Biochemistry and Molecular Biology Official Blog

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Monday, 14 January 2019

Protein modification fine-tunes the cell’s force producers

Actin is one of the most abundant proteins in our cells. It assembles into filaments that produce force for many processes that are essential to the life of animals, plants and fungi — including cell migration and division, and muscle contraction1. The organization and dynamics of actin filaments in cells are regulated by a large array of actin-binding proteins. Moreover, post-translational modifications of actin — the addition of certain chemical groups to its amino-acid residues, or their removal — is thought to have a role in controlling the cellular functions of actin filaments. However, the proteins that catalyse these changes have been elusive. Writing in Nature, Wilkinson et al.2 report the identification of the long-sought enzyme that catalyses the methylation (addition of a methyl group) of actin, and shed light on the biological role of this post-translational modification in animals.


Some post-translational modifications of actin are present in all isoforms (structural variants) of the protein, whereas others are more specific. 


The protein’s amino-terminal region can be modified by acetylation (addition of an acetyl group) and arginylation (addition of an arginine amino-acid residue)3. Recent studies identified the enzyme responsible for amino-terminal acetylation of actin and demonstrated that this modification affects the elongation and depolymerization of actin filaments4,5.
Most actin isoforms are also methylated at a particular histidine amino-acid residue known as His73, which is close to the site to which one of two nucleotides, ATP or ADP, binds. Hydrolysis of ATP to ADP plus one free phosphate molecule is essential for the turnover of actin filaments, and hence for their ability to produce force in cells. Although methylation of His73 was identified more than five decades ago6, the enzyme responsible and the biological functions of this modification have remained unknown.
The study by Wilkinson et al. and a related study published in eLife7 report that the SETD3 protein is the enzyme that methylates actin at His73 (Fig. 1). This is the first time an actin methyltransferase (an enzyme that catalyses methylation) has been identified, and also the first time a histidine methyltransferase has been identified in animals. Earlier work suggested that SETD3 methylates lysine amino-acid residues in histone H38, a protein associated with DNA, but Wilkinson et al. convincingly demonstrate that SETD3 is not a methyltransferase for histones. The authors provide extensive biochemical and cell-biological evidence showing that, at least in mammals, SETD3 is the only enzyme that catalyses the His73 methylation of actin, and that actin is the only substrate of SETD3. They also show that SETD3 and His73 methylation of actin are present in a wide range of organisms, including plants and animals, but that SETD3 is not present in budding yeast, which also lacks His73-methylated actin.
Figure 1 | Methylation of actin by the SETD3 protein.Wilkinson et al.2 show that SETD3 catalyses the addition of a methyl chemical group (methylation) to a histidine amino-acid residue (His73) of the protein actin, and that this modification fine-tunes the protein’s function. His73 is close to a site to which either an ATP or an ADP nucleotide binds. The switch between ATP and ADP is essential to allow actin filaments to produce force in cells. Other evolutionarily conserved post-translational modifications of actin, including the addition of an acetyl chemical group (acetylation) to its amino-terminal region, are distant from the nucleotide-binding pocket of actin.
Why does SETD3 methylate actin, but not other proteins? To answer this question, Wilkinson et al. determined the atomic structure of SETD3 in complex with a short chain of amino acids (a peptide) that has the same amino-acid sequence as the region of actin around His73. They found that this peptide occupies an extended groove in the domain of SETD3 that is responsible for the enzyme’s methyltransferase activity. The interface between SETD3 and the actin peptide has many specific interactions, which explain why SETD3 binds to and methylates only actin.
To examine the biological functions of this post-translational modification, Wilkinson et al. generated ‘knockout’ mice and cell lines in which the gene encoding SETD3 was inactive. They observed that actin is no longer methylated in these models. Surprisingly, the mice lacking SETD3 seemed to be healthy, which demonstrates that methylation of actin at His73 is not essential in mammals. However, female mice lacking SETD3 took longer to give birth than did mice in which this protein was present. The delay resulted from defective contraction of certain muscles of the uterus during labour. Moreover, the migration of SETD3-knockout cells in culture was slower than that of wild-type cells. Finally, non-methylated actin purified from the SETD3-knockout cells polymerized slightly more slowly than did methylated actin, and had a faster rate of exchange of nucleotides on single actin molecules than did actin purified from wild-type cells.
These experiments provide evidence that, despite being evolutionarily conserved across a broad group of organisms, methylation at His73 is not essential for the normal functioning of actin. Instead, this modification seems to fine-tune the protein’s biochemical properties and cellular roles.
Future studies should investigate the SETD3-knockout mice in more detail for possible additional differences from wild-type mice, and should examine the effects of SET
D3 deletion in other model organisms. Also, the effects of His73 methylation on actin biochemistry should be studied more precisely. Previously, analysing these effects was possible only by mutating the His73 residue in actin or by producing human actin in yeast, in which this protein cannot be methylated9,10. The new findings will enable careful side-by-side comparison of wild-type actin and actin that lacks methylation only at His73. 
Because His73 is close to the nucleotide-binding site of actin, it will be especially interesting to study how this modification affects the functions of proteins that catalyse nucleotide exchange on actin11and that rely on ATP hydrolysis and subsequent release of free phosphate for their interactions with actin filaments12.
Nature 565, 297-298 (2019)
doi: 10.1038/d41586-018-07882-0

Friday, 21 December 2018

Call for Microsoft Imagine Cup 2019 Pakistan

The Higher Education Commission & Microsoft are collaborating to bring to faculty, students and academia Microsoft’s Imagine Cup - the world’s most prestigious student technology competition, bringing together student innovators from all over the world. 
Each year, a team is chosen from Pakistan that completes against the best from around the world, to get a chance to win $100,000 USD.
This is an amazing opportunity for you to participate and utilize your potential by bringing your imagination and their passion towards creating technological solutions and compete to win great prizes! 
Microsoft along with the HEC is striving for nurturing innovation and transforming technology among the youth of Pakistan. It is hoped that the platform made available through this collaborated effort will help students of Pakistan in recognition of their innovative ideas and relative projects. 
To ensure quality output, the competing teams from Pakistan are initially evaluated in Regional finals that are held in different cities. The winning teams compete for National Finals to select a National winner. A mix of judges from both academia (as directed by HEC) and industry evaluates the solutions during both rounds. Both regional finals as well as National Finals evaluations are made based over team’s deliverables submitted online on the Imagine Cup portal using the criterion listed in 2019 Imagine Cup Competition Official Rules and Regulations (attached with this email).
Regional & National Finals detailed per team plan and relative winner’s announcements will be made on Official MSDN Pakistan Community Blog: https://blogs.msdn.microsoft.com/pakistan/.
The deadline for the project submission for the Regional Finals is 15 January 2019.
All interested students are requested to contact their faculty members concerned as early as possible to participate in the Imagine Cup 2019 with reference of this email. 
Please click onto https://imaginecup.microsoft.com/en-us/pakistan for further details. 




Thursday, 13 December 2018

Brain tumor related epileptic disorders


Diagnostic monitoring and modern technology based therapeutic strategies to manage the adverse effects


Tumor is a multifaceted, genetically complex disorder and the complications are further increased, when couple with some serious neural disturbances. 20-40% patients with brain tumor have been reported to suffer from different types of seizures.

Brain tumor related epilepsy (BTRE) are the most complicated neurological disorders for neuro-scientists and oncologists that demand intense molecular strategies and therapies to tackle the entangled cascade of neural network and at the same time there is need to understand the abnormal cellular architecture of cancerous cells in the brain. BTRE has also acquired multiple drug resistance (MDR) behavior, thus makes a challenge-able choice of anti-epileptic drug for physicians and also has adverse effect on the quality of life of the patients.

With the emergence of technological revolution in the modern clinical world, the onset of Nano-biotechnology and artificial intelligence has gain lot of interest and practical acceptance among scientific community. 

Recently couple of studies have been reported to use artificial neural network (ANN) for more precise diagnosis of epilepsy and to understand the clinical impact of human mutations with deep neural network system. There is a need to get maximum benefits from these emerging fields in parallel with biological advancements for the implication of treatment.


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STEM CELLS AND AGING


Stem cells have potential to differentiate into all types of cells depending upon need of the cell. Therefore , stem cells are considered main source for regeneration and replacement of damaged cells. But it is confirmed that aging has negative impact on development of stem cells.

Skeletal muscle cells have capacity to regenerate and replace damaged parts of muscle cells.The potential of satellite cells deminishes with the onset of aging. It disturbs the normal function of B and T cells.

The process of aging reduces the stem cells function. Neural stem cells (NSCs) which are responsible for replenishment of new neurons i.e maintaining brain function , starts to cause neurodegenerative diseases within the onset of aging.


Aging of skin:-

 There are various reasons of aging specifically when it relates to molecular and cellular level. The factors are supposed to involve in aging of skin are genetration of ROS , utraoviolet rays, smoking ,contamination and due to disturbace in metabolism. ROS promotes mechanism of gene expression resulting in collagen degeneration and aggre gation of elastin.moreover, ROS enhances the activation of matrix degenerating metalloproteases while suppresses the TIMP .

Stem cells have potential to differentiate into all types of cells depending upon need of the cell.

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Wednesday, 12 December 2018

Environmental biotechnology

Envoirmental biotechnology


Introduction:
 Environmental Biotechnology has come up at present time in its efforts to clean up our environment because our environment over the year has become a repository for dozen of chemical and the main purpose of this technology is to introduce Eco-friendly techniques which involve the use of microorganism. 

Environmental Biotechnology is extremely important constituent of the scientific and engineering tools which are required to handle environmental issues. This technology absorbs additional elucidation of biological principles that are bases of environmental engineering. 

Environmental biotechnology hang on a systematized overlook of dozen factors having a part in when organism used to resolve our environmental issues. For example, fungus is used for the treating unhealthy waste that comes from industries specifically paper making industry. By using this technology, we can more fruitfully clean up unhealthy chemical instead of using prevailing methods which greatly dis-rate our dependence for clean up on methodology which is burning process or waste dump sites.

We can say biotechnology is not a new technique to treat waste material. Most of the population already depends upon microbes, bacteria and microorganism to treat waste. Much of the bacteria survive on chemical material and few organism feed on toxic material. Environmental engineer apply different techniques to treat waste one of them is to add bacteria at hazardous place bacteria then eat waste and produce harmless byproduct (bioremediation)

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EPIGENETICS The heart of future biology


EPIGENETICS The heart of future biology

Epigenetic is the modern technique which involves the changes in the expression of the gene without change in the basic DNA sequence that determines the correct order of nucleotides with chromosomes and genome. Epigenetics research includes the appliance of strong alteration techniques for DNA.

Epigenetics is associated with DNA modification or protein modification. It includes histone modification, DNA methylation as well as chromatin modification. These modification effects the regulation of gene expression. 

It generally takes information from the nucleus of eukaryotic cells (having the nucleus in the cells) and packed that information. One of the examples of the epigenetic is the DNA methylation which is done by adding a methyl group to the cytosine. Methylation is a controlled process because of an enzyme that is methyltransferase in cell division
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Gut Microbiome and Dementia


Dementia basically a sort of symptoms that corresponding thinking skills, everyday performance of person and memory. It is infect a neuro-cognitive disorder. Alzheimer’s disease is almost its common cause. It is said that Dementia can’t be cure completely.

Role Of Gut Microbiome in Dementia:-

1.Nervous system disease, Neuro-inflammation and gut microbiome are closely related.

2. Neurotoxic metabolites D-lactic Acid and Ammonia processed by bacterial enzymes.

3.Human antigen and bacterial proteins cross-react with each other to vitalizing defective reactions of adaptive Immune Response.

4.The neurotransmittors and harmones made from gut microbes are similar to humans. Becterial growth for Harmones developed virulence and growth of microbes.

5. Clostridium difficile increased the chances of infections.



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Artificial skin for burn patients


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The skin is a complex organ that is difficult to replace when it is irreversibly damaged by burns, trauma or disease. These are now a number of commercially available. Skin is our body largest organ. Skin serve as a external barrier that protects unwanted substances from entering the body. Skin have three layers; epidermis, dermis, and hypodermis.


In the united states maximum 12,000 deaths annually are caused by thermal injury. Major contributors to mortality immediately following severe burn trauma are excessive fluid loss and rampant infection. It’s failure to achieve skin coverage within three to seven days increase the risk of death.

Since one of the main challenges in treating acute burn injuries is preventing infection, early excising of the eschar and covering of the wound becomes critical. Non-viable tissue is removed by initial aggressive surgical debridement. Many surgical options for covering the wound bed have been described, although split-thickness skin grafts remain the standard for the rapid and permanent closure of full-thickness burns.

Significant advances made in the past decades have greatly improved burns patient care, as such that major future improvements in survival rates seem to be more difficult. Research into stem cells, grafting, biomarkers, inflammation control, and rehabilitation will continue to improve individualized care and create new treatment options for these patients.

Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds. Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells.

According to new research if artificial grafting is used from buffalo and cows is a cheap grafting procedure now a days research is going on this method in Pakistan in Lahore. So modern technique can prevents lives which oocur due to burns




Genetic Engineering


Introduction.


Genetic engineering also termed as genetic modification or genetic manipulation is the process which involves the direct manipulation of DNA of an organism to alter the organism’s characteristics to either produce novel or improved traits. In simple words, it can be defined as: the science of manipulating and cloning the genes for the production of new trait or biological substances like proteins. The organism produced through genetic engineering are termed as GMOs: Genetically Modified Organisms.

genetic engineering

The organisms into which foreign DNA has been inserted are called transgenic organisms. Along with inserting the genes, genetic engineering can be used to remove or knock out a specific gene. The exigency of genetic engineering owes to its promising results. Human insulin was first time possible to obtain from non-animal cells by genetic engineering. The modification in DNA of an organism for a desired outcome and its success has led to the new ways in modern science.

The term ‘Genetic Engineering’ was used by Jack Williamson in his novel named ‘Dragon Island’ in 1951. Paul Berg is considered as the pioneer in genetic engineering. In 1972, he paved the ways to possibility of rDNA formation by experimentally combining the DNA from lambda virus with that of monkey virus SV40.After one year, Herbert Boyer and Stanley Cohen created first transgenic bacterium.

In 1973, Rudolph Jaenisch introduced the foreign DNA into the mouse embryo thus creating a transgenic mouse. In 1976, Herbert Boyer and Robert Swanson led the foundation of first genetic engineering company, Genentech. In 1982, FDA approved the insulin production by bacteria. In 1987, first genetically modified organism was released in environment. 

In 1994, first genetically modified food, a tomato (Falvr Savr), was approved for commercial use. In 1995, a genetically modified pesticide producing crop was approved by FDA for plantation in USA. In 2009, 25 different companies grew transgenic crops. Jennifer Doudna and Emmanuelle Charpentier developed a technique, CRISPR/Cas9 system in 2012, to specifically alter the genome of almost any of the organism.




CELL TO CELL NETWORKS


CELL TO CELL NETWORK


Image result for Gap JunctionGap Junction: Gap Junctions plays a very important role in cell to cell communication and regulate cell differentiation, cell growth and development. The most important function of Gap Junction Intercellular Communication (GJIC) is to maintain the vascular homeostasis between the cytoplasm of two neighboring cells and to regulate cell survival. This Gap Junction acts just like a transmembrane protein or channel and makes possible the passage of nutrients, ions and small molecules between the two cells. These gap junctions regulate the survival of the cells by exchange of metabolites, ions, glucose, secondary messengers and ATP.


Image result for ConnexinConnexin: Gap junctions are also present in many tissues such as retina in which Connexin 43 (Cx43) is mostly present. Connexins are the family of multigene and many members of this gene is present in the eye. If mutation occurs in the genes that encodes the several members of Connexin family cause many human diseases. In-vitro experiments have revealed that Gap junction activity is affected in the presence of high glucose in pericytes, retinal and microvascular endothelial cells. It is currently reported that 21 isoforms of connexins is present in human genome. A change in the gap junction activity and the expression of Connexin 43 has also been expressed in many diabetic tissues such as diabetic retina, skin, lens epithelium and kidney. Connexon is a connexin subunits and assemble in the form of hexamers. Intercellular channels are described as homotypic and heterotypic. If the molecular composition of two connexins is same it is known as homotypic, or if the molecular composition is different of two connexins it is known as heterotypic. In diabetic retinopathy destruction of the retinal cells causes the retinal lesions in the early stages of diabetic retinopathy. Connexin maintains the vascular function and GJIC activity for example, in growth and development. Connexin also modulates the growth signals. In diabetic condition, the activity of GJIC is reduced which cause the death of retinal endothelail cells and pericytes. Chronic hyperglycemia associated with many pathological changes which lead to the breakdown of retinal blood barriers.


Purinergic signalling.jpg
Simplified illustration of extracellular
purinergic signalling
Pannexin: Pannexins are a huge single membrane channels and pannexin gene family contains 3 members such as panx 1, 2 and 3. Pannexin express in many parts of the vertebrate body such as nose, ear or lens etc.Pannexin plays a very important role in the visual system and mainly focused on disease that leading to blindness. The first condition is Age-Related Macular Degeneration (AMD) that condition which leads to the loss of vision. AMD condition is developed when by the progressive destruction of retinal pig-ment epithelial (RPE) cells in the macula, which lead to increased intraocular pressure, and the neovascularization of the subretinal macular region. AMD also cause bleeding and leakage of the fluids from the eye




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