Botulinum toxin is a peptide produced by anaerobic bacteria Clostridium botulinum. This is one of the most potent neurotoxins in the world. Botulinum intoxication, characterized by severe paralysis that could end up fatally, is known as botulism. Large molecular mass prevents toxin to enter the brain, but it can interrupt synaptic connections in the peripheral nervous system and block acetylcholine (neurotransmitter) release. Despite numerous negative effects associated with botulinum toxin, it can be very useful in treating various medical conditions if applied properly.

Blepharospasm is medical condition characterized by uncontrolled eye blinking; it results from involuntary movement of the muscles around eyes. Disease could be triggered by impaired function of basal ganglia, fast life style and psychophysical stress, or due to dry eyes… Botulinum toxin provides relief by inducing the spasm of the muscles responsible for eye twitching. It needs to be applied every 3 months to maintain ocular muscle “under control”.

Strabismus is diagnosed when eyes are not properly aligned. Disorder results from extraocular muscles dysfunction or due to impaired brain - eyes coordination. Impaired binocular vision and depth perception are common disease attributes. Treatment options are limited to corrective glasses, lenses and patches that could correct the visual image created in the brain. Cosmetically, strabismus can be improved either by botulinum toxin injection or through surgery. Botulin toxin provokes muscle spasm and result in eye alignment. It needs to be injected every couple of months, since paralysis weakens in time.

Upper motor neuron syndrome results from lesion of the motor neurons (which innervate skeletal muscles). It is characterized by decreased muscle control, altered tonus, weakness, mioclonus, spasticity…. Severity of disease depends on the severity of motoneuron lesion and affected muscles. In the most cases, exercise combined with drug treatments could help restore muscle tonus and relief spasticity. Botulinum toxin is applied by direct injection in the muscle to alleviate muscle - neuron signals. There is a story about Australian that had a stroke 20 years ago and managed to leave the wheelchair recently thanks to botulinum applied for hypertonic muscles treatment.

Hyperchydrosis or excessive sweating results from increased activity of sympathetic nervous system; it could be triggered by some type of food, drink and smoking... Whether it is localized (palms, underarms, groins) or widely spread, surgical methods such as removal of the sweat glands or endoscopic thoracic sympathectomy could provide satisfying results. Less aggressive methods such as antiperspirant application could help also. Botulinum toxin can prevent perspiration by blocking neural control over sweat glands. Effects are visible during 3-9 months.

Cervical dystonia known as torticollis is medical condition associated with neck spasticity. Damaged sternocleidomastoid muscle can’t rotate and bend laterally resulting in abnormal head position (tilted in one side). Facial asymmetry can develop also. Disease can be congenital, induced by birth trauma or intrauterine malposition or can be acquired later in life (consequence of tumors, drugs, infectious diseases…). Typical treatments include muscle stretching and strengthening. When applied exercises doesn’t provide expected outcome, surgery could help release tensed muscle. Botulim toxin is often used in torticollis treatment; it effectively inhibits spastic contractions.

Chronic migraine is severe headache that affect one side of the head; it could last between 2 and 72 hours. Genetic predisposition (2/3 of all cases are inherited) and multiple environmental factors are implicated in migraine genesis. Nausea, vomiting, pain, sensitivity toward light and noise… are just few symptoms that typically occur during migraine. Analgesics and antiemetic are used for control of pain and nausea, respectively. Botulin injected in head and neck proved to be efficient in chronic migraine prophylaxis.

Achalasia or esophageal aperistalsis is disorder affecting smooth muscles of esophagus and lower esophageal sphincter. Food can’t pass esophagus normally due to low organ peristalsis and increased muscle tonus of the sphincter. Main symptoms are dysphagia (patients can’t swallow food normally), regurgitation and chest pain. Calcium channel blockers (decrease tonus of the sphincter) and surgical approach (Heller myotomy) are mostly used treatment options. Botulinum toxin induces sphincter paralysis. It can induce scarring of the muscle, so it’s avoided in patients who are planning surgical operation in the future. Botulinum is prescribed only to the patients that are not suitable for surgery.

Cosmetic industry exploits botulinum toxin very much. Most people consider that botulinum is used solely for wrinkle removal. Actually, list of disorders that could be treated with botulinum toxin is long. Unfortunately, effect is time limited and treatments need to be repeated every couple of months.

Among the most dreaded diseases, cancer is one of them and affects different organs or tissues within the body. In the present times, many types of cancers affecting different parts of the body with varied consequences have been unveiled, although the list may not be exhaustive. The different types of cancers affecting different organs or tissues are usually specific to that particular organ or tissue and may not affect any other remote organ or tissue, even though some rare cases may be observed, where a specific type of cancer affects a number of tissues and organs. A number of factors make some people predisposed and susceptible to the development of cancer within their body. Hence, like many other diseases, cancer may be regarded as a multi-factorial disease dependent on a number of factors that are summarized as follows:

a) Age makes some people predisposed to cancer. The advance in age leads to higher probability of development of genetic mistakes, which turns a normal cell into a cancerous one. The continuous exposure to carcinogens or other factors makes a cell prone to genetic changes during cell division that may result in cancerous growths.

b) Genetic makeup of some individuals increases the risk for development of cancer. Cancer results from a number of mutations in the genes of the individuals. These mutations may be inborn or may develop due to environmental factors like long-term exposure to carcinogens, etc. Although, the individuals inborn with genetic mutations may not develop cancer in all the cases, the chances of developing cancer is high among them, the phenomena being known as genetic predisposition. For e.g. the presence of one of the faulty genes BRCA1 and BRCA2 in the some women makes them predisposed to the development of breast cancer. However, the presence of genetic mutations is not always noticed in breast cancer patients that initiates the studies related to the viability of other factors in the cancer development.

c) The immunological system of the individuals has a promising role in the development of different types of cancers. The HIV positive individuals or AIDS patients have higher probability of developing cancer. Some individuals with history of organ transplantation with intake of immune system suppressing drugs for prevention of organ rejection or the individuals with inborn rare medical syndromes affecting immunity are predisposed to cancer development. Cervical cancer, cancers of genital areas, lymphomas, liver cancer, and stomach cancer may develop due to the overlapping of the mentioned conditions. The transplanted cells have the property of continuous cell division that makes them predisposed to develop genetic mistakes resulting in formation of cancerous cells.

d) The exposure to various environmental hazards in the daily life may also lead to cancer development. Different types of pollution, which may be man-made or natural consisting of harmful radiation, tobacco smoke, the ultra-violet rays of the sun, the hazards of work-place, effects of exposure to asbestos, etc are some of the possible reasons related to environment for the development of cancer.

e) Unhealthy lifestyle may also make people predisposed to cancer development. Smoking is one of the main reasons for the development of lung cancer. The intake of red and processed meat with alcohol accompanied with lack of physical activity also lead to predisposition to cancer development. In some cases, unhealthy lifestyle accompanied with eating junk food that may be laden with food additives may also lead to cancer.

f) In the daily life, people are exposed to a number of carcinogens or different cancer causing substances in different forms that may result in the development of cancer in one form or other. However, although everyone is exposed to carcinogens in one form or other, only some people are susceptible to cancer development. It is due to the extent of the influence of other factors.

g) In the development of most of the cancers, virus plays a major role by making genetic changes in the normal cells leading to the formation of cancerous cells e.g. cervical cancer, Lymphomas, T-cell Leukaemia, oro-pharyngeal cancer, etc are some of the cancers that are caused due to different types of viruses.

h) Infection resulting from different types of bacteria may in some cases lead to specific type of cancer for e.g. the stomach cancer results from the inflammation in the mucous lining of the stomach that is caused due to Helicobacter pylori. Different lymphomas of the stomach also result from the bacterial infections of the stomach.

In this way, it is seen that multiple factors play crucial roles in the development of cancer and the presence of some factors are closely linked with high risk making some people predisposed to the disease. Hence, to develop proper therapeutics for the disease, it is essential to consider the influence of all the factors and the possible roles played by them.

Transformation of the fruit from green to fully mature, desirable for eating, is called ripening. Process is induced by gaseous plant hormone called ethylene. Its production is associated with outer temperature, surface wounds, and diseases. Ethylene triggers enzymatic activity that will convert complex polysaccharides (starch) to simple sugars, degrade chlorophyll and produce other pigments. Enzyme pectinase will degrade pectin and result in softer surface layer of the plant. Each fruit species demand certain weather conditions and climate to develop normally. During the past couple of years (thanks to improved shipping methods) fruit is traveling faster and people all over the globe can eat different types of fruit all year long. Ripened fruit can’t be safely transported because it is too soft and decay prone. Besides applying delay ripening methods, fruit is normally collected while still green. Artificial ripening (using different chemicals) will provide expected color and taste when fruit reach its final destination. Methods used in fruit ripening can provide fast and effective results but they are not necessarily 100% safe for humans. Also, if they are not administered properly, fruit might overripe and decay completely.

Calcium carbide is used as ripening agent in some countries. When combined with water, it turns in acetylene which induces fruit ripening. Calcium carbide can contain traces of arsenic and phosphorus that are known toxicants in humans. Mostly used ripening agent is ethylene. Specially designed facilities used for fruit ripening release previously determined amount of ethylene. Iodine is used to check ripening status of the fruit. Interaction between iodine and fruit sugar will indicate whether fruit is still green, in the ripening phase or fully ripe. Reaction between starch and iodine result in dark blue colored complex. Since starch turn in more simple sugar during ripening, green fruit will color dark when sprayed with iodine, while ripe fruit will produce bright color.

List of fruits that is collected while still green is long: bananas, papayas, mangos, tomatoes… are typical examples of fruit that will be harvested during “commercial maturity” stage and ripen prior being delivered to the desired location. Each species demand specific amount of ethylene to ripen properly. Although ethylene is safe artificial ripening agent, his storage and release could be a problem. Explosive accidents associated with tanks containing ethylene were reported in the past. Compressed gas is not just unsafe, but hard to accomplish and expensive to maintain. Scientists from the University of Queensland recently discovered another biological material that might offer solution for this issue. Starch derived material have crystalline structure and cavities that could safely encapsulate ethylene in couple of powder forms. Rise of temperature and humidity will induce ethylene release (from the powder complexes). This system is much cheaper and safer than previously used storage facilities and it could even be incorporated in the trucks that are delivering the fruit to the market. As a result, customers will be able to buy a fruit that have just ripened.

Another group of scientist (from the Massachusetts Institute of Technology) discovered the way to detect amount of ethylene using the newly developed nanotech device. Ethylene is small non-polar hard to detect molecule. Conventional methods applied in ethylene measurement are expensive. Newly developed device is portable, safe and easily produced. Sensor consists of two gold electrodes. Single walled carbon nanotubes and specially designed complex copper mixture lies in between electrodes. Bond between copper and nanotubes is very strong. When sensor is exposed to ethylene atmosphere, copper will bind ethylene and loosen its connection with nanotubes. Sensor is highly sensitive: electronic properties of the nanotube will register the slightest change in connectivity between copper mixture and nanotubes. Change in electronic resistance is proportional to the level of ethylene. Device was used to establish amount of ethylene released during ripening phase (amount of released ethylene is species specific) and to determine the peak of ripening for each species (when fruit ripen, it doesn’t demand ethylene anymore and it will slowly decrease its production). This little device could help prevent fruit from overripe and assist manufacturers while determining the proper amount of ethylene during ripening phase.

Newly applied method could greatly improve fruit ripening industry. Potential ethylene associated accidents could be prevented, timing associated with harvest and fruit ripening could be improved, and decay could be avoided.

Influenza (flu) is infectious disorder induced by RNA viruses that belong to Orthomyxoviridae family. Three genera are associated with influenza disease in humans: Influenzavirus A, B and C. Flu is seasonal disorder, it reaches a peak in the winter. Being easily and highly spreadable, it often results in epidemics. Each year 3 to 5 million people get infected with influenza virus and between 250.000 and 500.000 cases end up fatally. Virus transmits trough bodily fluids, usually via coughing and sneezing (aerosol containing viral particles). People that are living or working in highly crowded spaces are at higher risk of developing disease due to close and often contacts with other individuals. Typical symptoms include chills, fever, muscle pain, sore throat, fatigue… It can lead to more severe disorder such as pneumonia. Worst case scenario is influenza pandemic: global spread of the virus ends up in mass infections. Several pandemic events were noted in 20th century. Most famous are Spanish flu in 1918 (with 50 million fatal cases), Asian flu in 1957 (between 1.5-2 million fatal cases) and Hong Kong flu in 1968 (1 million fatalities). In 2009, Swine flu triggered mass hysteria, but in reality, number of Swine flu fatalities didn't overcome typical seasonal flu mortality (~ 18.000 fatal cases).

Vaccination against flu is usual practice in most parts of the world and its popularity is growing each year. Idea behind flu vaccination is development of the "herd immunity": when 80% of people become immune against the virus - chances for further spreading are dropping down significantly. Vaccines are especially recommended for the sensitive group of people: children and elderly, immune-compromised and people with asthma, diabetes… Why flu and vaccinations against it are so important? Disease that spreads quickly and infects all age groups, result in less people available for work and hospitals full of elderly people that are treated longer than healthier (younger) groups of people. If 600.000 people die, 3 million people end up hospitalized and 30 million patients came to a hospital for a short visit, medical industry will have direct lost of ~10 billion dollars. Other institutions are affected by the seasonal flu also. Center for Disease Control and Prevention calculated that children in the USA missed 38.000 days in schools due to influenza. Influenza associated annual costs overcome 80 billion dollars. All this reasons accelerate vaccine industry and stimulate various experiments that could ensure novel, more efficient vaccination methods.

Influenza viruses are highly variable and each year new vaccine needs to develop. Typically, vaccine preparation will be guided by the seasonal viral strains (H1N1, H3N2, and B strain) recommended by WHO (World Health Organization). Most commonly, virus will be grown in the hen's egg. It takes around six months for vaccine to “mature”. Later, it will be mixed with other ingredients resulting in final vaccine. Cells in a culture could be used instead of an egg, but this is a long lasting process (several months). Latest improvement in the field of vaccine manufacturing could result in safer (egg allergy is prevented) and faster vaccines production (6 weeks in total).

mRNA is small molecule essential for genetic expression. It carries information about building protein from DNA to ribosome. If mRNA molecule is reprogrammed to induce synthesis of specific immune protein, desired immune response could be achieved. mRNA based vaccines are already used in carcinoma immunotherapy. They are applied intradermally; balanced immune response is achieved by targeted expression of immunoproteins that provide strong anti-tumor effect. Vaccination can be scheduled to fit the clinical situation. For the first time, mRNA vaccine for influenza treatment is designed. mRNA vaccine elicit predictive (B and T-cell dependent) immune response against influenza virus. Scientific team tested newly created mRNA vaccine against H1N1pdm09, swine flu and the H5N1 bird flu and so far - it proved to be effective against all of them. Vaccine could be manufactured easily in just a couple of weeks. It doesn’t have to be stored in refrigerator and tests in animals showed that is equally effective in old and young animals (tested in mice). Besides test on mice, vaccine proved to be safe and effective in ferrets and pigs.

Next step will be testing of safety/efficacy in humans. If it proves to be effective, mRNA vaccine could easily become a standard in future influenza vaccination programs. Personally, I believe that much better and safer way to boost immune system could be accomplished through regular sport and healthy diet and that is my favorite "vaccine". :-)

Reference: Lothar Stitz, Friedrich-Loeffler Institute in Riems Island, Germany

Symbiosis is tight, mutualistic (cooperative), relationship between two or more biological species. Most symbiotic relationships last for a life time. Lichen is typical examples of symbiotic organism. It looks like a single species, but is actually composed of fungus and algae that are living in a tight relationship. Algae provide food through photosynthesis, and fungus provides water and mineral material from the ground. This community is obligatory; neither one species would survive without the other one. When symbiosis is facultative, two organisms could live separately, but they prefer symbiosis because their well being will be improved after they join forces. Humans form symbiotic relationships also. Intestinal bacteria are important part of immune system serving as significant defense line against pathogenic microorganisms; other gut bacteria could produce certain vitamins or accelerate digestion…. Symbiotic relationships are old probably as nature itself. Today, using the advantages of modern technology, man is able to directly affect and improve different symbiotic organisms to meet his own needs.

Recently published story describes a man who injured himself while cutting the old crab apple tree (branch impaled between his fingers). Although he properly cleaned the wound, it became infected and painful. He visited a doctor who sampled a liquid from the formed cyst for the bacteriological analysis. That analysis couldn’t determine the strain of infected agent. There were similarities with the already known bacteria but perfect match was missing. Bacterial species living in the gut of the insects, named Sodalis, proved to be its closest relative. Sodalis was discovered in 1999 as simbiont in 17 different insect species (most significant are tsetse fly, weevils, bird lice…). Newly discovered bacterial strain was named HS (shorter version of Human Sodalis). When genomes of Sodalis species living in tsetse fly and grain weevils were compared with the genome of the newly discovered species, it was obvious they are related but some interesting difference were noted. Almost half of the genes of the two well known bacterial species were lost or inactivated compared to genome of the HS species. HS provided new insight in the way symbiotic relationships between insects and bacterial species arise. Pathogenic bacteria species could be collected from the environment and domesticated inside certain insect species. Initially it was believed that spreading of the symbiotic bacteria from one insect species to another is possible via mites and other insects that contain symbiotic bacteria in their guts. Observed changes in the genome of the investigated bacteria offered another theory. Plants and animals derived pathogenic bacteria could be easily collected by the insects from their environment. Their further evolution from pathogenic to symbiotic partner is unique and insect specific. Both species need to find a way to adjust to a newly created community. Bacteria will lose virulent genes and this change will guarantee successful spreading of the future bacteria generation to the insect's offspring (instead from one species to another). They will be well fed thanks to food provided by the insect. In return, bacteria produce vitamin K and amino acids that are beneficial for insect nutrition. Also, bacteria could produce toxins to prevent parasitic wasp to lay eggs or fungi to colonize the insect. Loss of large number of bacterial genes resulted from the change in the lifestyle - genes essential for the classic environmental survival became unimportant. These modifications are beneficial for both species.

Close genetic link between Sodalis species and newly discovered HS species inspired scientists to design new solution against insect transmitted diseases. Tsetse fly is carrying a protozoan, well known inducer of the sleeping sickness. Sodalis species live inside the tsetse fly and can’t be grown in the laboratory, but HS species can. HS species could be genetically modified to fit tsetse fly and at the same time be able to induce killing of the protozoan after they are brought back in tsetse fly. By introducing modified bacteria back to the tsetse fly, insect will still be “equipped” with its valuable simbiont and disease transmission will be prevented through protozoan elimination. Same is planned for aphids that transmit viruses responsible for crop sickness (soybeans, alfalfa, peanuts…).

If this method proves to be successful, completely new chapter in treating insect transmitted diseases will open.

Information or “recipe” for every living organism is contained in DNA material (or RNA, in some viral species). DNA is composed of nucleotides aligned in two chains that bond together through complementary base pairing. Result is typical double helix shaped molecule. Every living creature should be proud of his uniqueness - there aren’t two individuals (except identical twins) that have the same DNA. Thanks to that fact, molecular fingerprinting is used for identification of the single individual, forensics can identify suspects, and paternity test could be performed … Growing number of experiments use DNA for gathering different kind of information. Since DNA material is able to survive long period of times, excavation of the various plant or animal remains could tell us a lot of different stories about past on the Earth.

Ancient DNA represents DNA material extracted from old biological samples. Unlike classical DNA analysis, these specimens are of less quality. Archeological discoveries of different animal and plant materials precede DNA analysis. Even though DNA is present in each cell of the living organism, decomposition of the body after death limits the sources that could provide sufficient DNA for the further analysis. In the rare situations when body is entrapped in the ice or amber, high quality and quantity DNA is available. Various insects, plants and bacterial species were successfully investigated after DNA was extracted from amber entrapped specimens. For animal species, usual source of DNA are bones and teeth. Weather conditions (especially temperature and moisture) greatly affect the speed of DNA decay. At temperature of -5 Celsius, mitochondrial DNA is degraded to 1 base pair after 6.830.000 years. Degradation of the nuclear DNA is two times faster than mitochondrial. Using PCR method, scientists were able to multiply and investigate some very old samples dating back from Cretaceous period (145-66 million years ago). Not all ancient DNA samples are million years old. Some ancient DNA analysis investigates remains of much younger origin.

One recently published article investigates climate changes based on analysis of the ancient urine. Rock hyrax is cute little creature that looks like a rodent but is actually more closely related to the elephant. They inhabit rocky environment in Sub-Saharan Africa and Middle East. These social animals have specially designated area serving as mutual (communal) toilets. They are used for years, containing urine samples of a lot of hyrax generations. Urine crystallizes in time, forming stratified accumulations known as middens. Scientists found well preserved 10 thousands year old African middens that could provide more insight in climate changes associated with the hyrax habitat. Collected samples were investigated for organic molecules, metabolites and plant derived molecules. Forensic DNA analysis provided more information on the type of diet they have in the past revealing what plants were available 30.000 years ago. Since plant species are typical representatives of the each climate zone, list of available species on the hyrax menu precisely inform scientist which climate type existed 30.000 years ago. Middens were used for pollen analysis as well. That analysis increased the accuracy of predicted climate type. Given results showed that southern African climate underwent series of complex climate changes after last ice age (~20 000 years ago). Future experiments will investigate changes middens undergo when exposed to computerized simulations of past climate changes. Scientists are hoping that provided information would be helpful in revealing mysteries behind fast and unpredicted weather changes in this dynamic environment.

Another location and another set of animal excrements also provided evidence on previously lived flora and fauna. North West area of Australian continent is arid and any kind of old DNA is hard to find. However, scientists managed to found 700 - 30.000 years old samples of urine, fecal matter, hair, bones and eggshells cemented together in three locations. Different species (now extinct common brushtail possum and various arid grasses) that inhabited Western Australia were easily detected thanks to genetic analysis. Previous investigations focused on carbon dating, macrofossils and pollen identification; DNA analysis expanded previous data and helped in creating final image of the environment from the past.

Analyses of this kind are especially important for endangered species. Future conservation plans and efforts will work better if scientists become fully familiar with extinct species and be able to compare existing environmental data with the ones from the past.

All biochemical processes in the human body are tightly associated with gene expression. When some elements in this complex machinery doesn’t work properly, whole cascade of events will be disturbed, resulting in some kind of pathology. Mutated genes (carrying altered information) could be inherited. List of inherited conditions is long and well studied. Besides classical inherited disorders, a lot of pathologies arise during life. Mechanisms and/or triggers for a lot of different disorders are still waiting to be discovered. Most experiments are focused on DNA material and factors (both intrinsic and extrinsic) that are disturbing various processes on the molecular level. Mostly used model organisms for genetic experiments are fruit fly (Drosophila melanogaster). They are small, have a short and well known life cycle, and could be easily cultivated in the laboratory. Although it may look that insects don’t have much in common with humans, same ancestor and highly conserved genetic sequences allow scientists to analyze wide range of human disorders using Drosophila's genetic material. Latest set of valuable information derived from fruit fly experiment could help scientists in the future fight against cancer.

There are more than 200 different cancer types. With 13% of all registered cases, this is the leading cause of death worldwide (one out of 4 deaths in USA is cancer related). Cancer could affect all body parts, and most commonly affected organs are liver, lungs, stomach, colon, rectum, cervics. Some people have high predisposition to develop certain type of carcinoma (genetically inherited). External factors could greatly accelerate cancer development. Aggressive and toxic chemicals, UV radiation, radioactive elements, injuries, viruses… are usual cancerogenesis triggers. Removal of the cancerous tissue, chemotherapy and immune system boosting are only solutions for people diagnosed with cancer, but chances of winning the battle against the cancer are still small. Metastases are main reason of death because vital organs became affected when cancer start to spread. According to current statistics, number of diagnosed cases will continue rising and it is estimated that number of cancer related deaths will reach 13.1 million by 2030 (in 2008, “just” 7.6 million deaths were cancer related).

Scientists of the Stowers Institute for Medical Research investigate molecular mechanism behind human disease. They recently discovered and published unknown facts associated with cancer pathogenesis. Fruit fly was used as a model organism. Prior genetic expression, DNA needs to be uncoiled so that the transcriptional factors and other proteins could easily approach gene of interest. Methylation and demethylation will determine if “path” to the DNA molecule will be passable. These processes are associated with certain amino acids in histones. Histone complexes are responsible for DNA condensation. Usually, demethylation of histone amino acid residues result in activation of the genetic expression, while methylation prevents genetic expression (repression). Exception from this rule is seen with methylation of the lysine and arginine amino acid residues. When lysine 4 on the histone 3 (H3K4) is methylated - expression is allowed. Same could be applied with arginine residue on histone 3 (H3) and 4 (H4). Protein named Set1/COMPASS induces methylation of the H3K4 complex. It can be mono-, di- or trimethylated, which will determine the potential of genetic enhancer to approach DNA molecule. Trimethylation is associated with transcriptionally active genes. H3K4 monomethylation is associated with genetic expression in the tissue specific manner. Yeast genome has one COMPASS methylase, human genome contains 6 different families while drosophila genome contains 3 COMPASS families. Scientists from the Stowers Institute tested importance of each family by silencing their activity and observing further genetic expression patterns. When Trr complex (short version of Trithorax-related) was silenced, H3K4 methylation was decreased in the whole genome. Silencing the remaining two families didn’t provide the same effect. Further analysis of the Trr complex showed that it is closely associated with the enhancer (activator) of the genetic expression. Without Trr complex, enhancer couldn’t be activated and genetic expression will be suppressed. Two mutated forms of the genes MLL3 and MLL4 are often present in numerous cancer types (lymphomas, colorectal cancer, medulloblastoma, breast cancer) and they structurally highly resemble Trr complex. Using mouse fibroblast lacking MLL3, scientists wanted to examine changes in the methylation. They noticed decreased H3K4 monomethylation (in the enhancer region) when MLL3 was absent. This experiment showed for the first time that MLL3 and MLL4 could be important factors in cancer pathogenesis through activation and deactivation of the specific enhancers.

Precise role and mechanism of action during suppression/activation processes still need to be discovered.

Idea of fully developed and functional robots that will look and act like humans is not new. People are fascinated by the idea of having their own electronic replica that could perform each task they normally do. According to a lot of Sci-Fi movies, our life would be much easier with robots. Creation of humanoid robot may look like an easy thing to do, but so far - only robots able to perform simple tasks are developed. Those robots don’t contain living parts, they are 100% made of electronics. They are very helpful, especially in medical field. For example, medical snake robot is used for minimally invasive cardiac surgery; it is under the full control of the surgeon during operative procedure.

Fully humanoid robots are still waiting to be developed due to complex human physiology, anatomy and functionality, based on perfectly balanced interaction between millions of cells. Robot that contains both electronic and living part is biorobot. Discipline dealing with biorobots is called biorobotics and it could be described as collective effort of cybernetics, bionics and cellular (genetic) engineering to create artificial organism. Synthetic biology and bionanotechnology are also tightly associated and helpful in the field of biorobotics. While creating artificial organism, scientists work on incorporating natural (biochemical) processes and living cells into electronic device.

Signal transduction propagates the body, affects cell communication, metabolism and all biochemical processes. It is essential for normal functioning of all living organisms. Different type of molecules could act like signal transducers: hormones, neurotransmitters, proteins... Cellular response is triggered when signaling molecule binds directly to the cellular receptor or when enters the cell and induce physiological response inside. Molecules that induce cellular response directly by entering the cell are called second messengers. Nitric oxide (NO) is typical representative of that group. It remains in gaseous form in each cellular environment and enters the cell via diffusion. It is synthesized from arginine and oxygen thanks to nitric oxide synthase enzyme. Once NO enters the cell, it triggers another second messenger - cGMP through the activation of the soluble guanylyl cyclase. List of cascade events and biological processes associated with NO is long; some of the most important are apoptosis, erections, vasodilation, muscle relaxation…

NO is selected as signal transduction molecule for the following biorobotics study due to diversity of roles that plays in living organisms. This is the first time that electronic part wasn’t designed to fit biologic system (cellular part of the robot) -quite opposite thing was performed - cellular component was modified to fit electronic part of the robot. Nitric oxide synthase (eNOS enzyme) was genetically altered. Using the plasmid, light–oxygen–voltage domain was inserted in eNOS gene, resulting in photoactive enzyme formation. Genetically altered cells were attached to platinum electrode. Light triggered enzymatic activity and resulted in NO production. Electrode used in the study was modified by covering the surface with NO sensitive layer that will allow transformation of the generated chemical signals into electric signals. Chinese ovary cells cell line (CHO-K1) was used, simply because these cells express high protein level. Proportion between produced NO and generated electric impulses was easily calculated. This is the first biorobotic model showing successfully established signaling transduction: optical signals trigger chemical signals that are converted in electric signals at the end. Another important characteristic of this model is the ability to self-replicate (since it is formed out of living cells) and to combine incoming signals and calculate overall signal. Described experiment is part of a larger study dealing with bio-hybrid robot called “Cyberplasm”. That robot will be first robot able to swim. Modulated (photosensitive) cells will act like eyes and guide robot in different directions according to the provided light. Scientists are hoping that this robot would be of great help with contaminated water and harsh chemicals. Goal will be to swim, collect needed data and deliver them back. “Cyberplasm” project is still not finished. For now, this robot assembles piece by piece and hopefully, it will not pass much time before it become fully developed.

Next step in biorobotics is establishment of the cellular communication. Besides technical improvements, list of biorobotic associated purposes will probably expand in the near future.

Plants could be useful source of biofuel. Ethanol can be derived from lignocelluloses (structural element of the cell wall in plants), from inedible part of the plants, wood or grass. Cellulosic ethanol undergoes longer processing than starch ethanol derived from corn or cane sugar. Advantage of this type of biofuel is mainly in the availability of biomass used and its type; plants used for cellulosic ethanol production are more diverse and have greater productivity compared to ones used in conventional biofuel production. Switchgrass (Panicum virgatum) and Miscanthus (Miscanthus x giganteus) are mostly used due to high productivity rate. Also, cellulosic ethanol decreases green house emission by 85% compared to reformulated gasoline and it is more eco-friendly than starch ethanol (doesn’t affect green house emission at all).

Main obstacle in cellulosic ethanol production lays in complicated extraction procedure. Two mechanisms are applied today: enzymatically triggered cellulolysis (by degrading the cellulose to glucose that will be fermented to ethanol later) and gasification (converting the lignocellulose to carbon monoxide and hydrogen that will be transformed to ethanol via fermentation or chemical catalysis). Due to large size and rigid structure, biomass used for cellulosic ethanol production needs to be processed physically first. This procedure will reduce biomass size. Lignin and cellulose are tightly bound with one another and chemical pretreatment that will release cellulose is essential to provide successful hydrolysis and further processing. By removing chemical barrier, enzymes could digest cellulose maximally and this process is called cellulose liberalization. Hydrolysis can be achieved chemically (using acids) or enzymatically (usually fungi derived enzymes). Enzymes used in hydrolysis have been improved over the years and some companies are developing genetically modified fungi producing enzymes such as cellulose, hemicellulase, and xylanase. Saccharomyces cerevisiae (baking yeast) is mostly used in brewery industry for sugar fermentation. Yeast is often and widely used microorganism that could survive harsh environmental conditions (bacterial metabolites, low pH, and high ethanol level for example). Genetically improved, it can produce ethanol from xylose and arabinose (or from both sugars). Beside yeast, Escherichia coli and Zymomonas mobilis will probably be genetically modified to enhance their fermentation potential for future biofuel productions.

Cellulosic ethanol production could be accelerated thanks to group of scientists and their recent discoveries. Scientists wanted to explore complex structure of the cell and its structural element, and reveal weak points in the currently used method of cellulose ethanol production and finally eliminate them. Using special imagining techniques, cellular architecture was examined on the nanoscale. Enzymes are one of the most important factors in successful ethanol production as they degrade biomass and speed up chemical reactions. This study especially focused on the currently used enzymes to investigate their mechanisms of action and assess potential weak points. Fungus and bacterium derived enzymes were used for evaluation of the cell wall degradation and sugar intermediate production. Exact location of enzymes responsible for degradation and exact digestion spots were discovered. Bacterial enzymes used are organized in large scaffolds prior attacking the cell wall, while fungi derived enzymes attack cellular wall individually. In both approaches, non-sugar particle (lignin) prevents the enzyme from reaching the target (cellulose). Pretreatment that could remove lignin without disturbing established cellular structure would be the optimal for cellulosic ethanol production. Scientists compared the model with large house that needs to be remodeled. If all doors in the house would be removed or left open, workers would be able to reach each room (and desired wall) easily, without wasting time. That approach is opposite to currently used pretreatment method where all spongier carbohydrates are usually removed, resulting in the structure that could easily lose its stability and collapse. When cellular structure is disrupted, resulted half “demolished house” couldn't be easily approached or remodeled. Enzymes work perfectly if they are dealing with structures in their natural environment. By removing unwanted materials from the cellular wall (lignin) without disturbing its biochemical properties and main “skeleton”, enzymes would have optimal working surface and speed of work would be sufficiently increased.

This discovery could optimize biofuel production by changing the direction of the future experiments and operating procedures. Further experiments and even deeper analysis of cellular dynamic and structure will provide more valuable information that could be beneficial for the cellulosic ethanol production.

Hi all,
How do predict what types of secondary structure (left alpha helices, right alpha helices, parallel beta sheet, antiparallel beta sheet) from amino acid sequence?
Reply as soon as possible

Gluten is a plant protein. It provides elasticity, shape and chewy texture of pastas and other products made of plants containing gluten such as wheat, barley and ray. Prolamin and gluten are main wheat proteins (constitute 80% of total protein content). Plant uses those proteins as energy source during germination. They are equally good energy source for people. Wheat is a staple food for 20% of the people around the world. Gluten is especially important for vegetarians because plant proteins are only source of proteins for them. Besides being consumed directly, plant proteins are used as additives for numerous dietary products: to improve physical characteristic of the food, its consistency, texture, quantity…. Product labels usually contain information about gluten content. This protein is also used in cosmetic industry (hair and dermatology products) and in pet food production.

Gluten is important nutritional ingredient, but it is associated with couple of disorders that affect a lot of people around the globe. Those are wheat allergy, celiac disease and gluten sensitivity. Wheat allergy results from increased sensitivity toward some of the wheat proteins; it is manifested by nausea, urticaria, atopy… as a consequence of increased level of IgE and mast cells. Both prolamin and gluten might trigger allergy reaction, but gluten induced wheat allergy is more common. Gluten molecule is composed of gliadin and glutinen fractions. There are 9 subunits of low molecular weight glutinen that are known triggers of allergy reaction. When gluten sensitivity exists, body reacts to gliadin fraction by producing large amount of anti-gliadin antibodies (IgA and IgG). Symptoms of gluten sensitivity are bloating, diarrhea, stomach discomfort and pain. Gluten sensitivity is a less severe than celiac disease - severe autoimmune disorder of the small intestine. Celiac disorder can be confirmed through biopsy and blood analysis. Typical manifestations of celiac disease are fatigue, nausea and diarrhea, result of intestinal microvillus shortening. Disorder can develop at any time during the lifetime and so far, only solution for people diagnosed with celiac disease is strict gluten free diet. Between 0.5 and 1% of people in the USA and 22.4 million of people around the world are diagnosed with celiac disorder.

Gluten can be found everywhere, both in products that normally contain gluten (wheat and its products) and products that are boosted with gluten during industrial processing (yogurt, ice cream…). Due to increased rate of celiac disease in modern society, a lot of food companies oriented toward gluten free food production. While waiting for gluten free industry to develop, scientists are looking for a solution through genetic engineering of the plants. Team of international scientists recently published article on the latest achievement in this field, revealing that gluten free wheat is successfully created.

To obtain gluten free plant, scientists first had to identify mechanism of gluten production. This protein is essential nutrient during embryonal development. Gluten is produced after couple of genes are expressed. Enzyme that triggers expression of gluten associated genes is called DEMETER (DME). DME encodes 5-methylcytosine DNA glycosylase, enzyme responsible for transcriptional activation of gliadins and low molecular weight glutenins (via demethylation of their promoter site). When DME was suppressed by 85.6%, gluten production in the endosperm was decreased by 76.4%.

Study focused on DME homeologs sequences, their evolutionary changes, similarity between different plant species and potential silencing methods... Result was first gluten free plant. In the phylogenetic analysis, when DME sequences were compared between rice, Arabidopsis, barley, wheat and sorgum, it was shown that they are highly (evolutionary) conserved and homology between examined species proved to be high. DME homeologs are cytogenetically mapped in the barley and wheat (located on chromosome 5 in both species) and cloned. They are responsible for complex transcriptional regulation of gliadins and low molecular weight glutenins. Inverted repeats (known as hair pins) were used to “disable” DME expression. Result was decreased level of alpha, beta and gamma glutenins and glutadins in developing endosperm. Depending on the type of hair pin used and DME homeologs transformed, expression of different glutenins and glutadins family members were suppressed. Ideal plant would be one with completely knockout DME homeologs sequences, resulting in gluten 100% free seed. This is a goal for some future experiments.

After first gluten (almost) free plant is created, next step is assessment of its safety in transgenic mice, gluten sensitivity apes and finally in patients diagnosed with celiac disease.

Domestic pig (Sus scrofa) originates from the wild boar. It is domesticated ~13 000 years BC. People cultivate pigs mainly for their meat. Their bones and hair are used for brush production. Some types of pigs are popular nowadays as pets. Pigs are intelligent animals that share a lot of anatomical similarities with humans, which is the reason they are used for organ transplantations. Domesticated pigs could be found everywhere. They are the most numerous large mammals on the Earth with over 1 billion pigs present at each moment. Their genome is finally decoded.

Last mutual ancestor for pig and human lived ~ 97 million years ago. Sus scrofa emerged in East Asia ~ 3.5 million years ago. Pig has 18 autosomal chromosome pairs and one sex determining pair. There are 21,640 protein coding genes, and 1,478 mitochondrial genes. Beside protein coding genes, 2,965 non-coding RNA sequences and 380 pseudogenes were identified. 15,072 protein coding sequences are mutual for various species and 3,959 are pig specific. Identification of the porcine endogenous retroviruses (PERVs) was important because they could be transfered to humans during organ transplantations. Their number exceeds 175 in porcine genome. Analysis of 9,000 orthologs (genes that share same ancestor) in six species (dog, human, mouse, horse, cow and pig) provided info on genetic modulation during evolution. 311 proteins in pig were marked as quickly evolving. Genes associated with psychiatric disorders, various cancers, cardiovascular disease, immune diseases and metabolic and neurological disease in humans were easily located in the porcine genome. Altered proteins typical for certain human diseases were analyzed in pigs also. Aligned human and pig orthologous proteins showed 1,393,618 positions where amino acid differ. 112 substitutions are associated with human diseases such as: diabetes, obesity, Parkinson’s disease, Alzheimer’s disease, dyslexia… 32,548 non-sense mutations identified in 48 pigs revealed 6 protein variant that induce disease in humans. Another 157 non-sense mutations in 142 genes result in following human diseases: corneal dystrophy, hemolytic anemia, epidermolysis bullosa, laryngoonychocutaneous syndrome, paroxysmal nonkinesigenic dyskinesia 1, mental retardation, susceptibility to autoimmune disease development and sepsis, congenital contractural arachnodactyly, citrullinemia and pancreatic carcinoma.

Genetic similarity between humans and pigs will help scientists find better therapeutic solutions for existing diseases. Even before genetic similarity between pigs and humans was established, these animals were used as biomodels because their physiology, biochemistry and anatomy match perfectly to humans.

Retinitis pigmentosa is severe degenerative ocular disorder associated with progressive loss of rods, leading to night blindness first (usually in puberty), followed by progressive loss of cones resulting in complete blindness around the age of 40. It is not curable, and until recently, animal model used for disease analysis was transgenic mouse. Besides being too small for surgical operations, number of cones in two species is different. Development of a transgenic pig helped experiments a lot. Disease phenotype resembles human disease completely; first symptoms appear in 5-6 months old pig and complete disease progression is achieved after 20 months.

Cystic fibrosis is another example of severe genetic disorder that was easily established in the pig model. Disease disrupts normal functioning of lungs, pancreas and intestines, and leads to fibrous scars and cyst formation. It is characteristic for caucasians; one out of 25 European descendents carry allele for cystic fibrosis resulting in high prevalence of disease in European Union (one out of 2000-3000 babies will develop cystic fibrosis). Few treatment methods exist but disorder is not curable yet. Again, mice weren’t the perfect models for cystic fibrosis analysis because they don’t exhibit lung and pancreatic disorders (responsible for highest morbidity and mortality rate in humans). Transgenic pigs with cystic fibrosis were easily developed. Viral vector carrying altered genetic particle (delta F508 mutation, responsible for cystic fibrosis) will target cystic fibrosis transmembrane receptor gene in pig fetal fibroblast. Nucleus from the modified fibroblasts will be transferred to oocyte prior fertilization. Once heterozygous pigs (carrying altered cystic fibrosis transmembrane receptor gene) are born, they could serve as ideal models for future studies in the field of cystic fibrosis.

Humans and pigs are tightly connected for thousands of years. These animals were exploited in numerous ways throughout the history. Now when their genome is decoded they will probably accelerate research associated with untreatable human diseases and potentially provide medical solutions in the near future.

Antibiotics are naturally or synthetically produced drugs used for treatment of wide spectrum of microorganisms. As a result of uncontrolled antibiotics use, modern society faced antibiotic resistance phenomenon. Genes providing resistance could be transferred inside one or in between different species. Newly developed resistant organism is called superbug and it is usually resistant to more than one antibiotic. Number of newly created drugs couldn’t follow fast tempo of antibiotic resistance development. Medicine doesn’t have a solution for this problem yet; most experiments focused on this issue are dealing with genetic analysis of the resistant bacterial strains. Discovery of resistant microorganisms at the place where they were least expected, could change direction of the further investigation.

Lechuguilla cave is located in the Carlsbad Caverns National Park in New Mexico. It is discovered in 1986 and it is 7th longest known cave (>209 km in length). Due to unique appearance, only specially approved scientific research teams can cross its borders and explore it further. Besides interesting geological formation and cave decorations, chemolithoautotrophic bacteria were found inside. Laboratory experiments on sampled bacterial films revealed one important characteristic - they are antibiotic resistant. Out of 500 bacterial strains, 93 managed to survive medium containing 26 different antibiotics. 70% of 93 tested strains can grow when exposed to 3 or 4 different classes of antibiotics. 3 strains proved to be distant relatives of anthrax species and they managed to survive when exposed to 14 out of 26 tested antibiotics.

Lenchuguilla cave is old between 4 and 7 million years. Specific location and isolated entrance prevented water and modern era inventions from reaching the cave. That means that organisms in the cave have never been exposed to drugs, chemicals and other substances and they didn’t have the reason to develop antibiotic resistance for successful survival in the past. Antibiotic resistance was considered to be consequence of genetic mutation that allows bacterium to survive harsh environmental conditions. Mutated genes are transferred to the next generation through simple cell division, horizontally via plasmids or by viruses. This experiment showed that ancient non-pathogenic bacterial strains contain genes that provide antibiotics resistance even if they never have been exposed to antibiotics. New hypothesis about antibiotic resistant genes emerged: if those genes are not result of genetic mutation as a consequence of selective natural pressure to survive negative environmental conditions, than those genes must have been created during long evolutionary period, probably lasting thousands of years, for some other reason. Question is: why they developed and how those genes managed to reach pathogen strains of bacteria that develop antibiotic resistance in hospitals and animal farms today? Couple theories could explain this riddle. Maybe antibiotic resistant genes are created to provide some other beneficial characteristic essential for bacterial survival and ability to survive antibiotic exposure is simply a coincidence (related traits). Maybe cave contains some natural antibiotic that are still not found. Or, maybe, antibiotic resistant genes emerged when different bacterial species fight against each another in “chemical war” for food and environment. No matter which theory is correct, this revelation is important for future experiments focused on bacterial resistance. Detailed genetic analysis of the newly discovered bacterial strains will provide necessary information on their survival mechanism and possibly help combat future bacterial resistance cases.

Microorganisms resistant to various antibiotics could be seen everywhere in the nature. Unlike Lenchuguilla cave, they are result of careless and incautious human behavior. Garbage and its disposal is problem even when it comes to the medical waste. A lot of drugs end up in the sewage and enter feeding chain easily. Drugs could reach birds living on Antarctica or sharks swimming in the sea. Bacteria found in those animals prove that modified and fortified microorganisms could induce disaster in the natural population of animals as they couldn’t be eliminated by mechanisms that were efficient in the past. Besides affecting one animal species, they could be transferred from one organism to another and even end up in human plate.

Unfortunately, in the battle against antibiotic resistance, microorganisms are still winning. If we want to save human population and the ecosystems throughout the world, we need to find fast and efficient method as soon as possible.

When you think about successful business and innovations in biotechnology field, first thing that comes to your mind is probably a clever man surrounded by the group of scientists. Women, especially those on the leading positions, are still minority in the biotech industry. Luckily, this trend is changing and number of intelligent and skillful women in biotech industry is increasing each year. Here’s the list of most influential women in biotech industry created by Ryan McBride and John Carroll of FierceBiotech.

Kathryn Biberstein, Alkermes

Kathryn is senior VP and chief compliance officer at Alkermes. Before joining Alkermes, she was working as a general counsel for Merck Serono in Switzerland. Kathryn is successful negotiator with long multinational experience in biotech industry. She speaks French, German and English fluently. One of the greatest achievements was doubling Alkermes business by acquiring Elan Drug Technologies for 1 billion dollars in 2011.

Abbie Celniker, Eleven Biotherapeutics

Abbie is CEO at Eleven Biotherapeutics. She holds a PhD in molecular biology. Her career started in Genentech and continued in a couple of respected pharmaceutical companies such as Wyeth, Millennium and Novartis during the next two decades. After improving Taligen Therapeutics business, she sold its key assets for 111 million dollars to Alexion Therapeutics. Besides dealing with business team and investors, Abbie is currently focused on protein engineering and immunotherapeutic development.

Kathleen Sereda Glaub, Plexxikon

Kathleen is president at Plexxikon. Prior Plexxikon, she was working at Genentech and Cell Genesys. Thanks to collaboration and partnering with various pharmaceutical companies, her group at Plexxikon managed to collect over 200 million dollars worth funding. Also, she helped conclude buyout pact with Daiichi Sankyo (for 1 billion dollars) and improved marketing and sales strategies for the newly approved melanoma drug Zelboraf.

Mary Lynne Hedley, Tesaro

Mary Lynnes is CSO and co-founder at Tesaro. After post-doctoral studies at Harvard, she started her own small pharmaceutical company, Zycos, focused on cancer and anti-viral drug development. Company was later sold to MGI Pharma where she continued working in the R&D sector. MGI was acquired by Eisai for 3,9 billion dollars in 2008. At Tesaro, Dr. Hedley is focused on cancer drug and supportive care development.

Bahija Jallal, MedImmune

Before joining MedImmune, Bahija served as VP of drug development at Chiron. Today, she is head of R&D at Medimmune, responsible for 2000 investigators working on 140 R&D programs in Gaithersburg, Maryland and Cambridge, UK.

Kiran Mazumdar-Shaw, Biocon

Kiran is founder and chief of Biocon, biggest Indian biotech company. They are focused on the insulin production and peptide drug development (anti-CD6 for psoriasis). Thanks to successful collaboration with USA pharmaceutical companies, drugs could reach market faster. Deal with Pfizer provides the company 200 million dollars for biosimilar insulin development.

Susan Molineaux, Calithera Biosciences

Susan is CEO at Calithera Biosciences. She started her career in Merck, New Jersey, followed by Rigel Pharmaceuticals, where she worked as VP of biology, focused on drug research. Soon after, she moved to Proteolix. From the drug development, she switched to biotech menagment working as CEO at Calithera. Also, she is implicated in mentoring the middle school students in the San Fransisco area in a program known as We Teach Science.

Julie Overbaugh, Fred Hutchinson Cancer Research Center

Julie is a scientist at Fred Hutchinson Cancer Research Center. She is graduated biochemist, focused on HIV/AIDS research. She collaborates closely with epidemiologist and scientists in Kenya (area severely hit by HIV virus). Julie runs a laboratory, where she trains and educates a lot of future scientists, beside regular research work.

Anna Protopapas, Takeda

Anna is executive VP at Takeda. She entered biotech industry with master degree in chemical engineering. Her career started in Morten Metal Technology and Proctor & Gamble, followed by Millennium pharmaceuticals. Takeda acquired Millennium for 8.9 billion dollars in 2008 (she remained at the position of the business executive after company was merged), and Nycomed for 13.7 billion dollars in 2011. Both acquisitions were successfully closed thanks to Anna's excellent negotiation skills.

Laura Shawver, Cleave Biosciences

Laura is CEO at Cleave Biosciences. She started career as a molecular biologist at Triton. Later she worked as president at Sugen. Laura was in charge for diabetes focused research at Phenomix that shut down after one of the financial partners went out. She continue further biotech career in Cleave Biosciences. After being diagnosed with ovarian cancer, she found non-profit charity organization focused on molecular screening and new therapeutics development to help women dealing with recurrent carcinoma to find a better treatment solution.

Hopefully, list of significant and valuable women in biotech industry will continue growing.

Reference: www.fiercebiotech.com

Summary: All teratogens are toxins and not all toxins are teratogens

The drug or chemical with a potential to affect the fetus resulting in any malformation of the structure is called as teratogen. Teratogen is different from a toxicant as the former brings about any undesirable effect at the cellular level of the unborn fetus and during the organ formation and the later is known to affect at any stage of development. The effect of teratogen is not noticed once the organ formation of the fetus is completed. Hence Teratogen can be called as toxins of the fetus in the womb affecting the generative stage. The specialized subject to study the congenital malformation is called as Teratology and the substance responsible for causing malformation is called as teratogen.

There are various factors responsible for the congenital malformation. Heredity, presence of any particular infection in the pregnant women in early terms of pregnancy (Rubella infection is a good example), Nutritive deficit carrying mother, physical parameters like temperature and radiation and other environmental factors like pollutants present in air and water and chemicals are the factors to be considered while finding out the reason for either child born with defect or death of the fetus in the womb.

The teratogen acts in several ways. It affects the zygote resulting in the inhibition of further growth or cause mutation in the zygote. Teratogen is known to block any one of the steps in fertilization thus preventing the formation of the embryo. Also it has potential effect on the embryo, interferes in the cell division. The effect of teratogen is observed even at the time of implantation. Implantation is the process of embryo embedding in the endometrial lining of the uterus and exposure to teratogen at this stage may prevent the implantation resulting in the embryo leaving the uterus. Also teratogenic chemicals interfere in the organ development of the fetus causing malformation. Any undesirable effect on the fetus by a chemical after organ formation is completed is explained in the terms of toxicity and teratogen does not come into picture for the effects caused at this stage.

To identify and understand the teratogens affecting humans, the substance is initially experimented on laboratory animals. The selection of animal for this procedure is quite complicated as any animal tested should be closer to humans in the way that chemical is metabolized in humans, should have placenta similar to humans and the similar pregnancy term as that of humans and should be able to produce many offspring in order to understand the effects of the teratogen in subsequent generation. Also the size of the animal and the testing cost are other factors to be considered while selecting a test animal to study the effect of teratogens.

Also the route of administration of the drug under evaluation is important. The most preferred route of administration in the test animal is through peritoneal injection. As to evaluate the effect of different dosage of drug at different stages of gestation the time of injection of the drug to the test animal and the dosage selection are very crucial factors. After the full term the pups of the test animal are observed for three types of malformation like malformation seen visually, malformation in soft tissues and anomaly in the bone. The effects of teratogen are observed only in the stages of development whereas the effect of a toxicant is prenatal as well as postnatal.

Some of the drugs classified to be teratogenic to humans are Thalidomide, Vitamin D, androgen, estrogen, chemical agents used in chemotherapy and some of the antimetabolites and alkylating compounds. Few examples of compounds with teratogenic threats to humans are quinine, meclizine, phenmetrazine, tetracycline and cyclophosphamide. Examples of the beneficial teratogenic drug detected in animals are salicylates, Vitamin A, Vitamin D, adrenocorticoids, insulin and sulfonylureas.

It is not necessary that all the teratogens are chemicals/drugs, even radiation, some metals, minerals and pesticides are teratogens. X-ray is identified as a potential teratogen. Teratogenic effects of molybdenum, lead, zinc and manganese were identified in different animals. There is no evident of Teratogenic effect of pesticides in humans. The study by Green and team in 1967 reported the teratogenic effect of DDT, heptachlor, aldrin and endrin in eggs of chicken.

In simpler terms it can be explained as 'All teratogens are toxins and not all toxins are teratogens'.

Living creatures adjust their biological activities according to the local environmental factors. Thanks to those factors, animals could determine perfect time to eat, sleep, mate, migrate… Pattern of behavior is changing during the day, week or season. Day light is the most important factor that affects biological activity on a daily basis. Established rhythm of behavior is known as circadian rhythm and it is driven by circadian clock. This “clock” is endogenous and it is unique for each individual. People are usually classified as early birds or night owls. No matter which category you belong, latest discoveries reveal genetic background behind this phenomenon.

Suprachiasmatic nucleus is located in the hypothalamus. This organ receives information about day light from retina via tight neuronal connection (retinohypothalamic track). After day light information is processed, it will be sent to a pineal gland that is responsible for melatonin production. Melatonin is hormone essential for sleeping. Level of melatonin is highest in the night and lowest in the morning. This hormone is important marker for sleep-wake rhythm screening. Electric light in the evening can affect normal circadian rhythm by delaying sleeping phase. Every man has its own rhythm and not all people demand 7 hours of sleep to achieve body refreshment and prepare themselves for the up-coming daily activities. Sleep duration is dropping down with age and old people usually sleep just few hours per day.

Scientists from the Neurological department of the University of Toronto investigated sleeping patterns of older people and discovered connection between genotypes and circadian rhythm. It was shown that genotype could even predispose time of person’s death. Original idea of the study was to investigate potential triggers of Alzheimer’s and Parkinson’s disease in the certain age group. Since all patients were genotyped, Dr. Lim (leader of the project) decided to expand study goals and explore connection between sleep-wake patterns and specific genotypes. This was large study conducted on the 1200 individuals having 65 years or more. It lasted over a decade and participants donated their brains for further post mortem analysis. Period 1 and Period 2 genes are well known genes, recognized as important for light entrapment and establishment of normal sleep-wake rhythm. When those genes were altered in experiment with mice, animals couldn’t respond normally to the light changes and sleeping pattern was disrupted. In this study, single nucleotide, located near Period 1 gene, showed slight alteration that correlated with differences in sleep-wake pattern observed between study participants. Adenosine (nucleotide) was found in 60% participants at the mention location while guanine was found in the remaining 40% cases. Since DNA is double helix, chances that adenine will be seen in other chain was 36% (resulting in A-A genotype), chances that guanine will be seen at exact same spot in the other chain was 16% (resulting in G-G genotype) and finally there was 48% chance of having a mixture of adenine and guanine (resulting in A-G genotype). Three described genotypes showed different sleeping patterns. A-A genotype wakes up one hour before G-G genotype and waking time of the A-G is in the middle of the A-A and G-G genotypes. Expression of the Period 1 gene is lower in the individual with G-G genotype during the day when the gene is normally expressed. Since every biological activity is driven by circadian rhythm, Dr. Lim wanted to discover if genes affecting sleep-wake pattern could also affect the time of death. Patients enrolled in the study participated over 15 years and a lot of them died during the study due to natural causes. Closer analysis of brain tissue and genetic material showed direct correlation between most likely time of a death (part of a day) and genotype. Participants with A-A and A-G genotypes passed away around 11 o’clock in the morning and participants with G-G genotype passed away around 6 o’clock in the evening. For the first time, one study showed that circadian rhythm could affect not just the time people will wake up or go to sleep, but the time when they will die.

Further experiments and even more information on this subject would be helpful for people working in shifts, changing time-zone often (and dealing with jet lag) or having trouble with daily tasks organization.

A study on toxicants and factor influencing the toxicity:

Any substance that is known to cause deleterious effect on a biological system upon interacting with the system is called as toxicant and the ability of the substance to bring about such change is described as Toxicity. A substance classified as a toxicant requires a medium or host to exhibit its toxicity and it is not as simple as that for the substance to bring about immediate effect. The expression of toxicity by a toxicant is governed by various factors like nature of the toxicant, the mode of exposure and the biologic system (individual coming in contact with the toxicant).

The chemical and physical nature of a toxicant, presence of any adulterant, stability of the toxicant when stored and in the biological system and the elements used for proper delivery of the toxicant are the factors influencing toxicity classified under the nature of the toxicant. In case of any impurities present along with the toxicant, the chances are that the impurity may itself be more toxic than the toxicant or the impurity may alter the toxicity of the toxicant. Same is the case with the additional compounds used in the formulation of a toxic agent. Also the media used to either dissolve the toxicant or suspend the toxicant for the better mobility influences toxicity which draws a closer observation while selecting the media.

The dose of the toxic agent, the concentration and the quantity of the toxicant, the route and site of administration, the rate of absorption, time of exposure and the frequency and length of exposure are all the exposure related factors governing the toxicity of the toxic agent.

Next factor influencing the toxicity is the biological system. Biological system refers to the animal or the individual who is coming in contact with the toxicant. The internal environment of the individual and the external environment which acts as the habitat for the individual have influence over the toxic agent entering the individual. The internal environment includes the type of species, genetic profile, immunologic profile, the dietary factors, age and gender and health and the existing disease if any. The ill effect produced by a toxin may not be same for all the species. A substance more toxic in one species may be less toxic or may not be toxic in the other.

The genetic profile influencing toxicity is explained by difference in response shown by the rabbits to the drug atropine. Few rabbits were found to have developed effects of the drug whereas few others showed resistance to the drug and the reason for the resistance was explained by the detection of the enzyme atropine esterase in the blood. This experiment validates the role of genetic profile in determining the toxicity. An altered toxic response to the same toxicant by an individual who developed sensitized reactions in response to the same toxicant earlier explains the role of immune system in influencing toxicity. As diet has direct influence over the health, metabolic process, biological function of the body ultimately it also has influence over the toxicity of the toxicant. Effect of toxicants in starved animals, toxicity of the substance in partially fed animals, expression of toxicity by the toxicant in response to altered diets are the various researches conducted on animals to understand the complete relationship between the diet of the animal and its effects on the toxicity of the test element. Though it is a very complex criteria to derive the relationship between different diets and different toxicants, it is understood that toxicity is influenced by diet.

Many experiments have been conducted to validate the effect of sex and hormones on the toxicity. One such experiment is that chloroform was found to be lethal for male mice of specific strain whereas the female mice of the same strain were found to be unaffected. Introducing estrogens to the male mice and introducing androgens to female mice before exposure to chloroform showed altered effects like male mice was protected to an extent and the female mice was found to be susceptible to the effects of chloroform.

Temperature, pressure and radiation are the factors related to external environment influencing the toxicity. Temperature is directly proportional to the toxicity and inversely proportional to the period to develop response. Next the change in pressure builds a stress in the body which may have effect on the toxicity. So it is advisable to consider pressure as a factor while studying the toxicity of an element. The known effects of radiation on the biologic system make it another factor influencing the toxicity.

The effect of one toxicant varies over the other under the above discussed influential parameters making it really a complex matter of subject to understand while studying toxicants.

Recipe for every living creature is encoded in its DNA. Unique genetic combination inherited from parent determines phenotype of the newly created organism. DNA differences are smaller than expect. Out of 30.000 genes present in human genome, 99.9% is mutual for all humans and just 0.1% is unique and specific for each individual. That amount of genetic variability (genetic polymorphism) is responsible for wide range of phenotypical differences that exist in human population. Besides obvious physical differences, the way human body works is individual and specific. Metabolism, sensitivity toward one type of diseases and resistance toward others, effectiveness of given treatment or lack of its effect … are part of the genetic makeup that is unique for each person.

Medicine is developing faster than ever in the past couple of years. Slight genetic differences between people could provide useful information, accelerate treatment and reduce side effect of marketed drugs. Medical field focused on identification and utilization of the patient’s genetic and molecular background aiming to improve medical approach is known as personalized medicine.

Some disorders are genetically predisposed. Breast and ovarian cancers are associated with mutations in BRCA1 and BRCA2 genes. When family member is diagnosed with cancer, genetic testing could show whether altered gene is present (or not) in close relative. Specific mutations are associated with more or less aggressive type of the cancer. When genetic testing reveals “dangerous” form of gene, breasts or ovaries could be removed to prevent cancer development. Also, genetic testing could help determine which patients are suitable for chemotherapy, and which aren’t. It’s estimated that chemotherapy could be reduced by 34% if patients underwent genetic screening before treatment.

Pfizer has specially formed group focused on personalized medicine. Lung cancer statistics is not that bright. Recent experiments showed that life expectancy could be prolonged if genetic profiling is conducted prior therapy. Unselected cancer treatment (universal chemotherapy and radiation) during 5 years resulted in 6-15% survival rate (depending on the disease stage). Molecular targeting brought improvements in the field of lung carcinoma. Xalkori is non-small lung carcinoma selective drug that showed excellent results: partial or complete tumor response was noted in 60% of lung carcinoma cases and tumor shrinkage was noted in 90% of all non-small lung carcinoma cases. Also, life expectancy is prolonged.

Personal medicine provides useful information for physicians before prescribing the drug. Drug metabolism is controlled by various enzymes. Thanks to phenomenon known as single nucleotide polymorphism, expressed proteins could differ in one or more amino acids resulting in end product with different biochemical properties. When patient is familiar with its genetic polymorphism, doctor can prescribe certain dose or specific drugs that will be metabolized without serious side effects. Conventional approach of drug development (for the wide masses) is expensive and non-economic. Around 11 million dollars are spent every year for 15 new drugs that will induce more or less side effects (depending on the patient’s genetic profile) or prove to be ineffective for targeted disorder. Genetic identification of the patients would save money and time by pointing out the best therapeutic solution for each individual.

Number of drugs that are specifically tailored to fit patient’s genetic profile is increasing each year. From the 13 drugs marketed in 2006, number increased to 72 drugs of personalized medicine kind in 2011. 33 biomarkers are included in FDA's drug labels.

Personalized medicine is growing industry. Saliva is perfect source of DNA for the in-house testing. After delivering saliva to the specifically designed kit, it should be sent to a licensed laboratory for further processing. This method is not expensive and it is relatively fast (laboratory will send you results of genetic profiling in couple of weeks). Like every other medical innovation, this one couldn’t be implemented over the night. Not all doctors are thrilled that they will have to analyze another piece of paper prior prescribing the drug and some of them don’t find genetic profiling useful at all (16%). Electronic medicinal files are already in use in most hospitals over the world. By 2015, hospitals and healthcare professionals should collect as much molecular and genetic profiles as possible. Large (global) database could be used for targeted drug discovery and safer application of the already marketed drugs.

What is Alzheimer's Disease? And why is it called so?
Alzheimer's causes memory loss and is more prevalent among older people. Cure and causes of Alzheimer's disease are discussed in this article.



Symptoms and Severity of Alzheimer's Disease:
Dr. Alzheimer observed that Auguste had no sense of time or place. There was nearly total loss of memory about the details of her own life. The answers given by her to the questions asked were senseless and incoherent. There were frequent mood swings between anxiety, mistrust, withdrawal and 'whininess'! A part of pity as well as curiousness was that "she was aware of her helplessness, and would utter "Oh, God!", and, "I have lost myself, so to say".

Causes of Alzheimer's Disease

What leads to memory loss, fits, mood swings, screaming (or total dementia) in Alzheimer's disease has been very well researched. But what exactly leads to that particular state has been eluding the scientific community till date. Speculations though have always been pointed towards: Environmental factors, genetic pre-disposition (less than 5% cases owed to genetic causes), lifestyle etc.
Anatomical causes of Alzheimer's disease (that have been very well researched and established) include the following:

• Damage and death of brain cells
  
• Very few brain cells (neurons) and very few inter-neuronal connections among surviving cells
  
• Significant brain shrinkage
  

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Autopsy of brain tissue of Alzheimer affected patients has revealed two types of abnormalities under microscope, which have become the index (hallmark) of the disease:

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Tangles: 

Following videos should give you an idea about Alzheimer progression due to plaques and tangles:




Diagnosis and Treatment of Alzheimer's Disease

Alzheimer’s disease can be diagnosed using couple of techniques:
A. Brain imaging (computed tomography or magnetic imaging)
B. Neuropsychological tests
C. Blood analysis (couple of known markers exist)



Typical Mechanism of Action of Drugs used for treatment of Alzheimer's patients:

• Typical mechanism of action is focused on proteolysis of amyloid precursor protein; latest drugs could prevent proteolysis or bind to already formed beta amyloid prior its aggregation and eliminate it.
  
• Other drugs affect distribution of beta amiloid through the brain or decrease the rate of neuroinflammation.  Alzheimer’s disease is one of the most common neurodegenerative disorders associated with old age and one of the most expensive to be treated because patients demand special care due to physically, physiologically and socially altered behavior.
  

Some Drugs for Alzheimer's Patients (US FDA Approved)
The U.S. Food and Drug Administration (FDA) has approved two types of drugs/medications aimed at treating the cognitive symptoms (memory loss, confusions, behavioral swings, reasoning and thinking disability) of Alzheimer's disease:
a) Cholinesterase inhibitors (Poular brands: Aricept, Exelon, Razadyne)
b) Memantine (Popular brand: Namenda)

Three cholinesterase inhibitors are commonly prescribed:

• Donepezil (Aricept) is approved to treat all stages of Alzheimer's.
  
• Rivastigmine (Exelon) is approved to treat mild to moderate Alzheimer's.
  
• Galantamine (Razadyne) is approved to treat mild to moderate Alzheimer's.
  

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REFERENCES (for the content till now):

• RCSB
  
• Alzheimer Alois. Über eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medizin. 1907;64(1–2):146–148. (German).
  
• Deutsche Alzheimer Gesellschaft: https://www.deutsche-alzheimer.de/unser-...ste-d.html
  
• Mayoclinic
  
• http://www.alz.org
  

Developments in the treatment of pancreatic cancer using gene therapy:

Among the different types of cancers, pancreatic cancer remains to be one of the most prevalent one that is difficult to treat due to its complex nature and poor prognosis. Various issues in the diagnosis of the disease in the early stages including location in the anatomy and improper symptoms; the rapid spread of the disease to the nearby crucial organs including the duct of bile, the blood vessels and nerves; the metastasis of the disease due to a minor primary focal point such as tumor; and the meagre disease response to different cancer-specific therapies, are responsible for the difficult prognosis of the disease. Since, the diagnosis of the disease in the early stages is difficult, hence in-depth research and clinical trials are necessary to discover a new method of treatment for the disease.

Gene therapy has shown great promise in the therapeutics for different diseases, especially cancer in the past few years. The main reason for the success of gene therapy lies in the fact that it targets the genes involved in the progress or development of a particular disease. In the therapy for cancer, the process mainly targets the different genes that may be responsible for the spread of cancer or those that prevent the killing of cancer cells. It may also help in the delivery of different specific devices that help in the killing of cancer cells.

The molecular abnormalities related to the pancreatic cancer is the typical occurrence of a point mutation in the K-ras gene associated with the K-ras signalling mechanism; apart from the presence of abnormal p53 gene, abnormalities leading to suppression or loss of expression in the DPC4 gene and DCC gene, different types of mutation mainly somatic in APC gene, the above-normal expression of the different fibroblast growth factors (acidic as well as basic) and the instability of the microsatellite. Since, the main role of K-ras was observed in the potent transformation of the activity of NIH3T3 cell line of mouse fibroblasts, hence was chosen as the main target for the pancreatic cancer.

The experimental studies of T.Yoshida et.al., involved the targeting of the K-ras by the transduction of the human pancreatic cancer cell lines such as AsPC-1, MIAPaCa-2, Panc-1, PSN-1 and BxPC-3 with the plasmids expressing the antisense K-ras RNA, which resulted in the tumor suppressive effect. Hence, it showed the validity of K-ras point mutation as a molecular target and the use of antisense K-ras RNA as a possible targeting tool for the same with the data from the studies showing the dependency of the pancreatic cancer cells on the K-ras protein for the growth mechanisms. However, the role of the K-ras protein may be mainly in the initiation of the cancer and not on the progression of the disease as was shown by the absence of significant difference in the number of mutations in the K-ras gene in the different stages of the disease.

They performed the targeting of the K-ras mutation in the intraperitoneal tumor nodules in the nude mice peritoneal dissemination model, as peritoneal dissemination was one of the major metastatic modes of pancreatic cancer. However, the lipofection or polyfection of the nodules with synthetic non-viral vectors using cationic lipids had low transduction efficiency. Hence, the use of viral vectors with tissue or cell specific promoters can prove to be a better method. However, the expression profiling data related to pancreatic cancer is insufficient and requires the accumulation of the data for the identification of unique tissue or cell specific promoters.

The use of immune system is another procedure for the targeting of the pancreatic cancer cell lines. The role of Interferon-α protein in the growth inhibition of cells and the presence of its antitumor activity in pancreatic cancer may help in the targeting of the immune system, although there is not much significance in the results observed. Hence, the cytokine gene therapy involving the introduction of cytokines directly to the tumor cells using vectors can be potent in the therapeutics for pancreatic cancer.

Thus, it is observed that the approach for the therapeutics for pancreatic cancer should be multidisciplinary for the development of probable protocols that may be utilised for the clinical trials associated with the disease. The significant progress observed in the studies of gene therapy, cytokine gene therapy combined with stem cell biology, vectorology, immunology, etc may help in the development of effective therapeutics for pancreatic cancer in future.