Archive for the “Molecular Sciences” Category

To yet again prove Darwin’s theory, in a new study done in the University of Wisconsin, researchers have discovered that eight hearing-related genes have evolved over a time range of 40,000 years to cope with the ever-changing complex nature of verbal communication between human beings. Some of these changes are as recent as 2000 years ago.

As sound waves enter the ear, stereocilia “shown in orange” move. This movement is converted to electrical signals headed for the brain.

Seven of those genes are concerned with the production of proteins which make up the stereocilia & membranes that surround it. The 8th gene makes up structures which transmit sound waves to the inner ear.

Since communication requires both a talking tongue on one end & an ear capable of hearing on the other, the genetic changes concerning the ear must have favored a portion of the population to become better adapted to the “hearing process”. In any defense, they could have been able to detect on a more precise level, the emotional status of the person behind the spoken words, point out unconfidence in a specific speech, or even seperate out a conversation in the midst of a crowd.

This discovery certainly challenges the idea that languages have emerged from a single mutation which in somehow allowed the tongue to correctly twist, fold up & down, curve around within the buccal cavity & create the familiar sounds we know today.

This shows that not only human evolution has been going on since humans, or even neandertals for that fact, have existed but it continues all for the sake of a more prosperous life on our mother Earth.

Source & Image Credit: Science News

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The title stunned me as I was surfing the Yahoo News. At some evolutionary phase, birds really did have thumbs. So what happened to them? Researches at Yale University and the University of Wisconsin propose that it shifted its position after studies made on the gene expression in crocodiles, as published in PLoS ONE.

Going back now, birds have only three fingers, which until very recently where believed to be the 2nd, 3rd, and 4th respectively. The only problem this faced was that fingers in the early birds such as Archaeopteryx correspond to number 1, 2, and 3 “thumb, forefinger, and middle finger”. Fossil records clearly indicate that finger 4 and 5 “ring and pinky finger” were lost in the flying dinosaur ancestors of birds.

To end this debate, researchers began to focus on the expression of HoxD11 gene. In mice, digit 1 had no expression for this gene, which also held true for the 1st digit in birds, which suggests that in reality, it is actually a thumb. But to test this, it was compared to crocodiles, the closest living relatives to birds. The findings did in fact support what they suspected. The expression, as in mice, was absent only in finger one “the thumb”

So, birds at one time had thumbs. And the fact remains because they still do. It chose to develop at a different position in the body, that’s all.

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Who could possibly believe that our anaerobic spore-forming Clostridia will be used as an anti-tumor therapy?! It’s called Clostridium-based tumor targeted therapy. “Give me a break,” that’s exactly what I said when I read the review of the new book Clostridia: Molecular Biology in the Post-genomic Era.

So, how does it work? There are various non-pathogenic Clostridia strains which could replicate within solid tumors upon systemic administration. The interesting part is coming right up: Why solid tumors?! It’s because of its very unique physiology; it characterized by hypoxia & necrosis which totally fits the anaerobic Clostridia. The advantage will be the selectivity & targeting of the cancer cells leading to destroying them.

It was news to me to know that Cl. perfringens causes food poisoning like any food-borne illness & causes antibiotic-associated diarrhea (When I hear the name Cl. perfringens, I orient myself toward gas gangrene right away). Its enterotoxin gene (cpe) is present on the chromosome itself (in food poisoning isolates) and on the plasmid (in the antibiotic-associated diarrhea isolates). The enterotoxin binds to claudin receptors, then there’s oligomerization or “prepore” formation & finally prepore insertion takes place to form the functional pore which kills the cells by apoptosis. So CPE/CPE derivatives could be used for cancer therapy.

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Have you ever heard about the terrorist attacks of anthrax via mail in 2001 in US that finally ended with Bruce Ivins, the chief suspect in those attacks, committing suicide?

What about tracing microbe sources as in the Salmonella US outbreak?

This is microbial forensics.

Microbial forensics uses biological analysis such as genome sequencing, protein and carbohydrate fingerprinting to figure out the source of a biological agent. 2001 was not the year which witnessed the emergence of microbial forensics. Actually, in 1998 a doctor from Louisiana, who intentionally infected his former mistress with HIV, had a trial in court. But the anthrax attacks were really the reason for the amplification of the role of microbial forensics as it was followed by government funding and developing the sequencing techniques into more cheaper ones.

As a result, microbial forensics is extrapolated to further applications beyond biocrimes. In molecular epidemiology, it will help figuring out the source of food or water borne diseases such as in recent US Salmonella outbreak. The field also is expected to provide help in hospital-acquired infections. Many people sue hospitals every year claiming they got MRSA (methicillin-resistent Staphylococcus aureus) infection from a certain hospital. Tracing the source of the infection will prove whether those people really contracted the infection from the hospital or from any other outside source.

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Reference: Ontogeny

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In a study conducted by researchers in the University of Maryland School of Medicine, physical activity has proved to counteract FTO gene “fat, mass, and obesity-associated gene” in a group of European descendants who resided in the USA, known as Old Order Amish.

FTO gene has recently been linked to obesity & increased BMI “Body Mass Index” in numerous studies. Europeans usually have one or two copies of a variation of this gene. The research has enforced this prior assumption but brought, yet, another advantage since the study was done on 704 men & women of similar descent and thus similar genetic makeup, which what makes them ideal for genetic research. This helped researchers study the effect of physical activity on the expression of this gene.

In subjects, who were physically active throughout their daily routine, having multiple copies of the FTO gene didn’t seem to affect their BMI, despite the fact that in those, who were less active, a link between their BMI and FTO gene was obvious. This suggests that the choices one has to make in everyday life can deeply impact our body’s response to its own genes.

In order to compare the different variations in this gene, subjects were asked to wear accelerometers to measure their body movement on a 24-hour basis for seven days. They were then classified accordingly in order to conduct a comparative analysis. The genetic analysis revealed that 26 SNPs in the FTO gene were linked to BMI.

In the future, this may help tailor methods to prevent obesity in genetically susceptible individuals. So, after all we can’t blame it on our genes. Our decisions might in fact make up who we are & who we will become.

Source: Medical News today

Original research paper: Physical Activity and the Association of Common FTO Gene Variants With Body Mass Index and Obesity. PMID: 18779467 (Vote for the abstract on Biowizard)

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As we learned in pharmacology, the drug upon reaching the site of action, it gives a certain response. However, what if that response varies among individuals in terms of potency, duration or even adverse effects. As an example, in 1950s it has been noticed that Caucasians show prolonged effects to suxamethoniun chloride where further investigations revealed that 1 in every 3500 Caucasians has a less efficient butyryltranseferase, that metabolizes suxamethonium chloride, thus showing prolonged half-life & slower recovery from surgical paralysis. This fact has led to the emergence of a very unfavourable term “especially to clinicians”, Idiosyncrasy, which means the abnormal response to drugs, food & toxic agents that is peculiar to an individual. However, understanding the basic underlying mechanisms that led to this variation, made the scientists realize that in this case,  the drug response is not only a matter of pharmacodynamic effects but is considered as a ring holding pharmacology at one side and the genetic make up (which is the DNA sequence of any protein dealing with the drug as receptors, carriers, metabolizing enzymes………, etc) at the other side. This understanding led the scientists to replace the old term of Idiosyncrasy with a better descriptive term known as pharmacogenetics.

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Variations in the genetic make up are diverse in types. The most common type is Single Nucleotide Polymorphisms (SNPs) which are single nucleotide substitutions that can be found in coding and non-coding regions in the DNA sequences of protein systems dealing with the drug. Another form of variation can be chromosomal aneuploidy as Trisomy, where an extra copy of a chromosome, carrying a gene coding for any protein system dealing with the drug, will in turn lead to response variation. As an example for that is in leukemic patients with down syndrome, since there is a third copy of chromosome 21 which bears Reduced folate Carrier gene that codes for the transmembrane Reduced Folate carrier system which is responsible for the of transport methotrexate inside the cell, thus having a third extra copy of this gene leads to the over expression of RFC & methotrexate toxicity due to high levels of intracellular methotrexate.                                

Now, with the fact that the genetic make up of an individual dictates the response has been laid down, the clinical application has become a consequent step. For example, regarding leukemic patients having down syndrome, as mentioned previously, they are highly predisposed to methotrexate toxicity & thus as a routine, these patients should be set on lower doses of methotrexate. This particular example is a little bit simple that is easily characterized by the well known phenotype of down syndrome patients. However, translating the basic knowledge of pharmacogenetics to useful clinical guidelines is a more complicated approach in terms of both characterizing the alteration in the genetic make up and the subsequent clinical decision regarding the choice of the drug, dose and the dosing schedule. For instance carrying out a SNP Genotyping for DNA sequencing and identification of SNPs is a difficult matter as SNPs are very scattered along the human genome, where it has been estimated that every 1,ooo base pair, one SNP is found. In addition, the functional characterization of this SNP on the protein level is a matter of complexity that requires well controlled studies (i.e. all other causes of response variation regarding the drug of interest are eliminated).

Inspite of the complexity of the investigations for clinical application, it is a productive promising approach that does have three positive impacts on the clinical application where upon the tailoring of the treatment protocol according to each patient genetic make up (individualized therapy), this will increase the efficiency of the medications, decrease side effects, adverse drug reactions, morbidities Image credit:& mortalities and thus reduce the finances of the clincal mangement of adverse drug reactions as well as toxicities that may be result from incompatibility of the drug with the genetic make up of the patient.


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Image Source: College of Agriculture & Natural resourcesIn an on-going study at the University of Rochester Medical Center, scientists have come across a new form of inheritance which would probably astonish Mendel himself. Research has shown that parents pass on the human herpes virus 6 “HHV-6” to their offspring because the virus has integrated itself into the infected parent’s chromosomes. And it is actually not as odd as it sounds. One in every 116 newborns is affected by this unique congential infection. The virus appears to integrate itself into a position in the chromosome concerned with the maintenance of the body’s normal immune function.

Typically, HHV-6 causes roseola which is characterized by high fever, rash, and mild gastrointestinal symptoms. However, the number of viruses found in children, who carry the virus within their genes, is much higher than those who were infected merely through the placenta. 86% of the children included in the study had the virus integrated within their chromosomes. The HHV-6 DNA itself was found in a hair sample provided by one of the parents. Only six of the congenitally infected babies were infected by the mother through the placenta.

The odd part about this does not lay in the fact that the virus has integrated itself within the chromosomes, but that it was actually passed on. So far, the long-term consequences on the children’s immune system is unknown but to have a virus lying around like that in their DNA…simply frightening, yet fascinating.

Source: Biology News Net

Press release: URMC website

Original research paper: Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics. 2008 Sep;122(3):513-20. PMID: 18762520. (Vote for the abstract on Biowizard)

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You may remember HBV, the famous hepatitis virus with its partially double-stranded circular DNA genome. I always wondered: What is that supposed to mean?! HBV has a very complicated replication cycle. I’m pretty sure that all molecular biology fans will be totally thrilled by reading this.

HBV replication cycle is divided into 3 stages:

1- The infectious virion containing the partially double-stranded circular DNA, they call it RC-DNA (relaxed circular).

2- Right after the infection, inside the host nucleus, the genome becomes cccDNA (covalently closed circular DNA). It looks just like plasmids. HBV needs that highly stable form because it’s a chronic infection; it doesn’t want to be lost during host cell division. It may be still there in the host cells even after effective antiviral therapy.

3- Finally transcription takes place, several RNA molecules are produced, some of them are genomic (contain the whole genome) named pgRNA (pregenomic RNA) & some are subgenomic (encode needed enzymes) It uses the cell’s RNA polymerase II to do all this.

HBV replication

So, what happens to the pgRNA? They get inside progeny capsids ready to be reverse transcribed with the help of P protein (Its reverse transcriptase) which is “co-packed” in the pgRNA- progeny capsid package to get it back to the RC-DNA. Then the mature RC-DNA containing-nucleocapsids could undergo cccDNA amplification, or could be enveloped & ready for release from the cell. Of course all this is in equilibrium; if there’s only one copy in the cell, the priority is not to make cccDNA but to be enveloped & released.

Why the RC-DNA needs to be first cccDNA before transcription? As I got from this review, the RC-DNA has the normal (-)-strand (opposite sense to mRNA) but its complementary, the (+)-DNA strand, is not in full length. It results from the non-identical nucleotides supply; because the envelop is impermeable to nucleotides. At the 5′ end of the (-)-strand, there’s the P protein. But at the 5′ end of the (+)-strand, there’s some RNA nucleotides remains from the pgRNA…It was its primer, remember? All these are removed to be a cccDNA. The P protein may has a role in completing the (+)-strand.

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Hepatitis B Virus Replication:

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What could the two possibly have in common? Surprisingly, deep within the human genetic code, researchers have discovered a previously un-noticed gene that encodes a DNA-binding protein which closely resembles proteins produced by archaea bacteria. The gene, named hSSB1, was cloned to obtain sufficient hSSB1 protein closely resembles SSB protein illustrated hereamounts of the protein for analysis.

Studies have shown that this protein attaches to single stranded pieces of DNA. “Red marks shown in the picture indicate areas of attachment to the DNA”. Furthermore, it activates the production of other proteins which indicate the occurence of damage in that specific area of the genetic material. Cells deficient in this gene are more liable to DNA damage & eventually die at a faster rate.

Now, researchers are faced with the challenge of understanding the exact mechanism of how it signals the damage of the DNA & determining the roles, if any do exist, in the development of cancer.

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Dr. Jay Horton, the study's co-senior authorIn a new twist of events, aided by small tailor-made pieces of RNA, scientists have been able to successfully lower the levels of “bad” cholesterol in pre-clinical trials by two-thirds using single doses of siRNA.

Researchers have studied people with mutations in the PCSK9 gene “short for proprotein convertase subtilsin/kexin type 9” which is responsible for the production of a protein that raises the level of LDL & have found that they are less prone to hypercholesterolemia & other cardiovascular-associated disorders. In fact, they are 28% less liable to develop coronary heart diseases.

Therefore, eliminating the production of this protein is beneficial for patients suffering from high levels of blood cholesterol. In order to achieve this, little pieces of designer siRNAs were designed which attach upon the cell’s mRNA and put an end to the process of protein translation.

These trials have been performed on mice and rats that have been genetically altered to produce normal human PCSK9 protein end product.

In addition, non-human primates were also included where they showed an average of 56% reduction in cholesterol level, with one of them showing a surprising 70% reduction.

It is worthy to say that drugs available now in the market have only proved successful when taken at maximum doses over prolonged periods of time & showed only 20-50% drop in LDL cholesterol. This opens up a new horizon for patients who have not responded to conventional drug therapy or may be used in combination with the existing medication to produce more promising results.

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