User:Z3389343: Difference between revisions

From Embryology
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*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.
*'''Clinical Manifestations''': Very thorough and detailed, which is good.
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.
*'''Treatment''': Also quite thorough, well explained.
*'''Treatment''': Also quite thorough, well explained.
*'''Current and Future Research''': Very good and detailed, well explained.
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?
*'''Glossary''': More terms need explanations.
*'''Glossary''': More terms need explanations.
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?
*General: All the tables are slightly differently formatted, you might want to get that more uniform.


===Group 3===
===Group 3===

Revision as of 22:03, 23 September 2011


Lab 4 Online Assessment

  1. The allantois, identified in the placental cord, is continuous with what anatomical structure?
  2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.
  3. Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)



--Z3389343 12:56, 28 July 2011 (EST)


--Mark Hill 10:04, 3 August 2011 (EST) Where are your answers to first lab assessment? Need to be completed before Lab 2.

Lab Assesments

Lab 1 Assessment

1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.

In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice. Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html

2. Identify a recent paper on fertilisation and describe its key findings.

Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15. IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.

3. Identify 2 congenital anomalies.

Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes. The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.

--z3389343 12:53, 4 August 2011 (EST)


Lab 2 Assessment

1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.

In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.


2. Journal Articles:

--z3389343 21:12, 9 August 2011 (EST)


--z3389343 12:34, 11 August 2011 (EST)

Differentially expressed RefSeq genes in human trisomy 21.jpg

Differentially expressed RefSeq genes in human trisomy 21.jpg

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/

Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.

Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Lab 3 Assessment

  • 1. What is the maternal dietary requirement for late neural development?

Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/


  • 2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.
File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png
Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice

--z3389343 11:09, 18 August 2011 (EST)


Lab 4 Online Assessment

  • 1. The allantois, identified in the placental cord, is continuous with what anatomical structure?

It is continuous with the developing hindgut.

  • 2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.

Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.

  • 3. Identify the Group project sub-section that you will be researching.

I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.


--z3389343 11:42, 25 August 2011 (EST)


Lab 5 Assessment

  • Which side (L/R) is most common for diaphragmatic hernia and why?

The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.


--z3389343 11:41, 1 September 2011 (EST)


Lab 6 Assessment

  • What week of development do the palatal shelves fuse?

This occurs in week 9 of embryonic development.

  • What animal model helped elucidate the neural crest origin and migration of cells?

This was the chick embryo.

  • What abnormality results from neural crest not migrating into the cardiac outflow tract?

This leads to deficient smooth muscle differentiation around aortic arch arteries. [1]


--z3389343 11:18, 15 September 2011 (EST)


Lab 7 Assessment

  • 1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?

Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.

  • 2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?

Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.

  • Comments on the Trisomy 21 page:
    • The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?
    • Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.
    • A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.
    • The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.
    • The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.
    • The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?
    • Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?
    • Listing the screening by country is a good idea, but then should contain more than just information for 1 country.
    • Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.

--z3389343 11:09, 22 September 2011 (EST)


Lab 8 Assessment

Peer Assessment

Group 1 - Turner Syndrome

  • Introduction: The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...
  • Epidemiology: This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.
  • The table with the common abnormalities is good, but in a slightly random place.
  • None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.
  • Etiology: Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.
  • Clinical Manifestations: Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.
  • Diagnostic Procedures: Very well explained, good use of diagrams and figures to illustrate the text.
  • Treatment: Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.
  • Current research: Looks fine to me
  • Future research: Good idea!
  • Glossary: Could be more extensive, mainly because some sections do not contain any links to the glossary.
  • References: Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)
  • General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.

Group 2 - DiGeorge Syndrome

  • Introduction: Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?
  • Historical Background : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.
  • Epidemiology: Seems fine to me, though a figure would be nice to break up the text.
  • Etiology: Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?
  • Pathogenesis: Seems to repeat what was said in etiology, but in more detail. Well written and explained.
  • Diagnosis: There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.
  • Clinical Manifestations: Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.
  • Treatment: Also quite thorough, well explained.
  • Current and Future Research: Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?
  • Glossary: More terms need explanations.
  • References: Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?
  • General: All the tables are slightly differently formatted, you might want to get that more uniform.

Group 3

Group 4

Group 5

Group 6

Group 7

Group 9

Group 10

Group 11

Group Project References

Current research: [2]

Mapping of frataxin gene: [3]

Genetics: [4]

[5]

[6]

[7]

check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113. for developmental genetics



Group Project Work

Genetic Component

The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain et al (1988) [8], using a linkage study for the mapping. Subsequent studies further refined its location to 9q13-q21 [9].

The most common mutation leading to the FRDA phenotype is an expansion of the GAA triplet repeat in the first intron of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900[10] [9]. The mutation is recessive, thus heterozygous carriers of the repeat are clinically normal. Most FRDA patients are homozygous for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. [11]

Evolution

FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée et al (1997) [9] found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16. The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a founder event. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. [9]

Genetic instability

Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit [12]. The cause for this instability is replication slippage: during DNA replication, one strand of the DNA template may loop out and become displaced, alternatively, DNA polymerase might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera et al (2001) [12].) This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.

Consequences of the mutation

In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani et al (1998) [13] found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. [13] More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. [14] [15]

In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. [11]

The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.


Add more about histone modifications

Glossary


Inheritance

GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat

Genetic Expression

The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development.

In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons [10]. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.

Developmental expression has been investigated in mouse embroys [16], and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.



Notes:

Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci U S A 94: 7452–7457.

the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage from normal long repeat can get to pathological repeat within one single generation


transcriptional consequences of GAA repeat: check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities


Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?

Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene

References

  1. <pubmed>15226263</pubmed>
  2. http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli
  3. http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html
  4. http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground
  5. <pubmed>8596916</pubmed>
  6. <pubmed>11351269</pubmed>
  7. <pubmed>11269509</pubmed>
  8. <pubmed>2899844</pubmed>
  9. 9.0 9.1 9.2 9.3 <pubmed>9207112</pubmed>
  10. 10.0 10.1 <pubmed>21827895</pubmed>
  11. 11.0 11.1 <pubmed> 20156111 </pubmed>
  12. 12.0 12.1 <pubmed>11350948</pubmed>
  13. 13.0 13.1 <pubmed>9443873</pubmed>
  14. <pubmed>21127046</pubmed>
  15. <pubmed>20373285</pubmed>
  16. <pubmed>9331900</pubmed>