Archive for July, 2014

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The Methodology of Curation for Scientific Research Findings

OPINION LEADERSHIP on Cardiovascular Diseases

 Volume Two

Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation



Epilogue to Volume Two

Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books


Part 1: Curation is another Methodology for Creation of Scientific Knowledge.


OPINION LEADERSHIP: We are developers of new methodologies for Research Finding exposition and dissemination


The Curation process involves development of numerous avenues for exposition of the scientific product and its dissemination, among them:


  • scientific articles on Scientific Journals,
  • Books, e-Books
  • Addresses by Leader Scientists,
  • multimedia presentations (Audio and Video),
  • Expert Panel Discussions,
  • Correspondence among Scientists,
  • archive of experiment results, thematic Literature surveys,
  • Libraries of Open Source Code,
  • Comprehensive Thematic Bibliographies,
  • Shareable Libraries of Annotated Genomics Research


In our curations we have used several from the above list. We take great pride in our presentations of critiques and synthesis of research results. We represent one alternative to Academic Publishing. Instead of divergence into millions of publications per year, we focus on the Frontier, we select several seminal articles and aggregate the outcomes, their significance in context and creatively we identify interrelationsnot included in each of the components of the assembly.


Part 2: Cardiovascular Diseases – Predicted Cost of Care and the Affordable Care Act


  • Cost of Care for Cardiovascular Medical Diagnoses
  • Impact of 2013 HealthCare Reform in the US
  • Patient Protection and Affordable Care Act Featured at RAND


OPINION LEADERSHIP: We identify the potential of Cardiac Regeneration to be the frontier for Cardiovascular Disease near-cure


On Cardiac Regeneration, Prof. Anthony Rosenzweig wrote in Science 21 December 2012


In the United States, heart failure afflicts about 6 million people (1), costs $34.4 billion each year (2), and is now the single most common discharge diagnosis in those over 65 (3). Although enormous progress has been made in managing acute cardiovascular illnesses such as heart attacks, many patients go on to develop late sequelae of their disease, including heart failure and arrhythmia. Thus, the growing number of these patients in some ways represents a burden of our success. It also reflects the incomplete success of most current therapies, which mitigate and manage but do not cure the disease.


OPINION LEADERSHIP: We identify ACCESS to HealthCare Services to be the cardinal factor of success for the Affordable Care Act (ACA).


On  January 10, 2014 Jonathan Cohn wrote in the New Republic: The Kids Are Alright: Another Obamacare Lesson from Massachusetts 


It’s going to take insurers a few months, at least, to figure out exactly what kind of customers their plans are attracting. That’s focused attention on the one variable that can be measured now: Age.


Youth is not be the same thing as health. A 33-year-old with diabetes will run up bigger physician and drug bills than a 61-year-old with no serious medical problems. But, as a general rule, younger means healthier. And the early numbers haven’t seemed that encouraging.


Overall, according to a study by the Kaiser Family Foundation, about 40 percent of the people who could eventually buy coverage through Obamacare marketplaces are between the ages of 18 and 34. But, as of December, just 22 percent of the people signing up for coverage in California were in that demographic. Other states reported similar data. The federal government hasn’t yet provided an age breakdown for people getting insurance through, the website it operates on behalf of 36 other states. But it will probably provide that information soon. When it does, the numbers may not look any better.


Is this a big deal? One way to answer that question is by looking at the best test case available: Massachusetts, which introduced a similar reform scheme in 2007. Thanks to analysis from Jonathan Gruber, the MIT economist who was an architect of both the Massachusetts and federal reforms, we know that enrollment was slow to get rolling in Massachusetts—and that, relatively speaking, healthy people came into the system late. Now Gruber has done a new analysis, breaking down enrollment specifically by age, and provided it to the New Republic.


The graph above tells the story. Over the course of the first year, the proportion of young people (in this case, ages 19 to 34) who had obtained health coverage through the Massachusetts insurance exchange grew. In other words, they were more likely to sign up late.


The precise figures don’t mean a lot, in part because the Massachusetts analogy is hardly perfect. John Sexton of Breitbart (yes, that Breitbart) has written about some of the key distinctions. But the trend is pretty clear—and, according to Gruber, it provides some important lessons. “These data aren’t 100 percent predictive for every state, most importantly because of differences across states in the share of the potential market that is young,” Gruber says. “But these facts highlight two things. First, you don’t need a huge/majority share of enrollees to be young for markets to function well. Second, the young tend to wait to sign up until closer to the deadline.


Obamacare could obviously unfold differently, with plenty of variation from state to state. In some places, participation among the young might not rise the way it did in Massachusetts—or, at least, it might not reach the same levels. But that doesn’t mean those states are destined for an insurance “death spiral,” in which carriers jack up rates so high that only the very sick stay in the system.



Part 3: Causes of Cardiovascular Diseases


  • Human Genome: Congenital Etiological Sources of Cardiovascular Disease
  • The Role of Calcium in Health and Disease
  • Vasculature and Myocardium: Diagnosing the Conditions of Disease


OPINION LEADERSHIP: We identify two pivotal research directions in the effort to understand the Etiology of Cardiovascular Diseases


1. The Research Frontier on Cardiac Regeneration by Anthony Rosenzweig, M.D. 


Professor of Medicine, Beth Israel Deaconess Medical Center on Cardiac Regeneration and How does Excercise help the Heart



This article represents the FRONTIER on Cardiac Regeneration as developed by Anthony Rosenzweig in Science 338, 1549 (2012).

Point #1: Current Pharmacotherapy for Cardiovascular Diseases and Heart Failure

Point #2: Dynamic model for the Adult heart capacity for cardiomyogenesis to compensate for losses occurring in heart failure: recognition of even limited regenerative capacity in the heart 

Point #3: Results of Multiple Cell Therapy Clinical Trials

Point #4:  The Endogenous Regeneration Potential

Point #5: On pathways regulating cardiomyocyte regeneration in animal models

Point #6: Prof. A. Rosenzweig’s Summary and His Future Outlook of Cardiac Regeneration

Detailed, below is Point #6: Prof. A. Rosenzweig’s Summary and His Future Outlook of Cardiac Regeneration


  • We are still relatively early in the development of new approaches to cardiovascular disease. It will be some time before we know the conclusion of what will likely be a long and challenging road ahead.
  • Almost as challenging is conveying to patients and policymakers an appropriate perspective that balances unmitigated enthusiasm for the scientific discoveries, cautious optimism for the broader implications, and humble acknowledgment that though even the most appealing ideas may fail, there is only one way to find out.


Science 338, 1549 (2012)




Anthony Rosenzweig, M.D.  Professor of Medicine, Beth Israel Deaconess Medical Center


We are interested in why the heart fails. Heart failure is an enormous and growing cause of death and disability throughout the world. In addition, the heart provides a model system for studying fundamental cellular processes from cell growth and programmed death, to cell-lineage determination and regeneration. Recently we’ve been interested in understanding how exercise protects the heart against heart failure. A variety of high throughput profiling techniques are being used to identify pathways differentially regulated in heart growth associated with exercise in comparison to the heart growth that precedes heart failure. A recently identified transcriptional pathway involved C/EBPβ and CITED4 not only reproduces many of the effects of exercise and protects the heart from heart failure, but appears to enhance the heart’s regenerative capacity(Bostrom et al Cell, 2010). In vivo gain- and loss-of-function models are being used to explore the functional effects and molecular mechanisms of this pathway in more detail. Other ongoing studies are investigating cardiac micro-RNAs regulated by exercise and their potential protective effects in the heart.


2. Biology of the Nucleus and Gene Expression @ Spiegelman Lab, Harvard Medical School


  • Transcriptional Basis of Energy Metabolism
  • Regulation of Fat Cell Differentiation
  • Metabolic Control through the PGC-1 Coactivators
  • Chemical Biology of the PGC-1 Coactivators


β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors. Cell Metab. 2014 Jan 7;19(1):96-108. doi: 10.1016/j.cmet.2013.12.003.


Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013 Nov 5;18(5):649-59. doi: 10.1016/j.cmet.2013.09.008. Epub 2013 Oct 10.


Part 4: Risks and Biomarkers for Cardiovascular Diseases


OPINION LEADERSHIP: We identify as fruitful area of further study –


1. Genetic Determinants of Potassium Sensitivity and Hypertension. Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome


2. Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability.


3. There are many roles for biomarkers to be subject for further research:


  • risk assessment
  • disease status
  • mechanism of injury
  • severity of disease
  • response to interventions


The following topics address a small set of examples from an exhausting list of biomarkers:


  • The Role of Calcium in Health and Disease
  • Vasculature and Myocardium: Diagnosing the Conditions of Disease
  • Conduction Dysfunction and ElectroPhysiology of the Heart
  • Cardiovascular Imaging: Diagnosing the Condition of the Disease and Determining Course of Treatment


Part 5: Advances in Treatment of Cardiovascular Diseases


  • Vasculature and Myocardium: Diagnosing the Conditions of Disease
  • The Role of Calcium in Health and Disease
  • Conduction Dysfunction and ElectroPhysiology of the Heart
  • Cardiovascular Imaging: Diagnosing the Condition of the Disease and Determining Course of Treatment


OPINION LEADERSHIP: We identify the frontier of Treatment for Cardiovascular diseases to embrace potentially the following trends:


Sources of Evidence in Identifying Risk Factors for Cardiovascular Disease will continue to be derived from a combination of research methodologies:


  • Basic research
  • Epidemiological research
  • Descriptive
  • Analytical
  • Observational
  • Case-control studies
  • Cohort studies
  • Randomized trials


Physical Activity:


  • Cumulative long-term PA has a protective effect on incidence of all-cause and CVD-attributable mortality compared with long-term physical inactivity.
  • In men, but not women, long-term PA also appears to have a protective effect on incidence of CVD.


Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013


Heart doi:10.1136/heartjnl-2012-303461


Cardiovascular Imaging: 


Comparison of the longitudinal, radial, circumferential, rotational and torsional mechanics of the left ventricle (LV) in patients with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM), and detect the new quantitative parameters to differentiate CP and RCM using two-dimensional speckle tracking imaging (2-D STI) method. Torsion, longitudinal and radial strain measured by 2-D STI method can provide useful information to differentiate CP and RCM.


Increase in use of Biological Based Therapy (BBT) among cardiovascular patients to avoid side effects of prescription drugs.

In recent years, the interest of using Biological Based Therapy (BBT) in disease management has increased dramatically in the medical and layman communities. The amount of valid scientific research in this area of therapy continues to increase. Yet, there are still many unknowns concerning BBT, especially in the area of adverse effects and drug interactions. The finding of a high prevalence of BBT (47.5%) use among cardiovascular patients and the lack of communication between patients and their physicians/pharmacists should be addressed by the health care community. Higher education level, as shown in the present study and other previous investigations [1,3,6,22], is associated with an increased use of BBT, but it does not necessarily mean that these patients are aware of the potential detrimental effects of BBT, as demonstrated in the current study. In cardiovascular patients, the perceived effectiveness and safety of BBT, and assumed lack of side effects of these products as opposed to traditional medications, highlights an area for further education. A high incidence of potential drug-BBT interactions was also identified in this study (42 interactions in 94 users). Given that the use of BBT can have a direct effect on patient care, and users of these therapies do not always voluntarily report their use of these products to their providers, health care professionals need to inquire about BBT use routinely. Collecting complete patient histories and educating patients about potential dangers and possibilities of adverse effects and interactions between prescription medications and BBT (or other CAM) will lead to better overall patient care.

Genomics is been harnessed for Familial and non-familial Cardomyopathies Diagnosis and Treatment

Genetic and phenotypic heterogeneity that characterises all cardiomyopathies pose major clinical challenges. In this article, we focus on the task of diagnosis, exploring how a systematic clinical approach can be used to identify specific disorders and guide the selection of further diagnostic tests, including molecular genetic analysis.

Cardiomyopathies are defined as disorders of heart muscle unexplained by coronary artery disease, hypertension, valvular disease or congenital heart disease.1 They are classified by morphological and functional phenotype into

  • hypertrophic cardiomyopathy (HCM),
  • dilated cardiomyopathy (DCM),
  • restrictive cardiomyopathy (RCM), and
  • arrhythmogenic right ventricular cardiomyopathy (ARVC) subtypes

 Iron Metabolism and Mitochondrial Mechanisms

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

The field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich’s ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.

Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

Role of Calcium and Gene therapy in treatment of Pulmonary Arterial Hypertension and Heart Failure

Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure 

Sinus Node Dysfunction (SND): Patient Education

Educate patients to recognize symptoms of SND. Family members should learn cardiopulmonary resuscitation (CPR).

Because most pediatric patients with SND have already received surgery for CHD (eg, Mustard procedure, Fontan procedure), their education is focused on recognizing symptoms of CHF and tachyarrhythmias, such as atrial flutter/fibrillation, which are usually poorly tolerated.

Patients who are on antiarrhythmic medication for atrial flutter or fibrillation should be instructed to take their medication regularly and to visit the cardiologist as scheduled. They should also be cognizant of the adverse effects and toxicity of the medication.

In patents who have already received a Mustard or Fontan procedure, undergoing yearly echocardiography to monitor cardiac function is advisable. If cardiac function is decreased, anti-CHF management should be started and close follow-ups with the cardiologist are advisable.

Patients who have a pacemaker should be instructed on the means of obtaining regular checks. Such checks are usually achieved from home with a transtelephonic monitor that transmits to a central monitoring station, which, in turn, contacts the cardiologist in case a problem is detected (eg, device malfunction, arrhythmia).

Patients who have an intracardiac defibrillator (ICD) device should receive the same instructions that patients who have pacemakers receive. Because patients with ICDs often are placed on antiarrhythmic medication, they also should receive instruction regarding medication schedules and information about adverse effects and toxicity.

In addition, in patients with frequent atrial flutter or fibrillation episodes, which are followed by a shock from the ICD, patients are instructed to avoid activities that may pose a risk to themselves and/or other people (eg, driving). They also receive instruction on when to go to the cardiologist or the emergency department.




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What do you know about Plants and Neutraceuticals?

Author and Curator: Larry H. Bernstein, MD, FCAP


This is a series of articles that is within a multipart series on related and standalone topics of discussion that raise some issues and controversies, but perhaps open our eyes to our relationship to the environment and its effects on living organisms, our uniqueness among eukeriotes, and or interdependence with the living plant and animal world.  In our self-centerness, there is a cross-cultural, perhaps innate tendancy to disregard this interdependence and to disrupt our surroundings in the same manner that families within diverse and mixed-societies become corrupted.  The amazing use of herbal medicines precedes the development of a formal scientific method, and has existed in Asia and Africa for centuries, and probably prior to biblical record.   Of course, there is substantial knowledge in the last century that has led to a better understanding of previously unknown medicinal benefits from the emergence of organic, inorganic and medicinal chemistry, aligned with discoveries in microbiology, and of fungi and algae, and the only recent development of synthetic biology and application of chemical engineering to biology.  These topics do not stand alone.

The series will be segmented as follows:

  1. An introduction to plants and the microbiome.
  2. What do you know about plants and neutraceuticals?
  3. Antimicrobial and drug resistance.
  4. Proteomics
  5. Metabolomics
  6. What do you know about plants and neutraceuticals?


Other articles published in this Open Access Online Scientific Journal include the following:

The Omega-3 Lie

The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor

Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro

Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro

The Gonzalez protocol: Worse than useless for pancreatic cancer  SJ Williams, PhD

Plant flavonoid found to reduce inflammatory response in the brain: luteolin

Omega-3 fatty acids protect eyes against retinopathy, study finds  A Lev-Ari, PhD, RN

2,000-year-old herb regulates autoimmunity and inflammation / Chang Shan, from a type of hydrangea that grows in Tibet and Nepal

Turmeric-based drug effective on Alzheimer flies

Plant flavonoid luteolin blocks cell signaling pathways in colon cancer cells

Study Finds Shu Gan Liang Xue Herbal Formula Has Breast Cancer Anti Tumor Effect

HMPC Q&A Documents on Herbal Medicinal Products published

Health benefit of anthocyanins from apples and berries noted for men

Carrots Cut Men’s Prostate Cancer Risk by 50%

A Recipe To Make Cannabis Oil For A Chemotherapy Alternative

Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Scientists develop new cancer-killing compound from salad plant / 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs

Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin

Malnutrition in India, high newborn death rate and stunting of children age under five years

Inula helenium ( elecampane ) 100% Effective against MRSA in vitro, 200 Strains

Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.

Cinnamon is lethal weapon against E. coli O157:H7

Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics)

Study suggests consuming whey protein before meals could help improve blood glucose control in people with diabetes


There are several other contents to consider.

Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies

Federation of American Societies for Experimental Biology     April 30, 2013


A new research report shows that compounds that stimulate the cannabinoid type 2 receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection.

A new use for compounds related in composition to the active ingredient in marijuana may be on the horizon: a new research report published in the Journal of Leukocyte Biology shows that compounds that stimulate the cannabinoid type 2 (CB2) receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection. The CB2 receptor is the molecular link through which the pharmaceutical properties of cannabis are manifested. Diminishing HIV-1 infection in this manner might make current anti-viral therapies more effective and provide some protection against certain HIV-1 complications.

“The synthetic compounds we used in our study may show promise in helping the body fight HIV-1 infection,'” said Yuri Persidsky, M.D., Ph.D., a researcher involved in the work from the Department of Pathology and Laboratory Medicine at Temple University School of Medicine in Philadelphia, PA. “As compounds like these are improved further and made widely available, we will continue to explore their potential to fight other viral diseases that are notoriously difficult to treat.”

To make this discovery, scientists used a cell culture model to infect human macrophages with HIV-1 and added synthetic compounds similar to the active ingredient in marijuana to activate the CB2 receptor. At different times during the infection, samples from the culture were taken to see if the replication of the HIV virus was decreased. The researchers observed diminished HIV growth and a possible protective effect from some HIV-1 complications.

“HIV/AIDS has posed one of the most significant health challenges in modern medicine,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “Recent high profile vaccine failures mean that all options need to be on the table to prevent or treat this devastating infection. Research on the role of cannabinoid type 2 receptors and viral infection may one day allow targeting these receptors to be part of combination therapies that use exploit multiple weaknesses of the virus simultaneously.”

Story Source:

The above story is based on materials provided by Federation of American Societies for Experimental BiologyNote: Materials may be edited for content and length.

Journal Reference:

S. H. Ramirez, N. L. Reichenbach, S. Fan, S. Rom, S. F. Merkel, X. Wang, W.-z. Ho, Y. Persidsky. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonistsJournal of Leukocyte Biology, 2013; 93 (5): 801

Federation of American Societies for Experimental Biology. “Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies.” ScienceDaily. ScienceDaily, 30 April 2013. <>.


Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS

Mount Sinai Medical Center          March 20, 2012


Marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, research suggests.

Mount Sinai School of Medicine researchers have discovered that marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, according to new findings published online in the journal PLoS ONE.

Medical marijuana is prescribed to treat pain, debilitating weight loss and appetite suppression, side effects that are common in advanced AIDS. This is the first study to reveal how the marijuana receptors found on immune cells — called cannabinoid receptors CB1 and CB2 — can influence the spread of the virus. Understanding the effect of these receptors on the virus could help scientists develop new drugs to slow the progression of AIDS.

“We knew that cannabinoid drugs like marijuana can have a therapeutic effect in AIDS patients, but did not understand how they influence the spread of the virus itself,” said study author Cristina Costantino, PhD, Postdoctoral Fellow in the Department of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine. “We wanted to explore cannabinoid receptors as a target for pharmaceutical interventions that treat the symptoms of late-stage AIDS and prevent further progression of the disease without the undesirable side effects of medical marijuana.”

HIV infects active immune cells that carry the viral receptor CD4, which makes these cells unable to fight off the infection. In order to spread, the virus requires that “resting” immune cells be activated. In advanced AIDS, HIV mutates so it can infect these resting cells, gaining entry into the cell by using a signaling receptor called CXCR4. By treating the cells with a cannabinoid agonist that triggers CB2, Dr. Costantino and the Mount Sinai team found that CB2 blocked the signaling process, and suppressed infection in resting immune cells.

Triggering CB1 causes the drug high associated with marijuana, making it undesirable for physicians to prescribe. The researchers wanted to explore therapies that would target CB2 only. The Mount Sinai team infected healthy immune cells with HIV, then treated them with a chemical that triggers CB2 called an agonist. They found that the drug reduced the infection of the remaining cells.

“Developing a drug that triggers only CB2 as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading,” said Dr. Costantino. Because HIV does not use CXCR4 to enhance immune cell infection in the early stages of infection, CB2 agonists appear to be an effective antiviral drug only in late-stage disease.

As a result of this discovery, the research team led by Benjamin Chen, MD, PhD, Associate Professor of Infectious Diseases, and Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, plans to develop a mouse model of late-stage AIDS in order to test the efficacy of a drug that triggers CB2 in vivo. In 2009 Dr. Chen was part of a team that captured on video for the first time the transfer of HIV from infected T-cells to uninfected T-cells.

Funding for this study was provided to Drs. Chen and Devi by the National Institutes of Health in Bethesda, Maryland. Dr. Costantino is supported by a National Institutes of Health Clinical and Translational Science Award grant awarded to Mount Sinai School of Medicine.

Story Source:

The above story is based on materials provided by Mount Sinai Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

Cristina Maria Costantino, Achla Gupta, Alice W. Yewdall, Benjamin M. Dale, Lakshmi A. Devi, Benjamin K. Chen Cristina Maria Costantino. Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4 T CellsPLoS ONE, 20 Mar 2012

Mount Sinai Medical Center. “Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS.” ScienceDaily. ScienceDaily, 20 March 2012. <>.


Identification of Endocannabinoid System-Modulating N‑Alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii

Z Hajdu, S Nicolussi, M Rau, L Lorantfy, P Forgo, J Hohmann, D Csupor, J Gertsch

†Department of Pharmacognosy, University of Szeged, H-6720 Szeged, Hungary

‡Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland

J. Nat. Prod. Apr 2, 2014





ABSTRACT: The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous Nacylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2′-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2′-methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2−4 are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). NMethylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB1 receptor (Ki values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC50 = 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.


Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network
JC Nwachukwu, S Srinivasan, NE Bruno, AA Parent, TS Hughes, et al.
eLife Apr 2014;10.7554/eLife.02057

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. Here we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.


Diets rich in antioxidant resveratrol fail to reduce deaths, heart disease or cancer

Johns Hopkins Medicine    May 12, 2014

Summary:   A study of Italians who consume a diet rich in resveratrol — the compound found in red wine, dark chocolate and berries — finds they live no longer than and are just as likely to develop cardiovascular disease or cancer as those who eat or drink smaller amounts of the antioxidant.

A study of Italians who consume a diet rich in resveratrol — the compound found in red wine, dark chocolate and berries — finds they live no longer than and are just as likely to develop cardiovascular disease or cancer as those who eat or drink smaller amounts of the antioxidant.

“The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn’t stand the test of time,” says Richard D. Semba, M.D., M.P.H., a professor of ophthalmology at the Johns Hopkins University School of Medicine and leader of the study described May 12 in JAMA Internal Medicine. “The thinking was that certain foods are good for you because they contain resveratrol. We didn’t find that at all.”

Despite the negative results, Semba says, studies have shown that consumption of red wine, dark chocolate and berries does reduce inflammation in some people and still appears to protect the heart. “It’s just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs,” he says. “These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol.”

The new study did not include people taking resveratrol supplements, though few studies thus far have found benefits associated with them.

Semba is part of an international team of researchers that for 15 years has studied the effects of aging in a group of people who live in the Chianti region of Italy. For the current study, the researchers analyzed 24 hours of urine samples from 783 people over the age of 65 for metabolites of resveratrol. After accounting for such factors as age and gender, the people with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than those with no resveratrol found in their urine. The concentration of resveratrol was not associated with inflammatory markers, cardiovascular disease or cancer rates.

Semba and his colleagues used advanced mass spectrometry to analyze the urine samples.

The study participants make up a random group of people living in Tuscany where supplement use is uncommon and consumption of red wine — a specialty of the region — is the norm. The study participants were not on any prescribed diet.

Resveratrol is also found in relatively large amounts in grapes, peanuts and certain Asiatic plant roots. Excitement over its health benefits followed studies documenting anti-inflammatory effects in lower organisms and increased lifespan in mice fed a high-calorie diet rich in the compound.

The so-called “French paradox,” in which a low incidence of coronary heart disease occurs in the presence of a high dietary intake of cholesterol and saturated fat in France, has been attributed to the regular consumption of resveratrol and other polyphenols found in red wine.

Story Source:

The above story is based on materials provided by Johns Hopkins MedicineNote: Materials may be edited for content and length.

Johns Hopkins Medicine. “Diets rich in antioxidant resveratrol fail to reduce deaths, heart disease or cancer.” ScienceDaily. ScienceDaily, 12 May 2014. <>.

Journal Reference:

Richard D. Semba, Luigi Ferrucci, Benedetta Bartali, Mireia Urpí-Sarda, Raul Zamora-Ros, Kai Sun, Antonio Cherubini, Stefania Bandinelli, Cristina Andres-Lacueva. Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling AdultsJAMA Internal Medicine, 2014;


Curcumin  regulates gene expression of insulin like growth factor, B-cell CLL/lymphoma 2 and antioxidant enzymes in streptozotocin induced diabetic rats
Sabryl M El-Bahr
BMC Complementary and Alternative Medicine 2013, 13:368
The effects of curcumin on the activities and gene expression of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (G-ST), B-cell CLL/lymphoma 2 (Bcl-2) and insulin like growth factor-1 (IGF-1) in diabetic rats were studied.

The effects of curcumin on the activities and gene expression of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (G-ST), B-cell CLL/lymphoma 2 (Bcl-2) and insulin like growth factor-1 (IGF-1) in diabetic rats were studied.
Methods: Twenty four rats were assigned to three groups (8 rats for each). Rats of first group were non diabetic and rats of the second group were rendered diabetic by streptozotocin (STZ).
Both groups received vehicle, corn oil only (5 ml/kg body weight) and served as negative and positive controls, respectively. Rats of the third group were rendered diabetic and received oral curcumin dissolved in corn oil at a dose of 15 mg/5 ml/kg body weight for 6 weeks.
Results: Diabetic rats showed significant increase of blood glucose, thiobarbituric acid reactive substances (TBARS) and activities of all antioxidant enzymes with significant reduction of reduced glutathione (GSH) compare to the control non diabetic group.
Gene expression of Bcl2, SOD, CAT, GPX and GST was increased significantly in diabetic untreated rats compare to the control non diabetic group. The administration of curcumin to diabetic rats normalized significantly their blood sugar level and TBARS values and increased the activities of all antioxidant enzymes and reduced glutathione concentration.
In addition, curcumin treated rats showed significant increase in gene expression of IGF-1, Bcl2, SOD and GST compare to non diabetic and diabetic untreated rats.
Conclusion: Curcumin was antidiabetic therapy, induced hypoglycemia by up-regulation of IGF-1 gene and ameliorate the diabetes induced oxidative stress via increasing the availability of GSH, increasing the activities and gene expression of antioxidant enzymes and Bcl2. Further studies are required to investigate the actual mechanism of action of curcumin regarding the up regulation of gene expression of examined parameters.

Antioxidant biomaterial promotes healing

Purple corn anthocyanins inhibit diabetes-associated glomerular monocyte activation and macrophage infiltration 

Kang MK, Li J, Kim JL, Gong JH, Kwak SN, Park JH, Lee JY, Lim SS, Kang YH.
1Department of Food and Nutrition, Hallym University, Chuncheon, Korea; and 2Department of Biochemistry, School of Medicine, Hallym University, Chuncheon, Korea

Am J Physiol Renal Physiol 303: F1060–F1069, 2012.
Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. In early DN, renal injury and macrophage accumulation take place in the pathological environment of glomerular vessels adjacent to renal mesangial cells expressing proinflammatory mediators. Purple corn utilized as a daily food is rich in anthocyanins exerting disease-preventive activities as a functional food. This study elucidated whether anthocyanin-rich purple corn extract (PCA) could suppress monocyte activation and macrophage infiltration. In the in vitro study, human endothelial cells and THP-1 monocytes were cultured in conditioned media of human mesangial cells exposed to 33 mM glucose (HG-HRMC). PCA decreased the HG-HRMC-conditioned, media-induced expression of endothelial vascular cell adhesion molecule-1, E-selectin, and monocyte integrins-_1 and -_2 through blocking the mesangial Tyk2 pathway. In the in vivo animal study, db/db mice were treated with 10 mg/kg PCA daily for 8 wk. PCA attenuated CXCR2 induction and the activation of Tyk2 and STAT1/3 in db/db mice. Periodic acid-Schiff staining showed that PCA alleviated mesangial expansion-elicited renal injury in diabetic kidneys. In glomeruli, PCA attenuated the induction of intracellular cell adhesion molecule-1 and CD11b. PCA diminished monocyte chemoattractant protein-1 expression and macrophage inflammatory protein 2 transcription in the diabetic kidney, inhibiting the induction of the macrophage markers CD68 and F4/80. These results demonstrate that PCA antagonized the infiltration and accumulation of macrophages in diabetic kidneys through disturbing the mesangial IL-8-Tyk-STAT signaling pathway. Therefore, PCA may be a potential renoprotective agent treating diabetes-associated glomerulosclerosis.


Proximate analysis, phytochemical screening, and total phenolic and flavonoid content of Philippine bamboo Schizostachyum lumampao

Jovale Vincent V. Tongco1*, Remil M. Aguda2 and Ramon A. Razal1

1 Department of Forest Products and Paper Science, College of Forestry and Natural Resources,; 2 Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, College, Laguna, Philippines

Journal of Chemical and Pharmaceutical Research, 2014, 6(1):709-713



The chemical composition of the leaves of Schizostachyum lumampao, known as “buho” in the Philippines, was determined for its potential use as herbal tea with potential health benefits, such as antioxidant properties. Proximate analysis using standard AOAC methods showed that the air-dried leaves contain 10 % moisture, 30.5 % ash, 22.1 % crude protein, 1.6 % crude fat, 28.7 % crude fiber, and 7.2 % total sugar (by difference). Using a variety of reagents for qualitative phytochemical screening, saponins, diterpenes, triterpenes, phenols, tannins, and flavonoids were detected in both the ethanolic and aqueous leaf extracts, while phytosterols were only detected in the ethanolic extract. Using UV-Vis spectrophotometry, the total phenolic content (in GAE) were 76.7 and 13.5 gallic acid equivalents per 100 g air-dried sample for the ethanolic and aqueous extracts, respectively. The total flavonoid content were 70.2 and 17.86 mg quercetin equivalents per 100 g air-dried sample for the ethanolic and aqueous extracts, respectively. This preliminary study showed the total amount of phenolics and flavonoids present in buho, the phytochemicals present, and its proximate analysis.


Comparison of Nutritional Quality of the Vegan, Vegetarian, Semi-Vegetarian, Pesco-Vegetarian and Omnivorous Diet

Peter Clarys 1,2,Tom Deliens 1Inge Huybrechts 3,4Peter Deriemaeker 1,2Barbara Vanaelst 4Willem De Keyzer 4,5Marcel Hebbelinck 1 and Patrick Mullie 1,2,6

(This article belongs to the Special Issue Vegan diets and Human health)

Nutrients 20146(3), 1318-1332;

Abstract: The number of studies comparing nutritional quality of restrictive diets is limited. Data on vegan subjects are especially lacking. It was the aim of the present study to compare the quality and the contributing components of vegan, vegetarian, semi-vegetarian, pesco-vegetarian and omnivorous diets. Dietary intake was estimated using a cross-sectional online survey with a 52-items food frequency questionnaire (FFQ). Healthy Eating Index 2010 (HEI-2010) and the Mediterranean Diet Score (MDS) were calculated as indicators for diet quality. After analysis of the diet questionnaire and the FFQ, 1475 participants were classified as vegans (n = 104), vegetarians (n = 573), semi-vegetarians (n = 498), pesco-vegetarians (n = 145), and omnivores (n = 155). The most restricted diet, i.e., the vegan diet, had the lowest total energy intake, better fat intake profile, lowest protein and highest dietary fiber intake in contrast to the omnivorous diet. Calcium intake was lowest for the vegans and below national dietary recommendations. The vegan diet received the highest index values and the omnivorous the lowest for HEI-2010 and MDS. Typical aspects of a vegan diet (high fruit and vegetable intake, low sodium intake, and low intake of saturated fat) contributed substantially to the total score, independent of the indexing system used. The score for the more prudent diets (vegetarians, semi-vegetarians and pesco-vegetarians) differed as a function of the used indexing system but they were mostly better in terms of nutrient quality than the omnivores.

Comment (Larry H. Bernstein, MD): This article is problematic and makes me curious about the HEI-2010 and the MDS scoring systems.  Low intake of saturated fat gives weight to the vegan diet. The vegetarian diet would have higher content of high quality protein, and the omnivorous diet would be just as good if the fat were trimmed, and there was sufficient fruits and vegetables.  The problem is that quality of protein is not even weighted.  The ration of S/N is 1:20+ in plant sourced AAs, but it is 1:12.5 in animal sourced AAs.  This has consequences.

Influences of dietary methionine and cysteine on metabolic responses to immunological stress by Escherichia coli lipopolysaccharide injection, and mitogenic response in broiler chickens


Department of Animal Science, Faculty of Agriculture, Tohoku University, Sendai-shi, 981 Japan
British Journal of Nutrition (1997), 78, 815-821

The present experiments were conducted to investigate influences of dietary methionine and cysteine on metabolic responses to immunological stress induced by Escherichia coli lipopolysaccharide (LPS) injection, and concanavalin A (Con A)-induced mononuclear cell (MNC) proliferation in male broiler chickens. In Expt 1, chicks (12 d of age) were fed on a S amino acid (SAA)-deficient diet (5.6 g SAMg diet) or on three kinds of SAA-sufficient diet (9.3 g SAAkg diet; low-, medium- and high-cysteine diets) which contained 2.8, 4.65 and 6.5 g cysteinekg diet, respectively. Plasma (11-1 acid glycoprotein (AGP) concentration and interleukin (IL)-l-like activity in chicks fed on the SAA deficient diet were lower following a single injection of LPS than those in chicks fed on the SAAsufficient diets. At 16 h after LPS injection, plasma Fe and Zn concentrations and body weight were reduced, but AGP concentration and IL-1-like activity in plasma were significantly increased. These changes in body weight, plasma Zn and Fe concentrations following injection of LPS were not affected by dietary methi0nine:cysteine ratios. Plasma AGP concentration and IL-1-like activity in chicks fed on the high-cysteine diet were, however, greater than those in chicks fed on the other diets following a single injection of LPS. In Expt 2, chicks (7 d of age) were fed on the SAA-sufficient diets as in Expt 1 for 10 d. MNC proliferation in spleen induced by Con A in chicks fed on the high cysteine diet was greater than that in chicks fed on the low- or medium-cysteine diet. The results suggest that dietary cysteine has an impact on the immune and inflammatory responses.

The present experiment showed that plasma IL-1 like activity following LPS injection and T cell activity of the spleen estimated by Con A-induced MNC proliferation were greater in chicks fed on the high-cysteine diet than in chicks fed on the low- or medium cysteine diet, even though the diets contained 9.3 g SAA kg diet which is recommended by the National Research Council (1984) feeding standard. Tsiagbe et al. (19874 showed that cysteine was 70-84 % as efficient as methionine in enhancing IgG production and in delaying hypersensitivity to PHA-P stimulation. Thus dietary cysteine is not only important for T-cell function and antibody production, but also for macrophage response to LPS in broilers. However, our previous study (Takahashi et al. 1995) showed that a low-protein diet enhanced plasma IL-1-like activity compared with a high-protein diet in chicks, even though the supply of SAA from the diet in chicks fed on a low-protein diet was much less than that in chicks fed on a high-protein diet. These observations suggest that supply of SAA may not be the only factor affecting the immune responses. The combined results of the previous (Takahashi et al. 1995) and the present experiments, suggest that, as well as the supply of SAA, the methionine:cysteine ratio in the diet is an important factor affecting some immune responses, e.g. IL- 1-like activity, AGP concentration in plasma and mitogenic response of MNC in spleen. The present results also suggest that dietary cysteine intake has an impact on the immune and inflammatory responses, although replacement of cysteine with methionine in diets would not impair growth and reproduction within certain ratios in the diet (Graber & Baker, 1971; Ohta & Ishibashi, 1994 and the present study).

Methionine: Cysteine: Acute-phase response: Lipopolysaccharide


Antioxidant scaffolds for tissue engineering

When a foreign material like a medical device or surgical implant is put inside the human body, the body always responds. According to Northwestern’s Guillermo Ameer, most of the time, that response can be negative and affect the device’s function.

“You will always get an inflammatory response to some degree,” said Ameer, professor of biomedical engineering in McCormick School of Engineering and Applied Science and professor of surgery in the Feinberg School of Medicine. “A problem with commonly used plastic materials, in particular, is that in addition to that inflammatory response, oxidation occurs.”

We all need oxygen to survive, but a high concentration of oxygen in the body can cause oxidative reactions to fall out of balance, which modifies natural proteins, cells, and lipids and causes them to function abnormally. This oxidative stress is toxic and can contribute to chronic disease, chronic inflammation, and other complications that may cause the failure of implants.

For the first time ever, Ameer and his team have created a biodegradable biomaterial that is inherently antioxidant. The material can be used to create elastomers, liquids that turn into gels, or solids for building devices that are more compatible with cells and tissues. The research is described in the June 26 issue of Biomaterials.

“Plastics can self-oxidize, creating radicals as part of their degradation process,” Ameer said. “By implanting devices made from plastics, the oxidation process can injure nearby cells and create a cascade that leads to chronic inflammation. Our materials could significantly reduce the inflammatory response that we typically see.”

Ameer created the biomaterial, which is a polyester based on citric acid, by incorporating vitamin C as part of the building blocks. In preliminary experiments, his team coated vascular grafts with the antioxidant biomaterial, and the grafts were evaluated in animals by Ameer’s long-time collaborator Melina Kibbe, professor of surgery and the Edward G. Elcock Professor of Surgical Research at Feinberg and a vascular surgeon at Northwestern Memorial Hospital.

As part of the foreign body response, grafts tend to inflame nearby cells and slowly scar over time, which eventually leads to failure. When the antioxidant vascular graft was implanted, however, the scarring was significantly reduced. Ameer’s team, funded by a proof-of-concept grant from the Northwestern University Clinical and Translational Sciences Institute, also found that a water-soluble, thermo-reversible version of the material sped of the healing of diabetic ulcers. Because the material is biodegradable, it harmlessly is absorbed by the body over time.

“In the past, people have added antioxidant vitamins to a polymer and blended it in,” Ameer said. “That can affect the mechanical properties of the material and limit how much antioxidant you can add, so it doesn’t work well. What we’re doing is different. We’re building a material that is already inherently, intrinsically antioxidant.”

Ameer said the new biomaterial could be used to create scaffolds for tissue engineering, coat or build safer medical devices, promote healing in regenerative medicine, and protect cells, genes, and viruses during drug delivery. He added that the new biomaterial is easy to make and inexpensive.

“Citric acid is affordable and in pretty much everything we come in contact with on a daily basis—food and beverages, skin and hair products, drugs, etc.,” Ameer said. “It’s a common, inexpensive raw material to use, and our system can stabilize vitamin C, an antioxidant that we are all familiar with.”

The first author of the study was Robert van Lith, a PhD candidate in Ameer’s research laboratory.

Source: Northwestern Univ.


Pomegranate for Your Cardiovascular Health

Michael Aviram, D.Sc,* and Mira Rosenblat, M.Sc.

The Lipid Research Laboratory, The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, and Rambam Medical Center, Haifa, Israel
Rambam Medical Center J 2013;4 (2):e0013.


Pomegranate is a source of some very potent antioxidants (tannins, anthocyanins) which are considered to be also potent anti-atherogenic agents. The combination of the above unique various types of pomegranate polyphenols provides a much wider spectrum of action against several types of free radicals. Indeed, pomegranate is superior in comparison to other antioxidants in protecting low-density lipoprotein (LDL, “the bad cholesterol”) and high-density lipoprotein (HDL, “the good cholesterol”) from oxidation, and as a result it attenuates atherosclerosis development and its consequent cardiovascular events. Pomegranate antioxidants are not free, but are attached to the pomegranate sugars, and hence were shown to be beneficial even in diabetic patients. Furthermore, pomegranate antioxidants are unique in their ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques. Finally, unique pomegranate antioxidants beneficially decrease blood pressure. All the above beneficial characteristics make the pomegranate a uniquely healthy fruit.

Abbreviations: AAPH, 2,2′-azobis amidinopropane hydrochloride; ACE, angiotensin-converting enzyme; BP, blood pressure; CAS, carotid artery stenosis; CHD, coronary heart disease; CIMT, carotid intima-media thickness; EDV, end-diastolic velocity; GAE, gallic acid equivalents; HDL, high-density lipoprotein; HMDM, human monocyte-derived macrophages; LDL, low-density lipoprotein; LPDS, lipoprotein-deficient serum; MI, myocardial infarction; Ox-LDL, oxidized LDL; PJ, pomegranate juice; POMxl, an extract of the pomegranate outer peel; PON, paraoxonase; PSV, peak systolic velocity; ROS, reactive oxygen species; TAS, total antioxidant status; TBARS, thiobarbituric acid reactive substances; TGs, triglycerides; VLDL, very-low-density lipoprotein.
Citation: Aviram M, Rosenblat M. Pomegranate for Your Cardiovascular Health. RMMJ 2013;4 (2):e0013.


Cocoa Phenolic Extract Protects Pancreatic Beta Cells against Oxidative Stress


MÁ Martín, S Ramos, I Cordero-Herrero, L Bravo and L Goya
1 Department of Metabolism and Nutrition, Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN–CSIC), Madrid 28040, Spain
2 Centro de Investigación Biomédica en red de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII), Madrid 28039, Spain

Nutrients 2013, 5, 2955-2968;

Abstract: Diabetes mellitus is associated with reductions in glutathione, supporting the critical role of oxidative stress in its pathogenesis. Antioxidant food components such as flavonoids have a protective role against oxidative stress-induced degenerative and age-related diseases. Flavonoids constitute an important part of the human diet; they can be found in most plant foods, including green tea, grapes or cocoa and possess multiple biological activities. This study investigates the chemo-protective effect of a cocoa phenolic extract (CPE) containing mainly flavonoids against oxidative stress induced by tert-butylhydroperoxide (t-BOOH) on Ins-1E pancreatic beta cells. Cell viability and oxidative status were evaluated. Ins-1E cells treatment with 5–20 μg/mL CPE for 20 h evoked no cell damage and did not alter ROS production. Addition of 50 μM t-BOOH for 2 h increased ROS and carbonyl groups content and decreased reduced glutathione level. Pre-treatment of cells with CPE significantly prevented the t-BOOH-induced ROS and carbonyl groups and returned antioxidant defences to adequate levels. Thus, Ins-1E cells treated with CPE showed a remarkable recovery of cell viability damaged by t-BOOH, indicating that integrity of surviving machineries in the CPE-treated cells was notably protected against the oxidative insult.
Keywords: antioxidant defences; cocoa flavanols; dietary polyphenols; Ins-1E cells; oxidative biomarkers; type 2 diabetes mellitus


Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds

T Rodrigues, AS Ressurreição, FP da Cruz, IS Albuquerque, J Gut, MP Carrasco, D Gonçalves, RC Guedes, et al.

1Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Facultyof Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal
2Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
3Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, California, 94143, U.S.A.
4 REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, R. do Campo Alegre, 4169-007 Porto, Portugal
Reference: EJMECH 6410  European Journal of Medicinal Chemistry

PII: S0223-5234(13)00580-1

ABSTRACT: Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite l.berghei. Ligand efficient leads were identified as dual stage antimalarials, suggesting that scaffold optimization may afford potent antiplasmodial compounds.

 cite as: T. Rodrigues, A.S. Ressurreição, F.P. da Cruz, I.S. Albuquerque, J. Gut, M.P.

Carrasco, D. Gonçalves, R.C. Guedes, D.J.V.A. dos Santos, M.M. Mota, P.J. Rosenthal, R. Moreira, M. Prudêncio, F. Lopes, Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds, European Journal of Medicinal Chemistry (2013),  


Silencing of the sulfur rich α-gliadin storage protein family in wheat grains (Triticumae stivum L.) causes nounintended side-effects on other metabolites
C Zörb, D Becker, M Hasler, KH Mühling, V Gödde, K Niehaus and CM Geilfus
1 Institute of Biology, University Leipzig, Leipzig, Germany
2 Biocentre Klein Flottbek, EBBT, University of Hamburg, Hamburg, Germany
3 Lehrfach Variations statistik, 4 Institute of Plant Nutrition and Soil Science, Christian Albrechts University Kiel, Kiel, Germany
5 Department of Proteome and Metabolome Research, Faculty of Biology, Bielefeld University, Bielefeld, Germany
Frontiers in Plant Science 17 Sept, 2013;

Wheat is an important source of proteins and metabolites for human and animal nutrition. To assess the nutritional quality of wheat products, various protein and diverse metabolites have to be evaluated. The grain storage protein family of the α-gliadins are suggested to be the primary initiator of the inflammatory response to gluten in Celiac disease patients .With the technique of RNAi, the α-gliadin storage protein fraction in wheat grains was recently knocked down. From a patient’s perspective, this is a desired approach, however, this study aims to evaluate whether such a down-regulation of these problematic α-gliadins also has unintended side-effects on other plant metabolites. Such uncontrolled and unknown arbitrary effects on any metabolite in plants designated for food production would surely represent an avoidable risk for the consumer. In general,
α-gliadins are rich in sulfur, making their synthesis and content dependent on the sulfur supply. For this reason, the influence of the application of increasing sulfur amounts on the metabolome of α-gliadin-deficient wheat was additionally investigated because it might be possible that e.g., considerable high/low amounts of S might increase or even induce such unintended effects that are not observable under moderate S nutrition. By silencing the α-gliadin genes, a recently developed wheat-line that lacks the set of 75 corresponding α-gliadin proteins has become available. The plants were subsequently tested for RNAi– induced effects on metabolites that were not directly attributable to the specific effects of the RNAi– approach on the α-gliadin proteins. For this,GC-MS-based metabolite profiles were recorded. A comparison of wild type with gliadin-deficient plants cultivated in pot experiments revealed no differences in all 109 analyzed metabolites, regardless of the S-nutritional status.No unintended effects attributable to the RNAi– based specific genetic deletion of a storage protein fraction were observed.
Keywords: sulfur, wheat, gliadin, metabolites, Celiac disease, GC-MS


Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study

Guasch-Ferré et al. BMC Medicine 2014, 12(78):1741-7015


Background: It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk.

Methods: We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality.

Results: During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group.

Conclusions: Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk.

Trial registration: This study was registered at ( International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Keywords: Olive oil, Cardiovascular, Mortality, Mediterranean Diet, PREDIMED


Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Tresserra-Rimbau et al. BMC Medicine 2014, 12(77): 1741-7015;


Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk.

Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models.

Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids).

Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality.

Clinical trial registration: ISRCTN35739639.

Keywords: Polyphenol intake, All-cause mortality, PREDIMED, Mediterranean diet, Stilbenes, Lignans


Effects of Walnuts on Endothelial Function in Overweight Adults with Visceral Obesity: A Randomized, Controlled, Crossover Trial

David L Katz MD, MPHa, Anna Davidhi BSa, Yingying Ma MD, RVTa, Yasemin Kavak BSa,et al.
a Yale University Prevention Research Center, Griffin Hospital, Derby, Connecticut
Journal of the American College of Nutrition,  2013; 31(6) :415-423

Objectives: Metabolic syndrome is a precursor of diabetes and cardiovascular disease (CVD). Walnut ingestion has been shown to reduce CVD risk indices in diabetes. This randomized controlled crossover trial was performed to investigate the effects of daily walnut consumption on endothelial function and other biomarkers of cardiac risk in a population of overweight individuals with visceral adiposity.

Methods: Forty-six overweight adults (average age, 57.4 years; 28 women, 18 men) with elevated waist circumference and 1 or more additional signs of metabolic syndrome were randomly assigned to two 8-week sequences of walnut-enriched ad libitum diet and ad libitum diet without walnuts, which were separated by a 4-week washout period. The primary outcome measure was the change in flow-mediated vasodilation (FMD) of the brachial artery. Secondary measures included serum lipid panel, fasting glucose and insulin, Homeostasis Model Assessment–Insulin Resistance values, blood pressure, and anthropometric measures.

Results: FMD improved significantly from baseline when subjects consumed a walnut-enriched diet as compared with the control diet (1.4% 6 2.4% versus 0.3% 6 1.5%; p¼0.019). Beneficial trends in systolic blood pressure reduction were seen, and maintenance of the baseline anthropometric values was also observed. Other measures were unaltered.

Conclusion: Daily ingestion of 56 g of walnuts improves endothelial function in overweight adults with visceral adiposity. The addition of walnuts to the diet does not lead to weight gain. Further study of the potential role of walnut intake in diabetes and CVD prevention is warranted.

To cite this article: David L Katz MD, MPH, Anna Davidhi BS, Yingying Ma MD, RVT, Yasemin Kavak BS, Lauren Bifulco MPH & Valentine Yanchou Njike MD, MPH (2012) Effects of Walnuts on Endothelial Function in Overweight Adults with Visceral Obesity: A Randomized, Controlled, Crossover Trial, Journal of the American College of Nutrition, 31:6, 415-423,


Additional references

Antioxidant properties of ten high yielding rice varieties of Bangladesh

AK Dutta, PS Gope, S Banik, S Makhnoon, MA Siddiquee, Y Kabir
Asian Pacific Journal of Tropical Biomedicine (2012)S99-S103

Role Of Dietary Fiber In Improving Human Physiology And In Controlling Diseases
Yadav Pn, Srivastava S and Narayan Rp
IJBPAS, January, 2014, 3(1): 98-112

The Importance of Prebiotics in Functional Foods and Clinical Practice

VM Caselato de Sousa, EF dos Santos, VC Sgarbieri
Food and Nutrition Sciences, 2011, 2, 133-144

Phloem-specific expression of a melon Aux/IAA in tomato plants alters auxin sensitivity and plant development
Guy Golan, Rotem Betzer and Shmuel Wolf*
The Robert H. Smith Facultyof Agriculture, Food and Environment,Otto Warburg Minerva Center for Agricultural Biotechnology,The Robert H. Smith Institute of Plant Sciences and Genetics in Agriculture,The Hebrew University of Jerusalem, Rehovot, Israel
Frontiers in Plant Science Aug 2013;

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Dementia does not cause Depression, Depression is independent of Demensia Biomarkers

Reporter: Aviva Lev-Ari, PhD, RN


If the two Mental health conditions are independent, due to distinct etiologies —

What implications these research findings could have on Treatment of each of the diseases?


Depression in Elderly Not Related to Dementia Markers



Published: Jul 30, 2014








A New Risk Factor For Dementia: Depression Symptoms Linked To More Rapid Decline In Memory




Clinical-pathologic study of depressive symptoms and cognitive decline in old age

  1. Robert S. Wilson, PhD,
  2. Ana W. Capuano, PhD,
  3. Patricia A. Boyle, PhD,
  4. George M. Hoganson, MD,
  5. Loren P. Hizel, BA,
  6. Raj C. Shah, MD,
  7. Sukriti Nag, MD,
  8. Julie A. Schneider, MD,
  9. Steven E. Arnold, MD and
  10. David A. Bennett, MD



  1. Correspondence to Dr. Wilson:
  1. Neurology 10.1212/WNL.0000000000000715



  1. Also available:
  2. Data Supplement



Objective: To clarify the relationship between depressive symptoms and the clinical and neuropathologic manifestations of dementia.

Methods: In a clinical-pathologic cohort study, 1,764 older persons without cognitive impairment at enrollment completed annual clinical evaluations for a mean of 7.8 years. The evaluations included assessment of depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) and cognitive function (battery of 17 performance tests). A total of 582 individuals died during follow-up and underwent a uniform neuropathologic examination to quantify β-amyloid plaques and tau tangle density in multiple brain regions and identify neocortical Lewy bodies, hippocampal sclerosis, and gross and microscopic cerebral infarcts.

Results: Level of depressive symptoms slightly increased during follow-up. Incident mild cognitive impairment (52.2%) was associated with higher level of depressive symptoms before the diagnosis but not with change in symptoms after the diagnosis; incident dementia (17.9%) was associated with higher symptom level before dementia onset and with more rapid decline in symptoms after dementia onset. None of the neuropathologic markers was related to level of depressive symptoms or change in symptoms over time. In a mixed-effects model adjusted for the neuropathologic markers, higher level of depressive symptoms averaged over evaluations was associated with more rapid global cognitive decline, accounting for 4.4% of the variability in decline not attributable to the neuropathologic markers. Depressive symptoms did not modify the association of the neuropathologic markers with cognitive decline.

Conclusion: In old age, depressive symptoms have an association with cognitive decline that is independent of the neuropathologic hallmarks of dementia.


  • Received February 6, 2014.
  • Accepted in final form May 17, 2014.




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The Methodology of Curation for Scientific Research Findings

Author and Curator: Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books



This article became the Part One in Volume Two of e-Series A: Cardiovascular Diseases


Cardiovascular Original Research:

Cases in Methodology Design for Content Co-Curation

The Art of Scientific & Medical Curation

Justin D Pearlman, MD, PhD, FACC

Larry H Bernstein, MD, FCAP


Aviva Lev-Ari, PhD, RN


1.1 The Methodology Explained


Part 1 serves as an introduction to the Writing Methodology to be shared by the subsequent FIVE  volumes (and was used in Volume One.)  These volumes are created by applying the Curation Methodology explained by examples in Volume Two. The entire e-Series A: Cardiovascular Diseases, which consists of Seven Volumes of CURATIONS, were all created from critique and synthesis of Original Scientific Research Articles published in the Peer Reviewed literature.



Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC



Since 4/2012, Leaders in Pharmaceutical Business Intelligence, is developing an innovative methodology for the facilitation of Global access to Biomedical knowledge rather than the access to sheer search results on Scientific subject matters in the Life Sciences and Medicine. For the methodology to attain this complex goal it is to be dealing with popularization of ORIGINAL Scientific Research via Content Curation of Scientific Research Results by Experts, Authors, Writers using the critical  thinking process of expert interpretation of the original research results.


We make a distinction between Curation by a Single Curator and Co-Curation by Several Experts, Authors, Writers.


1.1.1 Curation by a Single Curator


One curator edifies the e-Reader via his/hers OWN creative mental processes of knowledge synthesis following the personal creative mental process of analytical critique of the subject matter. The outcome is a new FORM of writing Science and of writing about Science, as well as, a new FORM of framework been created for the organization of the interrelations exposed in the analytical phase of a dialectically generated original synthesis. This process has multi phases:


  • the conception of the structure of the knowledge presented,
  • culling in the midst of inclusion/exclusion dialectics, and finally
  • the exposition of the Curator’s own original synthetic statements of the new Art, a new conceptual perspective on Science.


1.1.2  Co-Curation by Several Experts, Authors, Writers


A similar process to the one in Curation by a Single Curator is taking place and  is been applied. However, the Co-Curation, brings on stage several players. The Actors in the Scientific Writers Theater,  all own scientific knowledge and master the process of creation of a new Synthesis for most writing engagements. Since the Co-curators are educated in different disciplines, they are skillfully providing interpretations for others’ and their own new conception of ideas. Thus, they are developing new views of the original scientific results presented in peer reviewed journals, just the leading ones in every field. The Co-Curators, their creation represents a new layer of comprehension for the subject matter derived from intersecting mental processes coming into being by cross fertilizations of ideas.


Example #1:


Action Potential, a well define concept in Physiology. For us,  Action Potential was a conceptual creation for the process of Co-Curation. Dr. Lev-Ari, requesting Dr. Bernstein to elaborate creatively, on the function of actin in cytoskeleton mobility, he did,  THEN a new conceptual creation process emerged and had YIELDED the following article:


Identification of Biomarkers that are Related to the Actin Cytoskeleton


Curator: Larry H Bernstein, MD, FCAP


Example #2:


The e-Reader reads first


High Serum Calcium Linked to Developing Diabetes: IRAS Study


 Sep 24, 2013


The e-Reader reads second the curation of that Source Interview


Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker


The e-Reader will compare which of the two is more beneficial for the e-Reader.


We believe that the curation of the Source Interview has remarkable value added analysis that the Reader can benefit from.


The unique process as described for the Single Curator and for Co-Curation, above, will be demonstrated, in this volume with an emphasis on Co-Curation,  by presentation of concrete cases, as we applied the methodology of curation by one or by several Experts, Authors, Writers in the field of Cardiovascular Diseases.


1.1.3 Editor’s Curation of an electronic Table of Contents (eTOCs) of an e-Book or a Hardcover Volume


The Voice of Content Consultant Justin D. Pearlman, MD, PhD, FACC


The superstructure of curations includes multiple additional creative elements:


1. eTOCs stands for electronic Table of Contents, a fresh thought-provoking organizing themes link a path to a diverse trail of publications (analogous to creating a path in the forest)
2. Extracts highlighting notable elements of publications that mark a path
3. Voice of Expert commentary providing context and direction


The Electronic Table of Contents (eTOCs) serves several functions:
1. eTOCs collates information from multiple sources into coherent themes
2. eTOCs enables multiple pathways to information, including both Longitudinal and cross-sectional organizational themes.
3. eTOCs presents nested pathways through the forest, including nesting of topics by overreaching theme, chapters, Curations, reports and references.
4. eTOCs assemblies of thought provide fresh vistas that promote innovation and rethinking





1.2 The Creation Process of a Curation as an Alternative Model for Scientific Publishing


  • We culled the scene for Cardiovascular Original Research in +24 Journals,
  • We pre-select domains of research to cover:


The Etiology of the Disease, the Risks of dysfunction at cellular, tissue, organelle, organ, anatomy, physiology, pathophysiology and diagnostics for all of the above.


  • We interpret the Disease Management Options in a comprehensive fashion, exposing the e-Reader to an integrative approach for the treatment of Cardiovascular Disease.


1.3 FIVE steps in the Creation Process of a Curation



1.3.1  CURATION and Co-CURATION of Scientific articles in conjunction with Experts, Authors, Writers critique and synthesis




  • Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker


Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN



Vivek Lal, MBBS, MD, F.Cl.R,  Justin D Pearlman, MD, PhD, FACC
 and Aviva Lev-Ari, PhD, RN


  • Alternative Designs for the Human Artificial Heart: The Patients in Heart Failure – Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community


Larry H. Bernstein, MD, FCAP, Justin D Pearlman, MD, PhD, FACC
 and Aviva Lev-Ari, PhD, RN



1.3.2  Assembly of articles into e-Books using ONE of a Kind electronic Table of Contents (eTOCs) architecture


Example of an electronic Table of Contents for an e-Book



Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

This e-Book has the following Parts:

Genomics and Medicine

Introduction to Volume Three

1.1  Genomics and Medicine: The Physician’s View
1.2  Ribozymes and RNA Machines – Work of Jennifer A. Doudna
1.3  Genomics and Medicine: Contributions of Genetics and Genomics to Cardiovascular Disease Diagnoses

1.4 Genomics Orientations for Individualized Medicine, Volume One

1.4.1 CVD Epidemiology, Ethnic subtypes Classification, and Medication Response Variability: Cardiology, Genomics and Individualized Heart Care: Framingham Heart Study (65 y-o study) & Jackson Heart Study (15 y-o study)

1.5  Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data

Epigenetics – Modifiable Factors Causing Cardiovascular Diseases

2.1 Diseases Etiology

2.1.1 Environmental Contributors Implicated as Causing Cardiovascular Diseases
2.1.2 Diet: Solids and Fluid Intake and Nutraceuticals

2.1.3 Physical Activity and Prevention of Cardiovascular Diseases

2.1.4 Psychological Stress and Mental Health: Risk for Cardiovascular Diseases

2.1.5 Correlation between Cancer and Cardiovascular Diseases

2.1.6 Medical Etiologies for Cardiovascular Diseases: Evidence-based Medicine – Leading DIAGNOSES of Cardiovascular Diseases, Risk Biomarkers and Therapies
2.1.7 Signaling Pathways
2.1.8 Proteomics and Metabolomics

2.2 Assessing Cardiovascular Disease with Miomarkers

2.2.1 Issues in Genomics of Cardiovascular Diseases
2.2.2 Endothelium, Angiogenesis, and Disordered Coagulation
2.2.3 Hypertension BioMarkers
2.2.4 Inflammatory, Atherosclerotic and Heart Failure Markers
2.2.5 Myocardial Markers

2.3  Therapeutic Implications: Focus on Ca(2+) signaling, platelets, endothelium

2.3.1 The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors

2.3.2 Platelets in Translational Research ­ 2

2.3.3 The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis

2.3.4 Nitric Oxide Synthase Inhibitors (NOS-I)

2.3.5 Resistance to Receptor of Tyrosine Kinase

2.3.6 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation

2.3.7 Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

2.4 Comorbidity of Diabetes and Aging

2.4.1 Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients

Determinants of Cardiovascular Diseases Genetics, Heredity and Genomics Discoveries


3.1 Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)

3.1.1 Aneuploidy and Carcinogenesis

3.2 Functional Characterization of Cardiovascular Genomics: Disease Case Studies @ 2013 ASHG

3.3 Leading DIAGNOSES of Cardiovascular Diseases covered in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013

3.3.1: Heredity of Cardiovascular Disorders

3.3.2: Myocardial Damage

3.3.3: Hypertention and Atherosclerosis

3.3.4: Ethnic Variation in Cardiac Structure and Systolic Function

3.3.5: Aging: Heart and Genetics

3.3.6: Genetics of Heart Rhythm

3.3.7: Hyperlipidemia, Hyper Cholesterolemia, Metabolic Syndrome

3.3.8: Stroke and Ischemic Stroke

3.3.9: Genetics and Vascular Pathologies and Platelet Aggregation, Cardiac Troponin T in Serum

3.3.10: Genomics and Valvular Disease

3.4  Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease

Individualized Medicine Guided by Genetics and Genomics Discoveries

4.1 Preventive Medicine: Cardiovascular Diseases

4.1.1  Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges

4.2 Gene-Therapy for Cardiovascular Diseases

4.2.1 Genetic Basis of Cardiomyopathy

4.3 Congenital Heart Disease/Defects

4.4 Pharmacogenomics for Cardiovascular Diseases

4.4.1 Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives

4.4.2 Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

4.4.3 Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

4.4.4 Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes

4.4.5 Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction – The GEOSTAT-1 Study



1.3.3 Assembly of e-Books into e-Series





Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC




1.3.4 Publishing of e-Series on


The BioMedicine e- Book Series has published of the following e-Books Titles with Amazon KINDLE:


Volume One: Perspectives on Nitric Oxide in Disease Mechanisms (2013) 


1.3.5 Distribution of e-Series to Professional Associations via their Internet websites


The Plan includes the following Associations:



In 2013 and Beyond, we are launching a Series of e-Books (electronic Books) in BioMedicine made up by articles published in this Open Access Online Scientific Journal.


BioMedicine e-Series Editor-in-Chief, Aviva Lev-Ari, PhD, RN has created over 800 articles in an inventory of 1,506 available on 12/30/2013 on http://pharmaceuticalintelligence.comThe Open Access Online Scientific Journal was launched on 4/2012.


BioMed e-Series was launched by Dr. Lev-Ari on 10/2013:


BioMed e-Series – Five Titles


Scientific Journal Site Statistics

Date |Views to Date |# of articles |NIH Clicks |Nature Clicks

07/29/2013   217,356 1,138 1,389 705
12/01/2013   287,645 1,428 1,676 828
02/09/2014   325,039 1,665 1,793 892
03/05/2014   338,958 1,717 1,830 965
03/21/2014   347,667 1,750 1,838 974

03/31/2014  352,683 1,768 1,869 991

05/12/2014  373.696  1,878  1,944  1,035

06/18/2014  393,111  1,992  1,982  1,087

7/27/2014  418,570  2,098  2.050  1,124

9/2/2014  444,222  2,226  2,104  1,170

10/9/2014 471,117  2,337  2,147  1,216

Date             |    Views to Date |# of articles |NIH Clicks |Nature Clicks

11/4/2014  492,736          2,471           2,194           1,234


1.4 Other Alternative Types to the Academic Publishing Model includes the following:


Alternative #1


PeerJ MODEL for Open Access Online Scientific Journal


Alternative #2

Read Cube

Alternative #3

eLife is a collaboration between the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust, and over 200 of the world’s most talented biomedical scientists.

SOURCE for Alternative Models to Academic Publishing


1.5 Methodology of Curation Applied to Medical Research Findings


Creation of Scientific knowledge involved development of numerous avenues for exposition of the scientific product, among them, scientific articles in Sceintific Journals, Books, Addresses by Leader Scientists, multimedia presentations (Audio and Video), Expert Panel Discussions, Correspondence among Scientists, archive of experiment results, thematic Literature surveys, Libraries of Open Source Code, Shareable Libraries of Annotated Genomics Research, to mention the main ones.



1.5.1 The Voice of Content Consultant on The Methodology of Curation


Justin D Pearlman, MD, PhD, FACC


The explosion of information by numerous media, hardcopy and electronic, written and video, has created difficulties tracking topics and tying together relevant but separated discoveries, ideas, and potential applications. Some methods to help assimilate diverse sources of knowledge include a content expert preparing a textbook summary, a panel of experts leading a discussion or think tank, and conventions moderating presentations by researchers. Each of those methods has value and an audience, but they also have limitations, particularly with respect to timeliness and pushing the edge. In the electronic data age, there is a need for further innovation, to make synthesis, stimulating associations, synergy and contrasts available to audiences in a more timely and less formal manner. Hence the birth of curation.


Curation is a process that collates numerous avenues of exposition on scientific products including Journal articles, monographs, textbooks, lectures, video and other media presentations, panel discussions, correspondence among scientists, archives of experiment results, thematic Literature surveys, personal experiences and shared libraries of data.


Curations represent summaries, highlights, critiques and synthesis of information, with an emphasis on the frontiers. So far there are three types of curation we offer:


(1) single curation, whereby a domain expert assembles seminal articles, outcomes, and context to summarize new directions, point out interrelations and implications, especially those not included in the components of the assembly.


(2) directed curation, whereby an Editor collates data, selects initial topics and assigns expert reviews to a team of experts.


(3) co-curation, whereby a theme or task sparks a collation of previously disparate works to promote new insights and thought stimulations with a team of curators serving as guides.


This volume presents examples of curation and co-curation which hopefully will stimulate new thoughts about the topics, as well thoughts about the novel methods of information promotion.



Below, the Curation Process is been contrasted with the Art of Scientific Creation. This contrast is in full analogy to the comparison of Primary Research(Creation of Scientific Knowledge) with Secondary Research (Critique and Synthesis of Original Scientific knowledge using the Methodology of Curation.)



1.5.2  Curation is Uniquely Distinguished by the Historical Exploratory Ties that Bind


Larry H Bernstein, MD, FCAP


A. The Scientific Creation


Important features and criteria that contribute to scientific curation of medical, biological, and pharmaceutical research, including structural and functional content from the sciences of anatomy, physiology, physics and chemistry.


The principles that I seek to realized is a foundation in the body of knowledge thatprecedes the discovery or innovation.  Is the discovery essential, but unnoticed because of unlinkings to prior established concepts.  This is extremely difficult to cull out, but it has had a recurrent history.  It might be easiest to refer to examples in physics, such as, the unique Nobel Prize discovery of pseudo-crystals that has had an impact on materials science. But actually, in the history of mathematics, astronomy, and physics, and later in anatomy and physiology, we have an “audit trail” in writings from the Hellenistic period, interrupted by the dark ages and the Bubonic Plague, and a reawakening in the period preceding and through the enlightenment and reformation. This carried significant risks for great thinkers in a society that changes slowly, and with repeated interruptions throughout all periods by wars.  One might say that this has no relevance to curation, but repeatedly, libraries and museums preserved discovery that could be re-examined later. Thus, we can’t discard the brilliance of Hipparchos, whose influence on Ptolemy is known, and who discovered the centrality of the Sun to our universe, even though the extent to which he accepted societal belief in astrology is at best limited.  The work of Copernicus later was under great duress, but gave precedence to Galileo and Newton.


The Hellenistic period also gave us Euclid and Archimedes, which was critical for the development of mathematics and measurement, and El Gibr’ gave us algebra. In his time, Archimedes found no-one who he could share his ideas with other than Conon, who died too early, but he was later read by Omar Kayyam,  Leonardo da Vinci, Galileo and Newton.  The Greek diagrams used by Archimedes of Syracuse were a major contribution to cognition and inference.  The Archimedes Palimpses, which were given to us as by the priest-scribe, Ioannes Myronas in 1229, is historically a major contribution revealing Archimedes work in the Method. There is the center of gravity of a triangle, and the treatise on Balancing Planes, from which he deduces that if you place two objects on a balance on which the distances are movable from the fulcrum, the distance of the lighter object is five times the distance of the heavier object.  The rule is that weights balance when they are reciprocal to their distance. Then there is Fermat’s Last Theorem, unsolved problem for centuries since the seventeenth century.The theorem state that while the square of a whole number can can be broken down into two other squares of whole numbers the same cannot be done for cubes or any higher power. The theorem took seven years to write, with a ynother year to edit.The principle was incorporated into the Pythagorean Theorem, and in 1955 two japanese mathematicians made a far reaching conjecture that paved the way to the solution by Andrew Wiles at Princeton in 1995.


Notably, the great mathematician, Gauss, who published Disquisition on Mathematics in 1801, on  number theory at age 24, refused to engage in the solution, but his work in complex analysis, based on earlier work by Euler involving imaginary numbers was crucial to the 20th century understanding.Perhaps another apt example is Einstein’s general theory of relativity, the prediction of gravitational radiation bringing a new attention to the tiny ripples in space-time that has opened our eyes to modern cosmology. Finally, we find that a small piece of our universe is viewed as a chunk of Hilbert space, developing as a nest of interacting probability waves. The waves of Hilbert space are actually the waves Schroedinger derived before we had the tools to observe their behavior.The mathematics of entanglement identifies the high-probability areas of a joint-Hilbert space developed from the interaction having consistent histories. This has led to the description of Schroedinger’s principle, the things that we consider to be real are stable persistent patterns. This gives rise to debate about many worlds.


We leave the seemingly esoteric world of problems in mathematics and theoretic physics and return to the world of biochemistry, molecular biology, genomics, proteomics and allied medical sciences.


The scientific underpinnings of biology and medicine transitioned from a largely observational and descriptive phase in the 19th century with the scientifc leadership of Rudolph VirchowLouis Pasteur, Robert Koch, John Hunter, Edward Jennings, Walter Reed, Karl Landsteiner, and Thomas Hunt Morgan.  Pasteur, Koch, Landsteiner and Morgan were outstanding experimentalists.  The latter two were to receive Nobel Prizes that began in 2001.  The idea of a more fundamental basis for biological sciences was concerned with studying the chemical structures and processes of biological phenomena that involve the basic units of life, and it developed out of the related fields of biochemistrygenetics, and biophysics. The primary focus became the study of proteins and nucleic acids—i.e., the macromolecules that are essential to life processes. A great impetus was provided by enabling the three-dimensional structure of these macromolecules through such techniques as X-ray diffraction and electron microscopy. In seeking to understand the molecular basis of genetic processes; molecular biologists map the location of genes on specific chromosomes, associate these genes with particular characters of an organism, and use recombinant DNA technology to isolate, sequence, and modify specific genes.


The above is tied to a dominance of Western scientific discovery, as seen in the recipients of the Nobel Prize, but it is only a two dimensional view. Here another type of graphical display would be more informative, and it has been developed. I might consider a separation by type for physics, chemistry and medicine, leaving out the others, and then, in combination. I would bet that there are interactions.


For instance – 2001 – Roentgen, Physics; Pierre and Marie Curie, Physics; E.O. Lawrence, Chemistry, Berkeley Radiation Lab; Max Planck, following on Boltzmann and on Josiah Willard Gibbs (pre-Nobel) work. Then you have radiology and radioisotope chemistry and photosynthesis, Martin Kamen. Of course, modern physiology and metabolism traces back to the work on oxygen, carcon dioxide, and heat, adiabatic systems, and leads to the calorimeter, the Warburg apparatus, which credits Pasteur’s work 60 years earlier. The fruit fly genetics was an impetus for cracking the genetic code, but the impetus for that was both from Gregor Mendel and Charles Darwin, and then the mathematical work of Pearson and of Fischer. The work on the chemical bond by Linus Pauling really opened up a foundation for understanding organic and inorganic reactions based on atomic orbital theory that was essential for pursuit of the double helix. This was so important that it unlocked the structure of polymeric proteins through the disulfide bond, and also metalloprotein complexes (heme, …). Wouldn’t it be incredible to map the Nobel work to seminal work done in the 100 years before the Prize with different colored arrows to show stromg and weaker associations? This is in a strong sense, a method of CURATION (as opposed to creation), that is very important for a fundamental grasp of the growth of and ties in the development of the knowledgebase.


Wouldn’t it be incredible to map the Nobel work to seminal work done in the 100 years before the Prize with different colored arrows to show stromg and weaker associations? This is in a strong sense, a method of CURATION (as opposed to creation), that is very important for a fundamental grasp of the growth of and ties in the development of the knowledge-base.


Such a discussion in depth is the curation that is intended for the strategic-plan-for-2014-1015/2014-milestones-in-physiology-discoveries-in-medicine



B. Scientific Findings 


Critique, Synthesis and Interpretation in Context –The Art of Curation


Dr. Lev-Ari continued her work, beyond Volume Two, above, on Curation as a Methodology for Critique of the Scientific Frontier and developed an effective method for synthesis of scientific milestones in the following selective list of articles:


e-Recognition via Friction-free Collaboration over the Internet: “Open Access to Curation of Scientific Research by Aviva Lev-Ari, PhD, RN


Digital Publishing Promotes Science and Popularizes it by Access to Scientific Discourse by Aviva Lev-Ari, PhD, RN


Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging


The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN


Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1


The Fatal Self Distraction of the Academic Publishing Industry: The Solution of the Open Access Online Scientific Journals


For a complete list of her Curations, go to



Other related articles published in this Open Access Online Scientific Journal include the following: 


The amazing history of the Nobel Prize, told in maps and charts


Quantum Biology And Computational Medicine
Curator: Larry H. Bernstein, MD, FCAP


Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes
Reporter: Aviva Lev-Ari, PhD, RN


Breast Cancer, drug resistance, and biopharmaceutical targets
Reporter: Larry H Bernstein, MD


The Initiation and Growth of Molecular Biology and Genomics – Part I
Curator: Larry H Bernstein, MD, FCAP


Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options
Curator, Reporter, EAW: Larry H Bernstein, MD, FCAP


Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control
Curator and Author: Larry H Bernstein, MD, FCAP


How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia
Curator: Larry H Bernstein, MD, FACP


Vegan Diet is Sulfur Deficient and Heart Unhealthy
Larry H. Bernstein, MD, FCAP, Curator


Portrait of a great scientist and mentor: Nathan Oram Kaplan
Author: Larry H. Bernstein, MD




1. George Sarton. A History of Science: Hellenistic Science and Culture in the last three centuries B.C. 1959. Harvard University Press. Cambridge, MA, USA.
2. Reviel Netz & William Noel. The Archimedes Codex: How a medieval prayer book is revealing the true genius of antiquity’s greatest scientist. 2007. Da Capo Press.
Perseus Books Group, Philadelphia, PA, USA.
3. Amir D Aczel. Fermat’s last theorem: Unlocking the secret of an ancient methematical problem.  Four Walls Eight Windows. 1996. New York, NY, USA.
4. Colin Bruce. Schroedinger’s Rabbits: the many worlds of quantum.  2004. Joseph Henry Press. Washington, DC, USA.
5. Marcia Bartusiak. Einstein’s Unfinished Symphony: listening to the sounds of spac^2 E-time.  The Berkley Publishing Group, New York, NY, USA.


SOURCES on Curation and Science




« Curation is the new research, »… et le nouveau média, Benoit Raphael, 2011


La curation : la révolution du webjournalisme?,


La curation : les 10 raisons de s’y intéresser, Pierre Tran


Curation : quelle valeur pour les entreprises, les médias, et sa « marque personnelle »?, Marie-Laure Vie


Cracking Open the Scientific Process, Thomas Lin, New York Times


La « massification » du web transforme les relations sociales, Valérie Varandat, INRIA


Internet a révolutionné le métier de chercheur, AgoraVox


Gérer ses références numériques, Université de Genève


Notre liste Scoop-it : Scientific Social Network, MyScienceWork

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A Primer on DNA and DNA Replication

Reporter and Curator: Larry H. Bernstein, MD, FCAP 



This is the FIRST discussion of a several part series leading from the genome, to protein synthesis (1), posttranslational modification of proteins (2), examples of protein effects on metabolism and signaling pathways (3), and leading to disruption of signaling pathways in disease (4), and effects leading to mutagenesis.

1.  A Primer on DNAand DNA Replication

















Polymerase Chain Reaction

Polymerase Chain Reaction






2. Overview of translational medicine

3. Genes, proteomes, and their interaction

4. Regulation of somatic stem cell Function

5.  Proteomics – The Pathway to Understanding and Decision-making in Medicine

6.  Genomics, Proteomics and standards

7.  Long Non-coding RNAs Can Encode Proteins After All

8.  Proteins and cellular adaptation to stress

9.  Loss of normal growth regulation



A Primer on DNA and DNA Replication


DNA Replication

DNA carries the information for making all of the cell’s proteins. These pro­teins implement all of the functions of a living organism and determine the organism’­s characteristics. When the cell reproduces, it has to pass all of this information on to the daughter cells.

Before a cell can reproduce, it must first replicate, or make a copy of, its DNA. Where DNA replication occurs depends upon whether the cells is a prokaryote or a eukaryote (see the RNA sidebar on the previous page for more about the types of cells). DNA replication occurs in the cytoplasm of prokaryotes and in the nucleus of eukaryotes. Regardless of where DNA replication occurs, the basic process is the same.

The structure of DNA lends itself easily to DNA replication. Each side of the double helix runs in opposite (anti-parallel) directions. The beauty of this structure is that it can unzip down the middle and each side can serve as a pattern or template for the other side (called semi-conservative replication). However, DNA does not unzip entirely. It unzips in a small area called a replication fork, which then moves down the entire length of the molecule.

Eukaryotic DNA replication (Wikipedia), is a conserved mechanism that restricts DNA replication to only once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

DNA replication is the action of DNA polymerases synthesizing a DNA strand complementary to the original template strand. To synthesize DNA, the double-stranded DNA is unwound by DNA helicases ahead of polymerases, forming a replication fork containing two single-stranded templates.

Replication processes permit the copying of a single DNA double helix into two DNA helices, which are divided into the daughter cells at mitosis. The major enzymatic functions carried out at the replication fork are well conserved from prokaryotes to eukaryotes, but the replication machinery in eukaryotic DNA replication is a much larger complex, coordinating many proteins at the site of replication, forming the replisome.[1]

The replisome is responsible for copying the entirety of genomic DNA in each proliferative cell. This process allows for the high-fidelity passage of hereditary/genetic information from parental cell to daughter cell and is thus essential to all organisms. Much of the cell cycle is built around ensuring that DNA replication occurs without errors.[1]

In G1 phase of the cell cycle, many of the DNA replication regulatory processes are initiated. In eukaryotes, the vast majority of DNA synthesis occurs during S phase of the cell cycle, and the entire genome must be unwound and duplicated to form two daughter copies. During G2, any damaged DNA or replication errors are corrected. Finally, one copy of the genomes is segregated to each daughter cell at mitosis or M phase.[2] These daughter copies each contain one strand from the parental duplex DNA and one nascent antiparallel strand.

This mechanism is conserved from prokaryotes to eukaryotes and is known as semiconservative DNA replication. The process of semiconservative replication for the site of DNA replication is a fork-like DNA structure, the replication fork, where the DNA helix is open, or unwound, exposing unpaired DNA nucleotides for recognition and base pairing for the incorporation of free nucleotides into double-stranded DNA.[3]


Let’s look at the details:

  1. An enzyme called DNA gyrase makes a nick in the double helix and each side separates
  2. An enzyme called helicase unwinds the double-stranded DNA
  3. Several small proteins called single strand binding proteins(SSB) temporarily bind to each side and keep them separated
  4. An enzyme complex called DNA polymerase“walks” down the DNA strands and adds new nucleotides to each strand. The nucleotides pair with the complementary nucleotides on the existing stand (A with T, G with C).
  5. A subunit of the DNA polymerase proofreads the new DNA
  6. An enzyme called DNA ligaseseals up the fragments into one long continuous strand
  7. The new copies automatically wind up again

Different types of cells replicated their DNA at different rates. Some cells constantly divide, like those in your hair and fingernails and bone marrow cells. Other cells go through several rounds of cell division and stop (including specialized cells, like those in your brainmuscle and heart). Finally, some cells stop dividing, but can be induced to divide to repair injury (such as skin cells and liver cells). In cells that do not constantly divide, the cues for DNA replication/cell division come in the form of chemicals. These chemicals can come from other parts of the body (hormones) or from the environment.









Diagram of the formation of the pre-replicative complex transforming into an active replisomeMcm 2-7 complex loads onto DNA at replication origins during G1 and unwinds DNA ahead of replicative polymerases.Cdc6 and Cdt1 bring Mcm complexes to replication origins. CDK/DDK-dependent phosphorylation of pre-replicative proteins leads toreplisome assembly and origin firing. Cdc6 and Cdt1 are no longer required and are removed from the nucleus or degraded. Mcms and associated proteins, GINS and Cdc45, unwind DNA to expose template DNA. At this point replisome assembly is completed and replication is initiated. “P” represents phosphorylation.


Minichromosome Maintenance Protein Complex[edit]

Main article: Minichromosome maintenance

The assembly of the minichromosome maintenance (Mcm) proteins function together as a complex in the cell. The assembly of the Mcm proteins onto chromatin requires the coordinated function of the Origin Recognition Complex (ORC), Cdc6, and Cdt1.[18] Once the Mcm proteins have been loaded onto the chromatin, ORC and Cdc6 can be removed from the chromatin without preventing subsequent DNA replication. This suggests that the primary role of the pre-replication complex is to correctly load the Mcm proteins.[19]

The Mcm proteins support roles both in the initiation and elongation steps of DNA synthesis.[20] Each Mcm protein is highly related to all others, but unique sequences distinguishing each of the subunit types are conserved across eukaryotes. All eukaryotes have exactly six Mcm protein analogs that each fall into one of the existing classes (Mcm2-7), which suggests that each Mcm protein has a unique and important function.[21]

Minichromosome maintenance proteins have been found to be required for DNA helicase activity and inactivation of any of the six Mcm proteins prevents further progression of the replication fork. This is consistent with the requirement of ORC, Cdc6, and Cdt1 function to assemble the Mcm proteins at the origin of replication.[22] The complex containing all six Mcm proteins creates a hexameric, doughnut like structure with a central cavity.[23] The helicase activity of the Mcm protein complex raises the question of how the ring-like complex is loaded onto the single-stranded DNA. One possibility is that the helicase activity of the Mcm protein complex can oscillate between an open and a closed ring formation to allow single-stranded DNA loading.[6]

Along with the minichromosome maintenance protein complex helicase activity, the complex also has associated ATPase activity.[24] A mutation in any one of the six Mcm proteins reduces the conserved ATP binding sites, which indicates that ATP hydrolysis is a coordinated event involving all six subunits of the Mcm complex.[25] Studies have shown that within the Mcm protein complex are specific catalytic pairs of Mcm proteins that function together to coordinate ATP hydrolysis. For example, Mcm3 but not Mcm6 can activate Mcm6 activity. These studies suggest that the structure for the Mcm complex is a hexamer with Mcm3 next to Mcm7Mcm2 next to Mcm6, and Mcm4 next to Mcm5. Both members of the catalytic pair contribute to the conformation that allows ATP binding and hydrolysis and the mixture of active and inactive subunits create a coordinated ATPase activity that allows the Mcm protein complex to complete ATP binding and hydrolysis as a whole.[26]

The nuclear localization of the minichromosome maintenance proteins is regulated in budding yeast cells. The Mcm proteins are present in the nucleus in G1 stage and S phase of the cell cycle, but are exported to the cytoplasm during the G2 stage and M phase. A complete and intact six subunit Mcm complex is required to enter into the cell nucleus.[27] InS. cerevisiaenuclear export is promoted by cyclin-dependent kinase (CDK) activity. Mcm proteins that are associated with chromatin are protected from CDK export machinery due to the lack of accessibility to CDK.[28]


Initiation Complex[edit]

During the G1 stage of the cell cycle, the replication initiation factors, origin recognition complex (ORC), Cdc6, Cdt1, and minichromosome maintenance (Mcm) protein complex, bind sequentially to DNA to form the pre-replication complex (pre-RC). At the transition of the G1 stage to the S phase of the cell cycle, S phase–specific cyclin-dependent protein kinase (CDK) and Cdc7/Dbf4 kinase (DDK) transform the pre-RC into an active replication fork. During this transformation, the pre-RC is disassembled with the loss of Cdc6, creating the initiation complex. In addition to the binding of the Mcm proteins, cell division cycle 45 (Cdc45) protein is also essential for initiating DNA replication.[29][30] Studies have shown that Mcm is critical for the loading of Cdc45 onto chromatin and this complex containing both Mcm and Cdc45 is formed at the onset of the S phase of the cell cycle.[31][32] Cdc45 targets the Mcm protein complex, which has been loaded onto the chromatin, as a component of the pre-RC at the origin of replication during the G1 stage of the cell cycle.[20]


The six minichromosome maintenance proteins and Cdc45 are essential during initiation and elongation for the movement of replication forks and for unwinding of the DNA. GINS are essential for the interaction of Mcm and Cdc45 at the origins of replication during initiation and then at DNA replication forks as the replisome progresses.[37][38] The GINS complex is composed of four small proteins Sld5 (Cdc105), Psf1 (Cdc101), Psf2 (Cdc102) and Psf3 (Cdc103), GINS represents ‘go, ichi, ni, san’ which means ‘5, 1, 2, 3’ in Japanese.[39]


Main article: MCM10

Mcm10 is essential for chromosome replication and interacts with the minichromosome maintenance 2-7 helicase that is loaded in an inactive form at origins of DNA replication. Mcm10 chaperones the catalytic DNA polymerase α and helps stabilize the polymerase.[40]

DDK and CDK Kinases[edit]

Main article: Cyclin-dependent kinase

At the onset of S phase, the pre-replicative complex must be activated by two S phase-specific kinases in order to form an initiation complex at an origin of replication. One kinase is the Cdc7-Dbf4 kinase called Dbf4-dependent kinase (DDK) and the other is cyclin-dependent kinase (CDK).[41] Chromatin-binding assays of Cdc45 in yeast and Xenopus have shown that a downstream event of CDK action is loading of Cdc45 onto chromatin.[30][31] Cdc6 has been speculated to be a target of CDK action, because of the association between Cdc6 and CDK, and the CDK-dependent phosphorylation of Cdc6. The CDK-dependent phosphorylation of Cdc6 has been considered to be required for entry into the S phase.[42]







Eukaryotic replisome complex and associated proteins.

The formation of the pre-replicative complex (pre-RC) marks the potential sites for the initiation of DNA replication. Consistent with the minichromosome maintenance complex encircling double stranded DNA, formation of the pre-RC does not lead to the immediate unwinding of origin DNA or the recruitment of DNA polymerases. Instead, the pre-RC that is formed during the G1 of the cell cycle is only activated to unwind the DNA and initiate replication after the cells pass from the G1 to the S phase of the cell cycle.[2]

Once the initiation complex is formed and the cells pass into the S phase, the complex then becomes a replisome. The eukaryotic replisome complex is responsible for coordinating DNA replication. Replication on the leading and lagging strands is performed by DNA polymerase ε and DNA polymerase δ. Many replisome factors including Claspin, And1, replication factor C clamp loader and the fork protection complex are responsible for regulating polymerase functions and coordinating DNA synthesis with the unwinding of the template strand by Cdc45-Mcm-GINS complex. As the DNA is unwound the twist number decreases. To compensate for this the writhe number increases, introducing positive supercoils in the DNA. These supercoils would cause DNA replication to halt if they were not removed. Topoisomerases are responsible for removing these supercoils ahead of the replication fork.

Replication Fork[edit]

The replication fork is the junction the between the newly separated template strands, known as the leading and lagging strands, and the double stranded DNA. Since duplex DNA is antiparallel, DNA replication occurs in opposite directions between the two new strands at the replication fork, but all DNA polymerases synthesize DNA in the 5′ to 3′ direction with respect to the newly synthesized strand. Further coordination is required during DNA replication. Two replicative polymerases synthesize DNA in opposite orientations. Polymerase ε synthesizes DNA on the “leading” DNA strand continuously as it is pointing in the same direction as DNA unwinding by the replisome. In contrast, polymerase δ synthesizes DNA on the “lagging” strand, which is the opposite DNA template strand, in a fragmented or discontinuous manner.

The discontinuous stretches of DNA replication products on the lagging strand are known as Okazaki fragments and are about 100 to 200 bases in length at eukaryotic replication forks. The lagging strand usually contains longer stretches of single-stranded DNA that is coated with single-stranded binding proteins, which help stabilize the single-stranded templates by preventing a secondary structure formation. In eukaryotes, these single-stranded binding proteins are a heterotrimeric complex known as replication protein A(RPA).[56]

Each Okazaki fragment is preceded by an RNA primer, which is displaced by the procession of the next Okazaki fragment during synthesis. RNAse H recognizes the DNA:RNA hybrids that are created by the use of RNA primers and is responsible for removing these from the replicated strand, leaving behind a primer:template junction. DNA polymerase α, recognizes these sites and elongates the breaks left by primer removal. In eukaryotic cells,




Depiction of DNA replication at replication fork. a: template strands, b: leading strand, c: lagging strand, d: replication fork, e: RNA primer, f: Okazaki fragment

Leading Strand

Lagging Strand

Replicative DNA Polymerases


After the replicative helicase has unwound the parental DNA duplex, exposing two single-stranded DNA templates, replicative polymerases are needed to generate two copies of the parental genome. DNA polymerase function is highly specialized and accomplish replication on specific templates and in narrow localizations. At the eukaryotic replication fork, there are three distinct replicative polymerase complexes that contribute to DNA replication: Polymerase α, Polymerase δ, and Polymerase ε. These three polymerases are essential for viability of the cell.[66]

Because DNA polymerases require a primer on which to begin DNA synthesis, polymerase α (Pol α) acts as a replicative primase. Pol α is associated with an RNA primase and this complex accomplishes the priming task by synthesizing a primer that contains a short 10 nucleotide stretch of RNA followed by 10 to 20 DNA bases.[3] Importantly, this priming action occurs at replication initiation at origins to begin leading-strand synthesis and also at the 5′ end of each Okazaki fragment on the lagging strand.

However, Pol α is not able to continue DNA replication and must be replaced with another polymerase to continue DNA synthesis.[67] Polymerase switching requires clamp loaders and it has been proven that normal DNA replication requires the coordinated actions of all three DNA polymerases: Pol α for priming synthesis, Pol ε for leading-strand replication, and the Pol δ, which is constantly loaded, for generating Okazaki fragments during lagging-strand synthesis.[68]

Cdc45–Mcm–GINS Helicase Complex[edit]

The DNA helicases and polymerases must remain in close contact at the replication fork. If unwinding occurs too far in advance of synthesis, large tracts of single-stranded DNA are exposed. This can activate DNA damage signaling or induce DNA repair processes. To thwart these problems, the eukaryotic replisome contains specialized proteins that are designed to regulate the helicase activity ahead of the replication fork. These proteins also provide docking sites for physical interaction between helicases and polymerases, thereby ensuring that duplex unwinding is coupled with DNA synthesis.[73]

Proliferating Cell Nuclear Antigen[edit]

Main article: proliferating cell nuclear antigen

To strengthen the interaction between the polymerase and the template DNA, DNA sliding clamps associate with the polymerase to promote the processivity of the replicative polymerase. In eukaryotes, the sliding clamp is a homotrimer ring structure known as the proliferating cell nuclear antigen (PCNA). The PCNA ring has polarity with surfaces that interact with DNA polymerases and tethers them securely to the DNA template. PCNA-dependent stabilization of DNA polymerases has a significant effect on DNA replication because PCNAs are able to enhance the polymerase processivity up to 1,000-fold.[85][86] PCNA is an essential cofactor and has the distinction of being one of the most common interaction platforms in the replisome to accommodate multiple processes at the replication fork, and so PCNA is also viewed as a regulatory cofactor for DNA polymerases.[87)

PCNA loading is accomplished by the replication factor C (RFC) complex. The RFC complex is composed of five ATPases: Rfc1, Rfc2, Rfc3, Rfc4 and Rfc5.[88] RFC recognizes primer-template junctions and loads PCNA at these sites.[89][90] The PCNA homotrimer is opened by RFC by ATP hydrolysis and is then loaded onto DNA in the proper orientation to facilitate its association with the polymerase.[91][92] Clamp loaders can also unload PNCA from DNA; a mechanism needed when replication must be terminated.[92]


The end replication problem is handled in eukaryotic cells by telomere regions and telomerase. Telomeres extend the 3′ end of the parental chromosome beyond the 5′ end of the daughter strand. This single-stranded DNA structure can act as an origin of replication that recruits telomerase. Telomerase is a specialized DNA polymerase that consists of multiple protein subunits and an RNA component. The RNA component of telomerase anneals to the single stranded 3′ end of the template DNA and contains 1.5 copies of the telomeric sequence.[60] Telomerase contains a protein subunit that is a reverse transcriptase called telomerase reverse transcriptase or TERT. TERT synthesizes DNA until the end of the template telomerase RNA and then disengages.[60] This process can be repeated as many times as needed with the extension of the 3′ end of the parental DNA molecule. This 3′ addition provides a template for extension of the 5′ end of the daughter strand by lagging strand DNA synthesis. Regulation of telomerase activity is handled by telomere-binding proteins.



A depiction of telomerase progressively elongating telomeric DNA.


DNA replication is a tightly orchestrated process that is controlled within the context of the cell cycle. Progress through the cell cycle and in turn DNA replication is tightly regulated by the formation and activation of pre-replicative complexs (pre-RCs) which is achieved through the activation and inactivation of cyclin-dependent kinases (Cdks). Specifically it is the interactions of cyclins and cyclin dependent kinases that are responsible for the transition from G1 into S-phase.














Bhatt et al., GA, 6-26-12















– G-quadruplex

It will be exactly 60 years ago in February that James Watson and Francis Crick famously burst into the pub next to their Cambridge laboratory to announce the discovery of the “secret of life”.

What they had actually done was describe the way in which two long chemical chains wound up around each other to encode the information cells need to build and maintain our bodies.

Today, the pair’s modern counterparts in the university city continue to work on DNA’s complexities.

Balasubramanian’s group has been pursuing a four-stranded version of the molecule that scientists have produced in the test tube now for a number of years.

It is called the G-quadruplex. The “G” refers to guanine, one of the four chemical groups, or “bases”, that hold DNA together and which encode our genetic information (the others being adenine, cytosine, and thymine).

The G-quadruplex seems to form in DNA where guanine exists in substantial quantities.

And although ciliates, relatively simple microscopic organisms, have displayed evidence for the incidence of such DNA, the new research is said to be the first to firmly pinpoint the quadruple helix in human cells.

‘Funny target’

The team, led by Giulia Biffi, a researcher in Balasubramaninan’s lab, produced antibody proteins that were designed specifically to track down and bind to regions of human DNA that were rich in the quadruplex structure. The antibodies were tagged with a fluorescence marker so that the time and place of the structures’ emergence in the cell cycle could be noted and imaged.

This revealed the four-stranded DNA arose most frequently during the so-called “s-phase” when a cell copies its DNA just prior to dividing.

Prof Balasubramaninan said that was of key interest in the study of cancers, which were usually driven by genes, or oncogenes, that had mutated to increase DNA replication.

If the G-quadruplex could be implicated in the development of some cancers, it might be possible, he said, to make synthetic molecules that contained the structure and blocked the runaway cell proliferation at the root of tumours.



John Berger

Founder at Novagon DNA

If the first and core mission of the genetic code is to faithfully replicate the “genetic material” encoded in the DNA and RNA nucleic acids, then every metabolic process must be functioning in a synchronous 24/7 manner. The only way to do this is to use all the purine and pyrmidine nucleotide, nucleoside and bases (ATUIXGC) =7 necessary and sufficient to make RNA first and then with the assistance of Thioredoxin i.e. ferredoxin purple sulphur bacteria to oxidize rna to dna.

In regards to purine metabolism which is my major area of focus. The two purine nucleotides left out of the current genetic code i.e. IMP and XMP have the following functions through their enzymes.1. Begin purine nucleotide synthesis de novo by IMPDH cyclodehydrogenase the last step in closing the purine ring and the current foundation molecular structure for DNA and RNA; 2. HPRT is the main enzyme is purine salvage for IMP and GMP; APRT provides same service for AMP; 3. Finally the last step in purine metabolism is by xanthine oxidase with the assistance of FES and molybendum. In essence the IMP and XMP families were the first to build the nucleic acid molecular structure; design a process to recycle functional side groups while keeping the purine ring intact and finally developing the biochemical pathway to eliminate toxic ammonia NH3 from the CNS and liver/kidneys.

I believe the 7 nucleotide Novagon DNA triplex genetic code should be called the epigenetic code since it works not only in protein metabolism which is 2% of the genome but noncoding intronic regions ie. rna editing, RNAi, piRNA, snMRN, long noncoding RNA and many other small rnas which operate above the level of the dna and rna base pair i.e. epigenesis suppressing or enhancing whole genes and networks of genes which control protein,lipid,carbohydrate and nucleic acid metabolism.

I am in the process of deveoping a 7 code epigenetic primer to control the gene switches which in turn allows the genetic material to be inherited from generation to generation as the species constantly adapts to external and internal stressors and competitive antagonist.

A Conserved Structural Core in Type II Restriction Enzymes.

A Conserved Structural Core in Type II Restriction Enzymes.





Dna triplex pic


















Agents that Damage DNA

  • Certain wavelengths of radiation
    • ionizing radiation such as gamma rays and X-rays
    • ultraviolet rays, especially the UV-C rays (~260 nm) that are absorbed strongly by DNA but also the longer-wavelength UV-B that penetrates the ozone shield [Link].
  • Highly-reactive oxygen radicals produced during normal cellular respiration as well as by other biochemical pathways. [Link to further discussion.]
  • Chemicals in the environment
    • many hydrocarbons, including some found in cigarette smoke

  Aflatoxin structures






Link to description of a test measuring the mutations caused by the hydrocarbon benzopyrene.
    • some plant and microbial products, e.g. the aflatoxins produced in moldy peanuts
  • Chemicals used in chemotherapy, especially chemotherapy of cancers

Types of DNA Damage

  1. All four of the bases in DNA(A, T, C, G)can be covalently modified at various positions.
    • One of the most frequent is the loss of an amino group(“deamination”) — resulting, for example, in a C being converted to a U.
  2. Mismatchesof the normal bases because of a failure of proofreading during DNA replication.
    • Common example: incorporation of the pyrimidineU (normally found only in RNA) instead of T.
  3. Breaksin the backbone.
    • Can be limited to one of the two strands (a single-stranded break, SSB) or
    • on both strands(a double-stranded break (DSB).
    • Ionizing radiation is a frequent cause, but some chemicals produce breaks as well.
  4. CrosslinksCovalent linkagescan be formed between bases
    • on the same DNA strand (“intrastrand”) or
    • on the opposite strand (“interstrand”).

Several chemotherapeutic drugs used against cancers crosslink DNA [Link].

Repairing Damaged Bases

Damaged or inappropriate bases can be repaired by several mechanisms:

  • Direct chemical reversal of the damage
  • Excision Repair, in which the damaged base or bases are removed and then replaced with the correct ones in a localized burst of DNA synthesis. There are three modes of excision repair, each of which employs specialized sets of enzymes.
    1. Base Excision Repair (BER)
    2. Nucleotide Excision Repair (NER)
    3. Mismatch Repair (MMR)



Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death

J Kim,  N Ghasemzadeh,  DJ Eapen, NC Chung, JD Storey, AA Quyyumi and G Gibson
Kim et al. Genome Medicine 2014, 6:40

Background: Genetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events. We asked whether peripheral blood expression profiles may be predictive of acute myocardial infarction (AMI) and/or cardiovascular death.

Methods: Peripheral blood samples from 338 subjects aged 62 ± 11 years with coronary artery disease (CAD) were analyzed in two phases (discovery N = 175, and replication N = 163), and followed for a mean 2.4 years for cardiovascular death. Gene expression was measured on Illumina HT-12 microarrays with two different normalization procedures to control technical and biological covariates. Whole genome genotyping was used to support comparative genome-wide association studies of gene expression. Analysis of variance was combined with receiver operating curve and survival analysis to define a transcriptional signature of cardiovascular death.

Results: In both phases, there was significant differential expression between healthy and AMI groups with overall down-regulation of genes involved in T-lymphocyte signaling and up-regulation of inflammatory genes. Expression quantitative trait loci analysis provided evidence for altered local genetic regulation of transcript abundance in AMI samples. On follow-up there were 31 cardiovascular deaths. A principal component (PC1) score capturing covariance of 238 genes that were differentially expressed between deceased and survivors in the discovery phase significantly predicted risk of cardiovascular death in the replication and combined samples (hazard ratio = 8.5, P< 0.0001) and improved the C-statistic (area under the curve 0.82 to 0.91, P= 0.03) after adjustment for traditional covariates.

Conclusions: A specific blood gene expression profile is associated with a significant risk of death in Caucasian subjects with CAD. This comprises a subset of transcripts that are also altered in expression during acute myocardial infarction.


Lecture Contents delivered at Koch Institute for Integrative Cancer Research, Summer Symposium 2014: RNA Biology, Cancer and Therapeutic Implications, June 13, 2014 @MIT

Curator of Lecture Contents: Aviva Lev-Ari, PhD, RN
3:15 – 3:45, 6/13/2014, Laurie Boyer “Long non-coding RNAs: molecular regulators of cell fate”


TAR DNA-binding protein 43

TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene.[2] A similar pseudogene is present on chromosome 20.[3]

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation.

TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[1] It was also reported to regulate alternate splicing of theCFTR gene and the apoA-II gene.

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight microfilament (hNFL) mRNA-binding protein.[4] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[5]

Clinical significance[edit]

Hyper-phosphorylatedubiquitinated and cleaved form of TDP-43, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U[6]) and in Amyotrophic lateral sclerosis (ALS).[7] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and other types of head injury.[8]

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator “Tat” is dependent on an RNA regulatory element (TAR) located “downstream” (i.e. to-be transcribed at a later point in time) of the transcription initiation site.

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[9] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[10][11] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[12]



General annotation (Comments)

Function DNA and RNA-binding protein which regulates transcription and
splicing. Involved in the regulation of CFTR splicing. It promotes
CFTR exon 9 skipping by binding to the UG repeated motifs in the
polymorphic region near the 3′-splice site of this exon. The resulting
aberrant splicing is associated with pathological features typical of
cystic fibrosis. May also be involved in microRNA biogenesis,
apoptosis and cell division. Can repress HIV-1 transcription by
binding to the HIV-1 long terminal repeat. Stabilizes the low
molecular weight neurofilament (NFL) mRNA through a direct
interaction with the 3′ UTR. Ref.2 Ref.12
Subunit structure Homodimer. Interacts with BRDT By similarity. Binds specifically to
pyrimidine-rich motifs of TAR DNA and to single stranded TG
repeated sequences. Binds to RNA, specifically to UG repeated
sequences with a minimun of six contiguous repeats. Interacts with
ATNX2; the interaction is RNA-dependent. Ref.16
Subcellular location Nucleus. Note: In patients with frontotemporal lobar degeneration
and amyotrophic lateral sclerosis, it is absent from the nucleus of
affected neurons but it is the primary component of cytoplasmic
ubiquitin-positive inclusion bodies. Ref.2 Ref.11
Tissue specificity Ubiquitously expressed. In particular, expression is high in pancreas,
placenta, lung, genital tract and spleen.
Domain The RRM domains can bind to both DNA and RNA By similarity.
Post-translational modification Hyperphosphorylated in hippocampus, neocortex, and spinal cord
from individuals affected with ALS and FTLDU. Ref.11Ubiquitinated in hippocampus, neocortex, and spinal cord from
individuals affected with ALS and FTLDU. Ref.2 Ref.11  Cleaved to
generate C-terminal fragments in hippocampus, neocortex, and
spinal cord from individuals affected with ALS and FTLDU.
Involvement in disease Amyotrophic lateral sclerosis 10 (ALS10) [MIM:612069]: A
neurodegenerative disorder affecting upper motor neurons in the
brain and lower motor neurons in the brain stem and spinal cord,
resulting in fatal paralysis. Sensory abnormalities are absent. The
pathologic hallmarks of the disease include pallor of the corticospinal
tract due to loss of motor neurons, presence of ubiquitin-positive
inclusions within surviving motor neurons, and deposition of
pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.  Note: The disease is caused by mutations affecting the gene represented in this

  1. 16Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31Ref.32
Sequence similarities Contains 2 RRM (RNA recognition motif) domains.



How DNA is made?

Deoxyribonucleic acid (DNA) synthesis is a process by which copies of nucleic acid strands are made. In nature, DNA synthesis takes place in cells by a mechanism known as DNA replication. Using genetic engineering and enzyme chemistry, scientists have developed man-made methods for synthesizing DNA. The most important of these is poly-merase chain reaction (PCR). First developed in the early 1980s, PCR has become a multi-billion dollar industry with the original patent being sold for $300 million dollars.


DNA was discovered in 1951 by Francis Crick, James Watson, and Maurice Wilkins. Using x-ray crystallography data generated by Rosalind Franklin, Watson and Crick determined that the structure of DNA was that of a double helix. For this work, Watson, Crick, and Wilkins received the Nobel Prize in Physiology or Medicine in 1962. Over the years, scientists worked with DNA trying to figure out the “code of life.” They found that DNA served as the instruction code for protein sequences. They also found that every organism has a unique DNA sequence and it could be used for screening, diagnostic, and identification purposes. One thing that proved limiting in these studies was the amount of DNA available from a single source.

After the nature of DNA was determined, scientists were able to examine the composition of the cellular genes. A gene is a specific sequence of DNA base pairs that provide the code for the construction of a protein. These proteins determine the traits of an organism, such as eye color or blood type. When a certain gene was isolated, it became desirable to synthesize copies of that molecule. One of the first ways in which a large amount of a specific DNA was synthesized was though genetic engineering.

Genetic engineering begins by combining a gene of interest with a bacterial plasmid. A plasmid is a small stretch of DNA that is found in many bacteria. The resulting hybrid DNA is called recombinant DNA. This new recombinant DNA plasmid is then injected into bacterial cells. The cells are then cloned by allowing it to grow and multiply in a culture. As the cells multiply so do copies of the inserted gene. When the bacteria has multiplied enough, the multiple copies of the inserted gene can then be isolated. This method of DNA synthesis can produce billions of copies of a gene in a couple of weeks.

In 1983, the time required to produce copies of DNA was significantly reduced when Kary Mullis developed a process for synthesizing DNA called polymerase chain reaction (PCR). This method is much faster than previous known methods producing billions of copies of a DNA strand in just a few hours. It begins by putting a small section of double stranded DNA in a solution containing DNA polymerase, nucleotides and primers. The solution is heated to separate the DNA strands. When it is cooled, the polymerase creates a copy of each strand. The process is repeated every five minutes until the desired amount of DNA is produced. In 1993, Mullis’s development of PCR earned him the Nobel Prize in Chemistry.


The key to understanding DNA synthesis is understanding its structure. Typically, DNA exists as two chains of chemically linked nucleotides. These links follow specific patterns dictated by the base pairing rules. Each nucleotide is made up of a deoxyribose sugar molecule, a phosphate group, and one of four nitrogen containing bases. The bases include the pyrimidines thymine (T) and cytosine (C)and the purines adenine (A) and guanine (G). In DNA, adenine generally links with thymine and guanine with cytosine. The molecule is arranged in a structure called a double helix which can be imagined by picturing a twisted ladder or spiral staircase. The bases make up the rungs of the ladder while the sugar and phosphate portions make up the ladder sides. The order in which the nucleotides are linked, called the sequence, is determined by a process known as DNA sequencing.

In a eukaryotic cell, DNA synthesis occurs just prior to cell division through a process called replication. When replication begins the two strands of DNA are separated by a variety of enzymes. Thus opened, each strand serves as a template for producing new strands. This whole process is catalyzed by an enzyme called DNA polymerase. This molecule brings corresponding, or complementary, nucleotides in line with each of the DNA strands. The nucleotides are then chemically linked to form new DNA strands which are exact copies of the original strand. These copies, called the daughter strands, contain half of the parent DNA molecule and half of a whole new molecule. Replication by this method is known as semiconservative replication.

Raw Materials

The primary raw materials used for DNA synthesis include DNA starting materials, taq DNA polymerase, primers, nucleotides, and the buffer solution. Each of these play an important role in the production of millions of DNA molecules.

Controlled DNA synthesis begins by identifying a small segment of DNA to copy. This is typically a specific sequence of DNA that contains the code for a desired protein. Called template DNA, this material must be highly purified.

While the process of DNA replication was known before 1980, PCR was not possible because there were no known heat stable DNA polymerases.  In the early 1980s, scientists found bacteria living around natural steam vents. It turned out that these organisms, called thermus aquaticus, had a DNA polymerase that was stable and functional at extreme levels of heat. This taq DNA polymerase became the cornerstone for modern DNA synthesis techniques. During a typical PCR process, 2-3 micrograms of taq DNA polymerase is needed.

The polymerase builds the DNA strands by combining corresponding nucleotides on each DNA strand. Chemically speaking, nucleotides are made up of three types of molecular groups including a sugar structure, a phosphate group, and a cyclic base. The sugar portion provides the primary structure for all nucleotides. In general, the sugars are composed of five carbon atoms with a number of hydroxy (-OH) groups attached. For DNA, the sugar is 2-deoxy-D-ribose. The defining part of a nucleotide is the hetero-cyclic base that is covalently bound to the sugar. These bases are either pyrimidine or purine groups, and they form the basis for the nucleic acid code. Two types of purine bases are found including adenine and guanine. In DNA, two types of pyrimidine bases are present, thymine and cytosine. A phosphate group makes up the final portion of a nucleotide. This group is derived from phosphoric acid and is covalently bonded to the sugar structure on the fifth carbon.

cost of oligo and gene synthesis





The first phase of polymerase chain reaction (PCR) involves the denaturation of DNA. This “opening up” of the DNA molecule provides the template for the next DNA molecule from which to be produced. With the DNA split into separate strands, the temperature is lowered—the primer annealing step. During the next phase, the DNA polymerase interacts with the strands and adds complementary nucleotides along the entire length. The time required at this phase is about one minute for every 1,000 base pairs.

To initiate DNA synthesis, short primer sections of DNA must be used. These primer sections, called oligo fragments, are about 18-25 nucleotides in length and correspond to a section on the template DNA. They typically have a C and G nucleotide concentration of about 60% with even distribution. This provides the maximum efficiency in the synthesis process.

The buffer solution provides the medium in which DNA synthesis can occur. This is an aqueous solution which contains MgCl2, HCI, EDTA, and KCI. The MgCl2 concentration is important because the Mg2+ ions interact with the DNA and the primers creating crucial complexes for DNA synthesis. The pH of this system is critical so it may also be buffered with ammonium sulfate. To energize the reaction, various energy molecules are added such as ATP, GTP, and NTP.

DNA synthesis involves three distinct processes, typically done in separate areas to avoid contamination, including sample preparation, DNA synthesis reaction cycle and DNA isolation. Following these procedures scientists are able to convert a few strands of DNA into millions and millions of exact copies.

Preparation of the samples

  • 1 Typically, all of the starting solutions except the primers, polymerases and the dNTPs are put in an autoclave to kill off any contaminating organism. Two separate solutions are made. One contains the buffer, primers and the polymerase. The other contains the MgCl2 and the template DNA. These solutions are all put into small tubes to begin the reaction.


Kary Banks Mullis.

Kary Banks Mullis was born in Lenoir, North Carolina, in 1944. Upon graduation from Georgia Tech in 1966 with a B.S. in chemistry, Muilis entered the biochemistry doctoral program at the University of California, Berkeley. Earning his Ph.D. in 1973, he accepted a teaching position at the University of Kansas Medical School in Kansas City. In 1977, he assumed a postdoctoral fellowship at the University of California, San Francisco.

Muilis accepted a position as a research scientist in 1979 with a growing biotech firm—Cetus Corporation, in Emeryville, California—that synthesized chemicals used by other scientists in genetic cloning. While there, he designed polymerase chain reaction (PCR), a fast and effective technique for reproducing specific genes or DNA (deoxyribonucleic acid) fragments that can create billions of copies in a few hours. The most effective way to reproduce DNA was by cloning, but it was problematic. It took time to convince Mullis’s colleagues of the importance of this discovery but soon PCR became the focus of intensive research. Scientists at Cetus developed a commercial version of the process and a machine called the Thermal Cycler (with the addition of the chemical building blocks of DNA [nucleotides] and a biochemical catalyst [polymerase], the machine would perform the process automatically on a target piece of DNA).

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lncRNA-s   A summary of the various functions described for lncRNA


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Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD, RN




Lower LDL Still Best: Very Low Levels of LDL Linked with Reduced CV Events

July 28, 2014



AMSTERDAM, THE NETHERLANDS — The question of how low LDL-cholesterol levels should be in the present statin era, recently addressed with the new US clinical guidelines, is once again questioned with the new publication of a patient-level meta-analysis of eight clinical trials investigating statin therapy[1].


The new meta-analysis, published July 28, 2014 in the Journal of the American College of Cardiology, suggests that lowering LDL-cholesterol levels to very low levels results in a significant reduction in cardiovascular events. Individuals with LDL-cholesterol levels <50 mg/dL had a significantly lower risk of major cardiovascular events compared with individuals who had higher LDL-cholesterol levels, including those with LDL levels 50 to <75 mg/dL and 75 to <100 mg/dL.


The Results From the Meta-analysis


The investigators, including first author Dr Matthijs Boekholdt (Academic Medical Center), analyzed eight trials and 38 153 patients treated with statin therapy. The studies included some of the landmark statin trials, including AFCAPS-TexCAPS 4S LIPID SPARCL , TNT IDEAL , and JUPITER .


The investigators observed a large degree of interindividual variability in the reductions of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB) levels with statin therapy. Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.


Compared with individuals with LDL-cholesterol levels >175 mg/dL, which served as the reference group, individuals who achieved lower levels of LDL cholesterol had a significantly lower risk of major cardiovascular events. For those with LDL-cholesterol levels <50 mg/dL, 50 to <75 mg/dL, and 75 to <100 mg/dL, the relative reduction in risk was 56%, 49%, and 44%, respectively. Regarding the end point of major coronary events and cerebrovascular events, a similar trend was observed with lower LDL cholesterol levels.



Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL)


Outcome LDL <50 50 to <75 75 to <100 100 to <125 125 to <150 150 to <175 > 175
Major cardiovascular events 0.44 (0.35–0.55) 0.51 (0.42–0.62) 0.56 (0.46–0.67) 0.58 (0.48–0.69) 0.64 (0.53–0.79) 0.71 (0.56–0.89) 1.00 (ref)





  1. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoprotein and the risk for cardiovascular events. J Am Coll Cardiol 2014; DOI:10.1016.j.jacc.2014.02.615. Available at:
  2. Ben-Yehuda O, DeMaria AN. LDL-cholesterol after the ACC/AHA 2013 guidelines. J Am Coll Cardiol 2014; DOI:10.1016.j.jacc.2014.05.020. Available at:



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