The dauer is able to survive these conditions by not feeding and is resistant to desiccation.<sup>2</sup>  The dauer stage is able to survive for several months without further developing; when there is change in the environment such as a availability of food the C. elegan will molt to the normal L4 stage.  C. elegans lives for about 18- 23 days.  There are two types of sexes which are hermaphrodites and males; its appearance is visually different at the adult stage. The male only produces sperm, in order to reproduce it must mate with a hermaphrodite. This cross fertilization produces both the males and hermaphrodites in a 1:1 proportion.  The hermaphrodites are able to produce both sperm and oocytes and undergo self-fertilization. During the self-fertilization it produces hermaphrodites and males arise spontaneously at an extremely low frequency.  
'''''Caenorhabditis elegans''''' is a simple organism that is an small free living nematode. It is found in various parts of the world.  A microscope is required to view a ''C. elegans'' because its length ranges up to 1 mm. The growth of ''C. elegans'' is rapid; under a standard laboratory condition it takes the entire life cycle from egg to an adult producing more eggs in just 3.5 days at 20°C.<ref name=Hope>Hope I.A, ed.  ''C. elegans: A Practical Approach''.  New York: Oxford University Press, 1999.</ref>  After the egg hatches, it undergoes four larval stages L1 to L4; the larval stages are punctuated by molts.<ref name=Wood>2. Wood  William Barry; ed. The Nematode Caenorhabditis Elegans.  New York: Cold Spring Harbor Laboratory, 1988.</ref>  After the L4 stage the ''C. elegans''   will undergo a final molt to produce an adult.<ref name=Hope/> It is an adult stage that its length is 1mm.  At a time when there is a food shortage and a high population, the ''C. elegans'' take an alternative pathway during the larval stages. At the alternative stage a dauer is formed after the molt of L2 instead of a L3.  The dauer is able to survive these conditions by not feeding and is resistant to desiccation.<sup>2</sup>  The dauer stage is able to survive for several months without further developing; when there is change in the environment such as a availability of food the ''C. elegans'' will molt to the normal L4 stage.  ''C. elegans'' lives for about 18- 23 days.  There are two types of sexes which are hermaphrodites and males; its appearance is visually different at the adult stage. The male only produces sperm, in order to reproduce it must mate with a hermaphrodite. This cross fertilization produces both the males and hermaphrodites in a 1:1 proportion.  The hermaphrodites are able to produce both sperm and oocytes and undergo self-fertilization. During the self-fertilization it produces hermaphrodites and males arise spontaneously at an extremely low frequency.  


The C. elegans are part of the model system. The key attributes of C. elegans as an experimental system for biological systems are its simplicity, transparency, ease of cultivation in the laboratory, short life cycle, suitability of genetic analysis and small genome size.<sup>2</sup> Its biological mechanisms are similar to majority of the animal species that allows an ideal model system.
The C. elegans are part of the model system. The key attributes of ''C. elegans'' as an experimental system for biological systems are its simplicity, transparency, ease of cultivation in the laboratory, short life cycle, suitability of genetic analysis and small genome size.<sup>2</sup> Its biological mechanisms are similar to majority of the animal species that allows an ideal model system.


==Genome structure==
==Genome structure==
The genes control all the functions and proper developments of the C.elegans. It is one of the first multicellular organisms that have the entire genome sequenced. The C. elegan has a small genome, yet a very complex one. It has over 19,000 protein coding genes.<sup>1</sup>  There are 8 x 107 base pairs of DNA in the genome.<sup>3</sup>  In the genome there are many mutable loci; that allow observing the genetic defects easier therefore making it an model organism. The C.elegans cells are diploid. Both the hermaphrodites and males have five autosomes; the only difference being that the hermaphrodites have one pair X chromsomes while the male has one X chromosome.
The genes control all the functions and proper developments of the ''C.elegans''. It is one of the first multicellular organisms that have the entire genome sequenced. The ''C. elegans'' has a small genome, yet a very complex one. It has over 19,000 protein coding genes.<ref name=Hope/>  There are 8 x 107 base pairs of DNA in the genome.<sup>3</sup>  In the genome there are many mutable loci; that allow observing the genetic defects easier therefore making it an model organism. The C.elegans cells are diploid. Both the hermaphrodites and males have five autosomes; the only difference being that the hermaphrodites have one pair X chromsomes while the male has one X chromosome.
 
==Cell structure and metabolism==
The C.elegans  have an simple anatomy. The c. elegans exterior contains an pseudocoelem, which also causes an separation along the body wall and the gut.  The body wall contains cells called hypodermal that secretes collagenous cuticle along the body wall that covers the surface.<ref name=Hope/> There are also many muscle cells beneath the body wall. Both the hermaphrodites and the male have an similar anatomy, the differences would be that the males are thinner, shorter and contain a cloaca that is ventral to the posterior end.  The anterior contains a tip of the head that contains a mouth. Then there is the gut which contains a pharynx and intestine.  The intestine is long that starts from the mouth and ends at the intestine.  There is an anus located at the posterior end of the worm.  The c. elegans have a simple nervous system, there are many nerves connected to the muscles that generates  simple movements.
 
The male and hermaphrodites differ in the arrangement of the gonad and in the tail.  The hermaphrodite has two symmetrical lobes with one single opening in the uterus.  The fertilization occurs in the spermatheca. The location of the spermatheca is between the uterine and vulvae <sup>1</sup>.  There are specific muscle cells that are responsible for egg laying in the hermaphrodite.  In the male gonad there is a one simple tube opening at the cloaca.  The tails of the two sexes are different; the male tail is  structurally different with  complex musculature and nerves required for mating.
 
The osmoregulation is regulated by the excretory system. This system consists of the excretory duct cell, excretory pore cell, excretory gland cell, and excretory cells <sup>1</sup>.  The excretory cell is the largest cell  in the c. elegan  which reaches the tip of the head to tail. The secretory  system regulates the secretion of the glycoproteins which is responsible to make up the replenishable  surface coat over the epicuticle. <sup>3</sup>
 
The C. elegan molts four times during each of the larval stages.  The molting is not required for growth in the c. elegans. It seems that the molting cycle activates the developmental cues controlling postembryonic cell lineages, and even in the development plasticity in cell morphology and function. <sup>3</sup>.


==Cell structure and metabolism==
==Ecology==
==Ecology==
C. elegans lives in the soil across most of the temperate regions of the world.<sup>1</sup>  In order to reproduce and grow it requires an humid environment, ambient temperature and atmospheric oxygen.<sup>1</sup>  C. elegan feeds on diverse microorganism one such example would be bacteria.   
C. elegans lives in the soil across most of the temperate regions of the world.<ref name=Hope/>  In order to reproduce and grow it requires an humid environment, ambient temperature and atmospheric oxygen.<ref name=Hope/>  C. elegan feeds on diverse microorganism one such example would be bacteria.   


In the laboratory it is easily maintained. Its food source in the lab would be e. coli.  The C. elegans are grown on agar plates or in a liquid culture.
In the laboratory it is easily maintained. Its food source in the lab would be e. coli.  The C. elegans are grown on agar plates or in a liquid culture.


==Application to Biotechnology==
==Application to Biotechnology==
There are many advantages that allow it to be applied to biotechnology such as the rapid  life cycle, ability to be easily cultivated in the laboratory, its small  genome size, and the genetic analysis can be applied. Due to its usefulness in the lab it allows  research to be done that answers variety of the problems in animal biology.
The C. elegans mutants allow a better understanding of the development and behavior of many animals. The genome of the C. elegans makes direct connections to many vertebrates.<ref name=Hope/>  There is a degree of similarity between the genome of the human and the C. elegans; that allows a better understanding and improvement of the human biology. It is found that from 84 human disease genes that have been cloned 25 have direct orthologues in the C. elegans genome and a further 43 have a considerable similarity with nematode genes.<ref name=Hope/>  It also has significant impact on the medicine and agriculture fields by being a model organism for many studies of the parasitic nermatodes.  The nervous system of the C. elegans is simple therefore allowing research opportunities for function and development in other animals.
==Current Research==
==Current Research==
'''Autophagy Genes are Essential for Dauer Development and Life Span Extension in C. elegans'''
At a time when there is a food shortage and a high population, the C. elegans take an alternative pathway during the larval stages. At this stage a dauer is formed after the molt of L2 instead of a L3. The dauer is able to survive these conditions. The entry into the dauer stage is regulated negatively by the insulin like signaling.  The same environmental cues that promote the morphogenesis of dauers in C. elegans, are potent in stimulators of autophagy in yeast and mammalian cells.  Autophagy is the route for degrading proteins and organelles in eukaryotes. The yeast APG6/VPS30 is an ortholog to the bec-1 c. elegan. This yeast plays an important part in autophagy, embryonic development, and tumor suppression.  It was shown  that worms with an loss of function mutation in insulin like signaling pathway, in the experiment it shown  that the bec-1, the C.elegans ortholog to the yeast and mammalian autophagy gene APG6/VPS30 is essential  for normal  dauer morphogenesis and life extension.  The lifespan of the daf-2 was done to show the effects of bec-1 RNAi treatment at 15 degree Celsius shows an increase in life extension to the wildtype.  When there is dauer formation, there is an association with autophagy and an increase. To test if autophagy is required for the dauer formation, the effects were tested on RNAi of other C. elegan orthologs of yeast autophagy genes.  It was shown that APGI, APG6/VPS30/beclin, 1, APG 7, APG 8, and AUTO10 are required for normal dauer morphogenesis in C. elegans.  Autophagy is essential because its plays a role in remodeling of the tissue and cells that allows the worm to successfully adapt to the environmental conditions.
'''Worms in Space? A MODEL BIOLOGICAL DOSIMETER'''
Not much is known about the biological effects of long term radiation exposure in space. We all know that radiation in humans causes cancer related sickness.  Now there is research going on to find out the long term affects of different types of radiation on experimented animals. <sup>5</sup>.  But the research for long term radiation exposure in space has not been due to difficulties of placing the organism in space.  The Caenorhabditis elegans offers potential for the design of a biological dosimeter. <sup>5</sup>. C. elegans also has many characteristics that make it an excellent model system for use in space. There are many advantages such as the rapid life cycle, ability to be easily cultivated in the laboratory, its small genome size, and the genetic analysis can be applied. It also can be grown in a small space. The food source for space has been changed to a chemically defined axenic media from bacteria.  The C. elegans will be able to survive in the CeMM media and be transferred to fresh ones and maintained for a long time. The knowledge of C. elegans will make it an ideal model system for studies of gravitational effects on muscle gene expression and mutational consequences of radiation exposure. <sup>5</sup>
'''Transgenic C. elegans as a Model in Alzheimer’s Research'''
Alzheimer’s disease is a devastating neurodegenerative disorder.  People who suffer from  Alzheimers have disorders such as decreased cognition and memory, and with time develop an dysfunction in all mental functions. It is an controversial theory that -amyloid peptide is assocaiated with oxidative stress that induces neurodegenration observed in Alzheimer’s disease.  This critical information of b-amyloid plays an important role in alzheimer’s disease that may work; in finding therapeutic strategies and mechanism of toxicity for b-amyloid peptide. For an better understanding of the pathology process of Alzheimers disease, researchers have attemetped to imitate this pathology in model organisms such as c. elegans, drosophila  melanogaster and the mouse mus musculus.  There were many in vitro and in vivo models of alzheimer’s disease, the transgenic C. elegans model system has been used because of the expression of human Ab. Also due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype.<sup>4</sup>.  Two of the C. elegans stress related genes that were upregulated are homologous to the human  B-crystallin and tumor necrosis factor-related protein which were also unregulated. <sup>4</sup>The C. elegans had shown an increase in levels of protein carbonyl and reactive oxygen species similar to patients with alzheimers disease.  These increases in levels were due to theory that A  play an important role that induces neurodegeneration in Alzheimer’s disease. Therefore the C. elegans model is used as a model in alzheimer’s research.
==References==
==References==
1. Hope I.A, ed.   C. elegans: A Practical Approach. New York: Oxford University Press, 1999.
<references/>
 
2Wood  William Barry; ed. ''The Nematode Caenorhabditis Elegans''.New York: Cold Spring Harbor Laboratory, 1988.
 
3.Riddle Donald, Blumenthal Thomas, Meyer Barbara, Priess James eds. ''C. elegans II''. New York: Cold Spring Harbor Laboratory, 1997.
 
4. Melendez Alicia, Talloczy Zsolt, Seaman Matthew, Eskelinen Eeva-Liisa, Hall H. David, Levine Beth. "Autophagy Genes are Essential for Dauer Development and Life Span Extension in C.elegans" www.science.org SCIENCE VOL 301. September 2003.


2. Wood  William Barry; ed. The Nematode Caenorhabditis Elegans. New York: Cold Spring Harbor Laboratory, 1988.
5. Yang Zhao, Johnsen Robert, David Baille, Ann Rose. Worms in Space? A Model Biological Desimeter. Gravitional and Space Biology 18(2). June 2005.


3. Riddle Donald, Blumenthal Thomas, Meyer Barbara, Priess James eds. C. elegans II. New York: Cold Spring Harbor      Laboratory, 1997.
6. Yanjue Wu, Yuan Luo. Transgenic C. elegans as a Model in Alzheimer’s Research. Current Alzheimer Research,2, 37-45. 2005.[[Category:Suggestion Bot Tag]]

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Caenorhabditis elegans
Nematode with stained nuclei.jpg
Scientific classification
Kingdom: Animalia
Phylum: Nematoda
Class: Secernentea
Order: Rhabditida
Family: Rhabditidae
Genus: Caenorhabdtis
Species: C.elegans
Binomial name
Caenorhabdtis elegans
Maupas 1900

Description and significance

Caenorhabditis elegans is a simple organism that is an small free living nematode. It is found in various parts of the world. A microscope is required to view a C. elegans because its length ranges up to 1 mm. The growth of C. elegans is rapid; under a standard laboratory condition it takes the entire life cycle from egg to an adult producing more eggs in just 3.5 days at 20°C.[1] After the egg hatches, it undergoes four larval stages L1 to L4; the larval stages are punctuated by molts.[2] After the L4 stage the C. elegans will undergo a final molt to produce an adult.[1] It is an adult stage that its length is 1mm. At a time when there is a food shortage and a high population, the C. elegans take an alternative pathway during the larval stages. At the alternative stage a dauer is formed after the molt of L2 instead of a L3. The dauer is able to survive these conditions by not feeding and is resistant to desiccation.2 The dauer stage is able to survive for several months without further developing; when there is change in the environment such as a availability of food the C. elegans will molt to the normal L4 stage. C. elegans lives for about 18- 23 days. There are two types of sexes which are hermaphrodites and males; its appearance is visually different at the adult stage. The male only produces sperm, in order to reproduce it must mate with a hermaphrodite. This cross fertilization produces both the males and hermaphrodites in a 1:1 proportion. The hermaphrodites are able to produce both sperm and oocytes and undergo self-fertilization. During the self-fertilization it produces hermaphrodites and males arise spontaneously at an extremely low frequency.

The C. elegans are part of the model system. The key attributes of C. elegans as an experimental system for biological systems are its simplicity, transparency, ease of cultivation in the laboratory, short life cycle, suitability of genetic analysis and small genome size.2 Its biological mechanisms are similar to majority of the animal species that allows an ideal model system.

Genome structure

The genes control all the functions and proper developments of the C.elegans. It is one of the first multicellular organisms that have the entire genome sequenced. The C. elegans has a small genome, yet a very complex one. It has over 19,000 protein coding genes.[1] There are 8 x 107 base pairs of DNA in the genome.3 In the genome there are many mutable loci; that allow observing the genetic defects easier therefore making it an model organism. The C.elegans cells are diploid. Both the hermaphrodites and males have five autosomes; the only difference being that the hermaphrodites have one pair X chromsomes while the male has one X chromosome.

Cell structure and metabolism

The C.elegans have an simple anatomy. The c. elegans exterior contains an pseudocoelem, which also causes an separation along the body wall and the gut. The body wall contains cells called hypodermal that secretes collagenous cuticle along the body wall that covers the surface.[1] There are also many muscle cells beneath the body wall. Both the hermaphrodites and the male have an similar anatomy, the differences would be that the males are thinner, shorter and contain a cloaca that is ventral to the posterior end. The anterior contains a tip of the head that contains a mouth. Then there is the gut which contains a pharynx and intestine. The intestine is long that starts from the mouth and ends at the intestine. There is an anus located at the posterior end of the worm. The c. elegans have a simple nervous system, there are many nerves connected to the muscles that generates simple movements.

The male and hermaphrodites differ in the arrangement of the gonad and in the tail. The hermaphrodite has two symmetrical lobes with one single opening in the uterus. The fertilization occurs in the spermatheca. The location of the spermatheca is between the uterine and vulvae 1. There are specific muscle cells that are responsible for egg laying in the hermaphrodite. In the male gonad there is a one simple tube opening at the cloaca. The tails of the two sexes are different; the male tail is structurally different with complex musculature and nerves required for mating.

The osmoregulation is regulated by the excretory system. This system consists of the excretory duct cell, excretory pore cell, excretory gland cell, and excretory cells 1. The excretory cell is the largest cell in the c. elegan which reaches the tip of the head to tail. The secretory system regulates the secretion of the glycoproteins which is responsible to make up the replenishable surface coat over the epicuticle. 3

The C. elegan molts four times during each of the larval stages. The molting is not required for growth in the c. elegans. It seems that the molting cycle activates the developmental cues controlling postembryonic cell lineages, and even in the development plasticity in cell morphology and function. 3.

Ecology

C. elegans lives in the soil across most of the temperate regions of the world.[1] In order to reproduce and grow it requires an humid environment, ambient temperature and atmospheric oxygen.[1] C. elegan feeds on diverse microorganism one such example would be bacteria.

In the laboratory it is easily maintained. Its food source in the lab would be e. coli. The C. elegans are grown on agar plates or in a liquid culture.

Application to Biotechnology

There are many advantages that allow it to be applied to biotechnology such as the rapid life cycle, ability to be easily cultivated in the laboratory, its small genome size, and the genetic analysis can be applied. Due to its usefulness in the lab it allows research to be done that answers variety of the problems in animal biology.

The C. elegans mutants allow a better understanding of the development and behavior of many animals. The genome of the C. elegans makes direct connections to many vertebrates.[1] There is a degree of similarity between the genome of the human and the C. elegans; that allows a better understanding and improvement of the human biology. It is found that from 84 human disease genes that have been cloned 25 have direct orthologues in the C. elegans genome and a further 43 have a considerable similarity with nematode genes.[1] It also has significant impact on the medicine and agriculture fields by being a model organism for many studies of the parasitic nermatodes. The nervous system of the C. elegans is simple therefore allowing research opportunities for function and development in other animals.

Current Research

Autophagy Genes are Essential for Dauer Development and Life Span Extension in C. elegans

At a time when there is a food shortage and a high population, the C. elegans take an alternative pathway during the larval stages. At this stage a dauer is formed after the molt of L2 instead of a L3. The dauer is able to survive these conditions. The entry into the dauer stage is regulated negatively by the insulin like signaling. The same environmental cues that promote the morphogenesis of dauers in C. elegans, are potent in stimulators of autophagy in yeast and mammalian cells. Autophagy is the route for degrading proteins and organelles in eukaryotes. The yeast APG6/VPS30 is an ortholog to the bec-1 c. elegan. This yeast plays an important part in autophagy, embryonic development, and tumor suppression. It was shown that worms with an loss of function mutation in insulin like signaling pathway, in the experiment it shown that the bec-1, the C.elegans ortholog to the yeast and mammalian autophagy gene APG6/VPS30 is essential for normal dauer morphogenesis and life extension. The lifespan of the daf-2 was done to show the effects of bec-1 RNAi treatment at 15 degree Celsius shows an increase in life extension to the wildtype. When there is dauer formation, there is an association with autophagy and an increase. To test if autophagy is required for the dauer formation, the effects were tested on RNAi of other C. elegan orthologs of yeast autophagy genes. It was shown that APGI, APG6/VPS30/beclin, 1, APG 7, APG 8, and AUTO10 are required for normal dauer morphogenesis in C. elegans. Autophagy is essential because its plays a role in remodeling of the tissue and cells that allows the worm to successfully adapt to the environmental conditions.


Worms in Space? A MODEL BIOLOGICAL DOSIMETER

Not much is known about the biological effects of long term radiation exposure in space. We all know that radiation in humans causes cancer related sickness. Now there is research going on to find out the long term affects of different types of radiation on experimented animals. 5. But the research for long term radiation exposure in space has not been due to difficulties of placing the organism in space. The Caenorhabditis elegans offers potential for the design of a biological dosimeter. 5. C. elegans also has many characteristics that make it an excellent model system for use in space. There are many advantages such as the rapid life cycle, ability to be easily cultivated in the laboratory, its small genome size, and the genetic analysis can be applied. It also can be grown in a small space. The food source for space has been changed to a chemically defined axenic media from bacteria. The C. elegans will be able to survive in the CeMM media and be transferred to fresh ones and maintained for a long time. The knowledge of C. elegans will make it an ideal model system for studies of gravitational effects on muscle gene expression and mutational consequences of radiation exposure. 5


Transgenic C. elegans as a Model in Alzheimer’s Research

Alzheimer’s disease is a devastating neurodegenerative disorder. People who suffer from Alzheimers have disorders such as decreased cognition and memory, and with time develop an dysfunction in all mental functions. It is an controversial theory that -amyloid peptide is assocaiated with oxidative stress that induces neurodegenration observed in Alzheimer’s disease. This critical information of b-amyloid plays an important role in alzheimer’s disease that may work; in finding therapeutic strategies and mechanism of toxicity for b-amyloid peptide. For an better understanding of the pathology process of Alzheimers disease, researchers have attemetped to imitate this pathology in model organisms such as c. elegans, drosophila melanogaster and the mouse mus musculus. There were many in vitro and in vivo models of alzheimer’s disease, the transgenic C. elegans model system has been used because of the expression of human Ab. Also due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype.4. Two of the C. elegans stress related genes that were upregulated are homologous to the human B-crystallin and tumor necrosis factor-related protein which were also unregulated. 4The C. elegans had shown an increase in levels of protein carbonyl and reactive oxygen species similar to patients with alzheimers disease. These increases in levels were due to theory that A play an important role that induces neurodegeneration in Alzheimer’s disease. Therefore the C. elegans model is used as a model in alzheimer’s research.

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Hope I.A, ed. C. elegans: A Practical Approach. New York: Oxford University Press, 1999.
  2. 2. Wood William Barry; ed. The Nematode Caenorhabditis Elegans. New York: Cold Spring Harbor Laboratory, 1988.

2. Wood William Barry; ed. The Nematode Caenorhabditis Elegans.New York: Cold Spring Harbor Laboratory, 1988.

3.Riddle Donald, Blumenthal Thomas, Meyer Barbara, Priess James eds. C. elegans II. New York: Cold Spring Harbor Laboratory, 1997.

4. Melendez Alicia, Talloczy Zsolt, Seaman Matthew, Eskelinen Eeva-Liisa, Hall H. David, Levine Beth. "Autophagy Genes are Essential for Dauer Development and Life Span Extension in C.elegans" www.science.org SCIENCE VOL 301. September 2003.

5. Yang Zhao, Johnsen Robert, David Baille, Ann Rose. Worms in Space? A Model Biological Desimeter. Gravitional and Space Biology 18(2). June 2005.

6. Yanjue Wu, Yuan Luo. Transgenic C. elegans as a Model in Alzheimer’s Research. Current Alzheimer Research,2, 37-45. 2005.