Tuesday, December 16, 2014

Prevention and Cure of Rotavirus Infection

Rotavirus (RV) is an RNA virus that causes diarrhea leading to severe dehydration in children and moderate intestinal discomfort in adults.  Mice have proven to be a useful animal model in studying infection of RV – the findings in mice are consistent with what is found in regards to human infection as well.  In this model, it has been shown that the level of infection of this virus can be ascertained by the appearance of the appropriate viral antigens in feces.    It has also been shown that the typical target for RV is the epithelial cells that line the small intestine.  

Furthermore, it seems that the predominant antigen that activates host cell gene expression as a defense against infection in intestinal epithelial cells (IECs) is the protein flagellin – a major component of bacterial flagella.  Flagellin seems to be the dominant activator of the immune system in the intestine.   It has been shown that flagellin-activated responses protect mice against bacterial infection, chemical insult and radiation.  In addition, administration of flagellin to mice seems to reduce the likelihood of infection with a cultured and attenuated form of RV.

Benyue Zhang and his colleagues at the Center of Inflammation, Immunity and Infection at the Institute of Biomedical Sciences Georgia State University, Atlanta Georgia, sought to discover if the administration of flagellin could serve as a prophylactic to protect mice from a highly contagious and pathogenic mouse RV strain.

The result of this study was very encouraging since the data demonstrated that not only did the administration of flagellin to mice prevent the onset of RV infection, but also cured infected mice who suffered from a chronic infection of the virus.  Interestingly, their findings have shown that this protective effect was not dependent upon adaptive immunological responses nor did the underlying mechanism require the participation of Interferon (IFN) – a substance known for its potent anti-viral properties.
The data did show, however, that the flagellin-initiated response required Toll-like receptor 5 (TLR5) and the involvement of Dendritic cells that produce interleukin-22 (IL-22).  Interleukins are members of a family of cytokines that play an essential role in immune responses.  The net result of these processes is the expression of a so-called “protective gene expression program” within intestinal epithelial cells.

These results may have public health implications in regards to rotavirus infections within the human population.   This is of particular importance since it is estimated that RV infections result in the deaths of approximately 600,000 children annually throughout the world.    

Saturday, November 22, 2014

How the Influenza A Virus Enters the Host Cell

Influenza A Virus (IAV) has, of course, major implications in regards to public health.  Given the possibility of an influenza pandemic, it is vitally important to understand the mechanism of infection for this virus, since all viruses are unique in this regard. 

IAV is a single-stranded RNA virus that is subdivided into eight RNA molecules.  Each of these is precisely packaged into helical ribonucleoproteins (vRNPs).   These vRNPs carry a copy of a viral polymerase enzyme complex and the nucleoprotein (NP).   Within the structure of the virus, these vRNPs are arranged into a capsid-like complex that forms a shell around the vRNPs.   This is the state of the virus prior to its entry into the host cell.

As IAV gains entry into the host cell, it begins a process of uncoating initiated by the acidic conditions within the endosome – a membrane-bound structure providing transport within eukaryotic cells.  In the later stages of the process, the protein hemagglutunin (HA) – native to the virus – is activated and the IAV finally is transferred to the cell cytosol – cytoplasm .  Ultimately, the vRNPs gain access to the nucleus through the nuclear membrane.  It is at this final stage that the viral genome begins to co-opt the host cellular machinery to make more copies of the virus leading to the death of the host cell and the release of many more infectious agents into the surrounding tissue.
Dr. Indranil Banerjee and his colleagues at the Institute of Biochemistry, Eidgenossische Technische Hochschule in Zurich, Switzerland studied the process of capsid disassembly in detail, since it plays such a crucial role in IAV entry into the host cell.  They found that the virus exploits the host cell’s aggresome formation and disassembly mechanisms.  An aggresome is a cellular complex that is created in response to cell stress characterized by misfolded or unfolded proteins .

By helping to elucidate the underlying mechanisms responsible for host cell entry of IAV, this knowledge creates opportunities for the application of novel therapeutic approaches to combat infection.    

Sunday, October 26, 2014

Ocean Acidification Disrupts Chemical Signaling In Marine Organisms

The relationship between the apparently inexorable increase in atmospheric carbon dioxide (CO2) as a direct result of human activity and the increasing acidity in the world’s oceans has been well documented. The current projected estimate is that at the current rate of atmospheric CO2 buildup, the pH in the oceans will drop from the current and historic range of 8.15 – 8.25 to ~ 7.8 or below by the end of the 21st century.

In addition to the disastrous impact of acidification upon the calcification that impedes coral and shell formation in the affected organisms, there is an additional side effect of this acidification that is worthy of attention. Many of the waterborne biologically-significant chemical signals, such as pheromones, that play essential roles in marine biology are disrupted by changes in the pH of the local marine environment. These signaling processes play a crucial role in important biological activities associated with mating, foraging, recruitment and alarm mechanisms.

The impact of this chemical disruption resides on two distinct levels. Increased acidity can affect the signaling compounds directly, and, secondly, impact their required interaction with specific receptor proteins designed to bind with the signaling molecule. This specific interaction between a signaling compound and its unique receptor represents the essential first step in producing the desired effect. This kind of interaction is found throughout metazoan biology.

The mechanism of this disruption caused by increased acidity within the marine environment can be attributed to changes in hydrogen bonding, electrostatic potential and hydrophilic and hydrophobic interactions that affect both ligands and their specific receptors. The types of organic compounds that are so affected include pheromones, nucleosides, thiols (sulfur-based compounds) organic acids and others.

The critical behavioral patterns that suffer from continued acidification of the oceans include sexual reproduction, recognition of the presence of predators, fertilization, larval settlement and many others. Unfortunately, the rate of acidification exceeds the ability of evolutionary mechanisms to respond to the kinds of changes described. This kind of impact of the increase of greenhouse gases within the natural environment needs further study, for the implications can prove to be devastating.

Wednesday, October 1, 2014


Epigenetics is the study of the changes in phenotype brought about by modification of genetic expression rather than through changes in the actual structural information found within the DNA i.e. genetic mutations.

Although the individual organisms within a species share the same essential blueprint imbedded within the DNA, they express individual phenotypes.  In addition, complex traits and diseases cannot be fully explained via differences in genotype.  This suggests that developmental and environmental factors that are unique to the individual play an important role in determining the terminal phenotype.

The kinds of chemical modifications that are associated with epigenetics are DNA methylation and histone modification.  Histones are the family proteins that are intimately associated with DNA and play an important role in genetic expression.  Other factors that have been implicated in epigenetics are nonocoding RNAs and nucleosome location.

Since much current genetic research is focused on the role of epigenetics in determining phenotypic characteristics, there has been considerable confusion as to what constitutes epigenetics.  An epigenetic system needs to meet the following criteria:

  • Heritable
  • Self-perpetuating
  • Reversible.

Prions – infectious proteins – meet these criteria since they perpetuate themselves through altered protein folding states and may, in fact, serve as indicators of environmental stressors.  Prions certainly alter phenotype as exemplified by the diseases they produce – Creutzfeldt-Jakob disease (CJD) being an example.

Some metazoans – metazoans encompass all animals advanced enough to have differentiated tissue - undergo genome-wide reprogramming of DNA methylation and histone modifications during gametogenesis and embryogenesis as a way of clearing those epigenetic changes that were introduced by environmental factors during the life of the individual.  Furthermore, there is evidence that small noncoding RNAs may serve as tags for marking deleterious sequences within the DNA. This Reprogramming may play a critical role in cell differentiation, and has been linked to pluripotency in both gametes and zygotes.

The field of epigenetics is undergoing rapid expansion; the implication of the critical role epigenetic processes play in the development of the individual is just beginning to be understood.

Thursday, August 21, 2014

Implications of the Continually Growing Accumulation of Microplastics in the World’s Oceans

In an article appearing in the journal Science, authored by Kara Lavender Law of the Department of Oceanography at Woods Hole, Massachusetts and Richard C. Thompson of the School of Marine Science and Engineering at Plymouth University UK, attention is drawn to microplastics in the world's oceans. 

Although the focus of the pollution of the marine environment with plastics is usually on the unsightly appearance of this detritus, there is now growing concern among the scientific community of the presence of so-called, “microplastics” – particles of plastic so small as to be essentially undetectable by the eye.  Microplastics have been used to describe particles smaller than 5 mm in diameter (where 5 mm = .197 inches).  This particular population of marine pollutants is ever-growing due to the ineluctable degradation of plastic pollutants to microplastic-sized particles. 

One of the chief environmentally-based concerns is focused on the fact that particles of this size are readily ingested by organisms as small as zooplankton – organisms that play a crucial role in the marine food chain. The sources for microplastics in the marine ecosystem are manifold including –
·         Degradation of larger items entering rivers through runoff, tides, wind and catastrophic events such as tsunamis, hurricanes and earthquakes
·         Cargo lost at sea and other debris originating from on board ocean vessels
·         Microplastic-size particles such as cosmetic beads and clothing fibers that on account of their size can readily pass through waste water treatment facilities.

Once in the oceans these particles are passively transported by many and diverse factors.  They are found ubiquitously in coastal sediments around the world and, as stated previously, are readily ingested by many types of marine organisms including mussels that can retain these particles long after ingestion.  The impact of the presence of these particles on the biology of the organisms that ingest them is not clearly understood.
One of the more disturbing properties of microplastics is their propensity to adsorb environmentally harmful chemicals such as dichlorodiphenyl-trichloromethane (DDT) and polychlorinated biphenyls (PCBs) on their surface and consequently passively concentrate these dangerous substances.

Although the real risk of the presence of microplastics upon the health of the marine ecosystem is exceedingly difficult to ascertain, it is certainly worthy of further study.

Wednesday, August 6, 2014

A Possible Relationship Between Preeclampsia and Proteins

Approximately 5% to 10% of pregnant women worldwide suffer from preeclampsia.   This is a condition in which there is a sudden and precipitous rise in the pregnant woman’s blood pressure.   In many cases, if the baby isn’t delivered immediately, the mother may die, for the full-blown development of eclampsia can lead to seizures and severe hemorrhaging.  This is especially problematic In low-resource countries that do not have access to the sophisticated equipment required to sustain the life of premature infants.  In fact, the death toll from this condition worldwide is estimated to be 76,000.

The etiology of this disease remains an enigma.  Some of the suggested causes include abnormalities in the immune system’s tolerance of the presence of the fetus, abnormalities in the development of the placenta or dietary factors. 

In spite of the apparent mysterious nature of this syndrome, there is a revealing aspect to its presentation.  It has recently been shown that preeclampsia is marked by the appearance of misfolded and clumped proteins.  Interestingly, among the proteins implicated is amyloid precursor protein – the same protein that is implicated in Alzheimer’s disease.   There is to date not enough evidence to unambiguously describe preeclampsia as a “misfolding” disease - It is also possible that the presence of misfolded proteins is a symptom rather than the cause.

Taking these data into account, Dr. Irina Buhimschi, an investigator from Nationwide Children’s Hospital and Ohio State University, decided to look for a diagnostic tool that would be a better predictor for this condition in pregnant women.   In a study involving 600 pregnant women, urine samples were taken and subsequently analyzed for the presence of misfolded proteins.   From this study, a simple test was devised using the dye Congo Red.  It was found that Congo Red binds to clumped and misfolded proteins producing a distinctive red color.  It was shown that this test has an accuracy of 80% or higher in indicating the presence of preeclampsia.

This is a very important discovery especially in regards to its worldwide application, for it is a very inexpensive and simple procedure that has the potential to save countless lives especially in low-resource environments.

Tuesday, July 15, 2014

In Search of New Classes of Antibiotics

Over the history of medicine, the development of antibiotics (1930 – 1980) to combat virulent and dangerous infections has saved countless lives and helped avoid the onset of dangerous pandemics.  The use of these antibiotics has been of immense value in increasing the longevity of human populations.

Antibiotics currently fit into five classes as described in the following table –

Mode of Action
Inhibits bacterial cell wall biosynthesis
Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus
Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome
Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome
Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA

Note: Antibiotics are of no use in treating viral infections since the biology of the virus is markedly different than that of bacterial agents.

However, no new classes of antibiotics have been developed since 1980 and the overuse of the standard antibiotics has led to the insidious development of antibiotic –resistant strains of disease like tuberculosis (TB) and gonorrhea.  From a public health perspective, it is of enormous importance to encourage the development of new classes of antibiotics with unique modes of action.

Wednesday, July 2, 2014

Nature of the Resistance of Flavivirus Infection to Host Cell Defenses

Flaviviruses (FVs) represent a family of viral pathogens responsible for human life-threatening diseases such as Dengue Fever, West Nile, Yellow Fever and Japanese Encephalitis.   The infectious agent within this family of viruses is single-stranded RNA.  During the process of infection (through arthropod vectors), the viral genome (gRNA) is successfully replicated and  subgenomic flaviviral  RNAs (sfRNAs) are also produced.  In animal studies, it has been demonstrated that these sfRNAs are an integral part of the disease process.  It is interesting to note that these sfRNAs are produced as a result of the incomplete degradation of gRNA by the host-derived exonuclease Xm1 – an enzyme that is a part of the host cell defense against infection.  In this scenario, host cell defenses inadvertently play a crucial role in producing disease.

This resistance to complete degradation of gRNA by Xm1 has been shown to be due to specific RNA sequences that are referred to as Xm1-resistant RNAs (xrRNAs).  It is therefore of interest to more fully understand the molecular structure of xrRNAs and, therefore, elucidate the nature of the resistance to the action of Xm1.

Dr. Erich G. Chapman and his colleagues at the Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado at Denver focused their research efforts on establishing the unique and precise structural aspects of xrRNAs  that make them impervious  to Xm1-mediated degradation.

As a result of their extensive analysis they were able to show that the three-dimensional structure of xrRNAs consist of a “ringlike” conformation that prevents Xm1 from breaking down sfRNAs.  In addition, the investigators purposefully disrupted this structure and effectively prevented the formation of sfRNAs during infection.  This is an important finding; for, it helps clarify the mechanism of FV infections that impact many individuals throughout the world.

Monday, June 9, 2014

Therapeutic Cloning

In April of 2014, a major breakthrough was established in human stem cell research.  In that month two laboratories independently reported the successful production of human embryonic stem (ES) cells derived from skin cells cultured in the laboratory ( in-vitro).  This a significant achievement in that an application of this technique could be exceedingly useful in the production of replacement tissues in-vitro for the treatment of such diseases as  juvenile (type 1)diabetes and Parkinson’s disease – both of which arise from the precipitous loss of the cells required to manufacture insulin and dopamine, respectively.  The added benefit of such an approach is that since the cells can be derived from the patient being treated, graft rejection is no longer an issue.

The cloning technique that was employed is referred to as somatic cell nuclear transfer (SCNT); an analogous method was used to clone the now famous sheep, Dolly.  It was subsequently applied to cloning cattle, mice dogs and other animals.  There is no desire among members of the scientific community to apply this approach to cloning humans but rather to produce early-stage human embryos from which ES cells could be derived.   Heretofore, human cells have been problematic in regards to cloning.

Dr. Dong Ryul Lee and his colleagues at CHA University in Seoul, Korea successfully created human ES cells from the skin cells of two individuals – men ranging in ages from 35 to 75 years old.  Later in April of the same year, Dr. Dieter Egli and his collaborators from the New York Stem Cell Foundation (NYSCF) Research Institute used the skin cells of a young woman patient suffering from type 1 diabetes to also produce ES cells and then induced these cells to become insulin-producing cells.  Following this momentous result, the investigative team then introduced these insulin-producing  cells into experimental mice where it was shown that the hormone insulin was made in-vivo.  This latter finding has yet to be published.

The overall technique that was employed in Egli’s laboratory is briefly described below –
·         DNA is removed from an unfertilized human egg cell (oocyte)
·         The DNA from skin cells grown in-vitro from a patient with type 1 diabetes is transferred to the oocyte that had its own DNA removed
·         If the transfer is successful, the oocyte begins to divide
·         At a very early point in cell division – the Blastocyst stage – ES cells are harvested
·         Finally, these cells are coaxed into differentiating into insulin-producing pancreatic cells.

These results are very exciting; however, the possible application to human disease faces considerable obstacles that need to be addressed.  Nonetheless, it is a significant step in the goal to successfully treat implacable diseases such as type 1 diabetes and Parkinson’s through tissue –replacement therapies. 

Wednesday, May 28, 2014

Antibiotic Treatment for Yaws – A Plan to Eradicate the Disease

Yaws is an infectious disease that is prevalent among human populations in the tropical regions.  It is a disfiguring ailment that impacts hundreds of thousands of individuals.   There are not many fatalities associated with yaws; however, it produces considerable suffering among those afflicted, especially children.  The primary symptoms include serious skin ulcers especially on the face, back, buttocks and legs.  It has been reported that approximately 100,000 new cases show up every year, of which 75% are children.  Although most suffers heal over time with no chronic side effects, about 10% suffer from erosion of connective tissues including cartilage and bone.

The pathogen responsible for yaws is Treponema pallidum - an organism closely related to the infectious agent that causes syphilis.  However, unlike syphilis, yaws is not sexually transmitted.  Yaws is readily treated by the use of antibiotics.  An attempt was made in 1952 to completely eradicate this disease using benzathine penicillin in over 46 countries.  As a result of this intensive effort, disease incidence had dropped by 95 percent, but by the 1970s, the disease began to return and ultimately reached current levels.

In 2012, a new plan has emerged, sponsored by the World Health Organization (WHO), to eradicate the disease – referred to as the Morges Plan.  The ambitious strategy involved is to use the relatively inexpensive antibiotic azithromycin requiring only one oral dose.  In addition to administering this drug to those individuals infected, the plan is to include at least 90% of the population in the infected areas.  This strategy is designed to treat not only those individuals who are clearly ill but also those with latent infection and who are asymptomatic.

Epidemiologists are hopeful that this scheme might prove successful, but are also aware of the many obstacles that have to be overcome including the magnitude of the administrative task involved, the scope of the project and its cost. 

Thursday, May 8, 2014

The Role of Dopamine Deficiency in Obesity

Dopamine, a potent neural transmitter found in the human brain, has been implicated in a variety of reward circuits including eating.  It has been well established that the production of dopamine in the dorsal striatum of the brain markedly increases during feeding in both rodents and humans.  Controlled levels of dopamine production are also required for normal eating behavior.  These finding are consistent with the known role that dopamine plays in the reward circuitry of the brain. 

Given this critical role played by dopamine in relation to eating behavior, it has been suggested that overeating may be a compensation for a diminished function in regard to the reward circuitry dependent upon dopamine levels.  In fact, dopamine receptor deficiency has been reported in studies involving obese patients.  This is certainly consistent with significantly reduced response to food stimuli in individuals suffering from obesity.  Additionally, rats that were purposefully depleted of dopamine receptors demonstrated obsessive feeding behavior.

The physiological mechanism linking incessant high-fat intake to dopamine deficiency has been unclear.   Dr. Luis A. Tellez and his colleagues at the John B Pierce Laboratory in New Haven, CT focused their research in an attempt to elucidate the physiological mechanism linking obesity and dopamine levels in the brain.  In their experimental approach, they administered oleoylethanolamine to mice fed a diet rich in fat.  Oleoylethanolamine is, in fact, a lipid messenger whose production is suppressed in individuals subjected to high-fat dietary intake.  Upon administration of this lipid messenger, the experimental mice demonstrated increased levels of dopamine release.   Exposure of these mice to oleoylethanolamine also reinstated normal eating habits.
From these data, the authors of this report concluded that high-fat dietary intake as evidence of gastrointestinal malfunction seems to play a pivotal role in dopamine deficiency and, most importantly, restoring gut-related lipid messenger may  increase the reward feedback mechanism in regard to the intake of healthier lower-fat food.    

Sunday, April 27, 2014

Mechanism of Immune Reponses Related to Allergic Airway Diseases such as Asthma

Asthma is a chronic condition that adversely impacts the airway passages. This disease presents as episodic events typified by difficulty in breathing as a result of obstruction of the airways as well as inflammatory responses. This condition is provoked by response of the immune system to allergens. The inflammatory response manifests itself by the enhanced production of interleukin-4 (IL-4), increased activity of a particular subset of T helper lymphocytes (TH2) and serum immunoglobulins. A link has also been established between proteinases – enzymes that cleave proteins, the immune Toll-like receptor 4 (TLR4) and asthma. These proteinases that have been shown to initiate TH2-mediated allergic reactions are secreted by fungi, pollen and dust mite antigens.

 A full understanding of the underlying factors that trigger asthmatic episodes would, of course, be invaluable in developing therapeutic strategies to treat this illness. Dr. Valentine Ongeri Millien and colleagues from the Translational and Molecular Medicine Program at Baylor College of Medicine at Houston Texas have made some important discoveries in this light. The research efforts of this investigative team have established that airway- derived proteinases trigger allergic disease and innate immunity against fungal infection. Furthermore, they have shown that these particular outcomes were a direct result of the breakdown of fibrinogen, an essential clotting factor, by these proteinases. It is the products of this breakdown that bind to TLR4 on both epithelial cells that line the airways and to macrophages – a type of circulating cell of the immune system that has the role of ingesting invading infectious agents. From these results, it seems apparent that inflammation of the airways that is characteristic of asthma is a direct result of the immune antifungal defense strategy.

The Elucidation of this mechanism may prove to be invaluable in terms of developing therapeutic strategies for the treatment of allergen-induced pulmonary diseases such as asthma. In fact, this group when on to show that the use of hirudin, a drug that functions as a potent protease inhibitor, can lessen the severity of allergic lung disease. This may prove to be a very important finding.

Friday, March 7, 2014

A Long Noncoding RNA Involved in Activation and Repression of Immune Genes

The human body’s immune-based response to the presence of deleterious microbes engages a very intricate and complex system that has evolved over many millions of years.  In this regard, we share many aspects in common with the entire vertebrate world.   Immunity can be regarded as consisting of two categories of responses – innate and adaptive.  In the present discussion, we will focus our attention on the innate immune system.
The innate immune system has the extraordinary capability of recognizing a wide range of microbes and inducing the production of many proteins that become engaged in an elaborate defense against the invading organism and ultimately involve the adaptive response.  Over many years of concerted research efforts, it has been shown that the molecular basis of this recognition system involves a host of genetically determined pattern recognition receptors – an example being the so-called “Toll-like receptors” (TLRs).  It is the binding to these receptors that triggers a cascade of immune responses.

It has recently been discovered that long non-coding RNAs (lncRNAs) play a significant role in this process.  As a class of biologically active compounds, literally thousands of these lncRNAs have been discovered in mammalian genomes and they have been shown to regulate gene expression in a number of biological processes.   It is, therefore, of some interest to determine whether lncRNAs play a role in the innate immune system as well.

The work of Dr. Susan Carpenter and her colleagues at the Division of Infectious Diseases and Immunology in the Department of Medicine at the University of Massachusetts Medical School has helped answer this question.  The efficacy of the antimicrobial innate defense is wholly dependent upon the induction of inflammatory gene expression.   Implicated in this complex response is the activation of transcription factors, transcription co-regulators and other factors.

Carpenter and her associates have found that the activation of TLRs – as described previously – induce the expression of many lncRNAs and one of these – lincRNA-Cox2 – has been shown to be involved in the activation and repression of distinct groups of immune-related genes.  This finding is significant in that it helps to further elucidate the mechanism that underlies the innate immune response.

Wednesday, February 26, 2014

Hypercholesterolemia and Breast Cancer

It has been clearly established that obesity and the metabolic syndrome are risk factors for estrogen receptor (ER) positive breast cancer – a type of breast cancer in which the tumor cells bind the female hormone estrogen – in postmenopausal women.

This increased risk has been attributed to a number of factors including:
  • Increased levels of insulin and insulin-like substances in the circulation
  • Localized production of estrogen in adipose (fat) tissues
  • The role of inflammatory substances like cytokines in enhancing tumor cell growth.

Recent studies have implicated hypercholesterolemia – high levels of cholesterol in the bloodstream – as a definitive risk factor in for estrogen receptor (ER) positive breast cancer in postmenopausal women.  Hypercholesterolemia correlates with obesity and together these conditions have been shown to increase morbidity.  In addition, it has been shown that disease-free survival is improved in those patients who were taking statins prior to diagnosis.  Statins are members of  a class of compounds designed to inhibit cholesterol production in the liver

Although it has been proposed that statins exert their effect by directly inhibiting tumor cell growth, the amount of circulating statins in individuals who use the drug at the typical dose level is far below the amount required to inhibit cancer cell growth as has been reported in–vitro  (in the laboratory).  Therefore, there must be some other explanation.  An understanding of the role of cholesterol in breast cancer pathology would be invaluable in regards to possible therapeutic approaches.  Dr. Eric R. Nelson and his colleagues from the Department of Pharmacology and Cancer Biology at the Duke Institute for Genome Sciences and Policy at Duke University in Durham, NC, have made a significant contribution in this regard.

Nelson and his group have shown that the actual substance that seems to be responsible for accelerating the growth of breast cancer tumors is a metabolite of cholesterol – 27-Hydoxycholesterol (27HC).  Furthermore, 27HC is a product of the action of the enzyme cytochrome P450 oxidase (CYP27A1).   The expressed level of CYP27A1 correlates well with tumor grade in breast cancer patients and inhibition of this enzyme had a positive impact on the suppression of tumor growth.

From this data, the authors conclude that lowering the level of circulating cholesterol or inhibiting its conversion to 27HC represent effective strategies in the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women.  This is, indeed, an important finding.

Friday, February 21, 2014

Carbon Dioxide Emissions from Areas of Tropical Deforestation

Although the levels in increased atmospheric carbon dioxide (CO2) as a direct outcome of the burning of fossil fuels have been extensively studied, the amount of COproduced as a direct result of tropical deforestation has been inadequately examined.  In fact, emissions that are a direct result of anthropogenic land-use modifications represent the most ambiguous and under-studied of that set of human activities that impact the planetary carbon cycle.
There are many factors that make this avenue of investigation particularly challenging.  They include the following:
  • An assessment of the rates of deforestation in relation to the amount of carbon contained within soils and vegetation
  • The methodology used in clearing carbon and the fate of the cleared material
  • The response of the soil-based carbon pool to the deforestation
  • The longer term impact of the drastic modification of land cover that results from tropical deforestation.

In order to more effectively quantitate the carbon emissions that are a direct result of tropical deforestation, Dr. Nancy L. Harris and her colleagues at the Ecosystem Services Unit of Winrock International in Arlington Virginia used satellite observations of the loss of forest cover and mapped forest carbon stocks.  With these tools and methodologies, this group was able to estimate gross carbon emissions in targeted tropical regions between the years 2000 and 2005.

The result they obtained from this systematic approach was 0.81 petagrams of carbon emissions per year – a petagram is equivalent to 1000 trillion grams.  This value corresponds to ~ 1.8 trillion pounds of carbon emissions per year.  The authors of this study believe that their approach serves as a much more reliable model for estimating global progress on curbing CO2 emissions from deforestation.   

Monday, January 27, 2014

A Gene Mutation Linked to Respiratory Infection and Airway Damage

Respiratory infections are known to be the most common illness experienced by individuals worldwide.  It has been shown that repeated respiratory infections can lead to a condition known as “bronchiectasis” that results from a dilation of the bronchi – specialized tubes that carry air from the trachea to the lungs.  Susceptibility to repeated respiratory infections and the resulting bronchiectasis may be due to an underlying primary immunodeficiency (PID).

There have been over 200 genes implicated in PIDs.  This expanded understanding of the role of genetic mutations in regards to susceptibility to respiratory infections among the world’s human population, is due in large part to the application of the advances made in genetic engineering and the fact that the human genome has been entirely deciphered.

To further elucidate the molecular biology of PID, Dr. Ivan Angulo and his colleagues in the Department of Medicine at the University of Cambridge, Cambridge UK, searched for the presence of genetic mutation(s) that might account for PIDs in thirty-five patients suffering from this syndrome.  These patients all suffered from repeated respiratory infections and a family history of susceptibility to these infections.   The fact that a family history was demonstrated, reinforced the assumption of a genetic predisposition.

In regards to the patients studied, the investigators were able to implicate a mutation in the PIK3CD gene that is responsible for the production of the catalytic subunit for the phosphoinositide 3-kinase δ enzyme.  The PID associated with this particular mutation is referred to as the activated PI3K- δ syndrome (APDS).  

An obvious question follows from these results as to the nature of the relationship between the phosphoinositide 3-kinase δ enzyme and the resulting disease state.  The investigators were able to show that the patient-derived immune-competent lymphocytes responsible for combating infection were prone to premature cell death, thereby increasing the likelihood of respiratory distress.  The application of these findings could eventually lead to therapeutic approaches to combat APDS.  

Saturday, January 4, 2014

Hepatitis C Virus – the Core Structure of a Key Viral Protein

Hepatitis C virus (HCV) is a major cause of liver diseases such as hepatitis, cirrhosis of the liver and liver cancer.  This virus was discovered in 1989 and was identified as the causative agent of non-A, non-B hepatitis.  It has now been estimated that 2-3% of the entire world population – an estimated 170 million individuals - is infected with this viral agent.  This reality represents an extraordinary incidence of infection on a global scale.  Therefore, there is much interest in developing an effective vaccine.  This has proved problematic on account of the high variability of the genetic structure of this pathogen analogous to the difficulty in developing an effective vaccine against the human immunodeficiency virus 1 (HIV-1).

A virus, as a class of disease-producing organisms, is essentially dormant until it gains access to its cellular target.  Once it does so, it can subvert the cellular machinery of its host to produce proteins whose structure is dictated by the information found within the virus’ genetic material.  The end result of this process allows the virus to effectively make many copies of itself and eventually kill the host cell and spread the infection. 
Some of the problematic issues that face researchers are the fact that the virus has, as of yet, remained resistant to efforts to grow it in culture and that there is no suitable animal model for the disease.  HCV is a member of the hepacivirus genus.  HV is a so-called retrovirus – analogous to the HIV/AIDS virus.  Its infectious genetic material is RNA.  One of its disturbing features is its ability to produce chronic infection.  An unfortunate side effect of this capability is that of HCV infection can lead to liver cancer – hepatocellular carcinoma.  The development of a reliable vaccine is dependent on a fuller understanding of the particular mode of action of this virus.

In an effort to understand the mechanism of infection of HCV, Dr. Leopold Kong and his associates at the Department of Integrative Structural and Computational Biology at the Scripps Research Institute in La Jolla, California, have examined the molecular mechanism through which HCV gains entry into the target hepatic (liver) cell.  What they have discovered is of particular interest in regards to the eventual production of an effective vaccine.

It seems that at the surface of the virus there is a key glycoprotein (E2) that V H
combines with another glycoprotein, E1, on its surface – a glycoprotein is a kind of protein that is bonded to a sugar.  It is this E1/E2 complex that allows the virus to gain entry into the target cell by preferentially binding to a receptor protein on the cell membrane of liver cells – this receptor is referred to as CD81.  Interestingly, E2 is a target for the body’s natural immune response; however, due to the great variability in the structure of E2, this strategy is essentially ineffective.
These investigators were able to determine the three dimensional structure of E2 with a resolution of 2.65 angstroms using X-ray crystallography – an angstrom  is equivalent to one ten-billionth of a meter.  This level of detail may prove to be invaluable in future drug and vaccine design.