Monday, November 21, 2016

Site Specific Phosphorylation of Tau Inhibits Alzheimer’s in Mice

Alzheimer’s disease impacts many individuals in the latter stages of life.  It is a form of dementia that is very devastating to the individuals affected and their families.  On the molecular level, the disease is indicated by extracellular protein “plaques” that are composed of amyloid-β (Aβ) and an accumulation of so-called, “neurofibrillary tangles” within the neurons (see images below).  These tangles are composed of tau protein.  Amyloids represent aggregates of proteins that are stuck together and pose problems for cellular health and development in tissues.  This is especially important within the central nervous system since communication between neurons is of such vital importance.





The accumulated evidence suggests that it is the combined impact of Aβ and tau that lead to the neuronal dysfunction that is indicated by the severe cognitive deficits exhibited by individual with this disease.  Furthermore, the production of Aβ seems to trigger the subsequent phosphorylation of tau protein that lead to its deposition and ultimately to cognitive deficits.  In mouse animal models, the depletion of tau prevents Aβ toxicity.  It seems that by the time the symptoms are evident, significant cell damage has already occurred.

However, recent studies by Dr. Arne Ittner and his colleagues from the School of Medical Sciences at UNSW Australia have shown that site-specific phosphorylation of tau directed by the neuronal p38 mitogen-activated protein kinase enzyme (p38γ) actually inhibited Aβ toxicity.  Furthermore, the depletion of p38γ worsened cognitive defects and increasing p38γ eliminated these deficits.
 

These results are of importance; for, they demonstrate that phosphorylation of tau may or may not be detrimental depending upon the site(s) on the protein structure that are impacted.

Saturday, November 5, 2016

The Impact of Climate Change on Desertification

Climate Change and Desertification - The following is a link to an extensive New York Times article regarding the expansion of the Tengger desert in China and the impact of this change on the affected population - http://nyti.ms/2eweXJF

Saturday, October 29, 2016

Integration of Newly-Formed Neurons within the Adult Human Brain

The learning process that proceeds within the adult human brain has long been an intense interest of study for neuroscientists especially in regards to the events that unfold on a cellular and molecular level.  It has been shown that physical activity as well as the experience that comes with being in novel environments triggers the production, development and eventual connectivity of newly-formed neurons within the adult human brain.

Diego D. Alvarez and his colleagues (Laboratorio de Plasticidad Neuronal, Fundación Instituto Leloir–Instituto de Investigaciones Bioquímicas de Buenos Aires–Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Patricias Argentinas 435, Buenos Aires C1405BWE, Argentina) focused their studies on the mechanism through which the experience of an enriched environment (EE) impacts the incorporation of newly-formed adult neurons into the hippocampal network – an area of the human brain involved in retaining declarative (explicit) memory.  Declarative memory refers to the memory of facts and events.

The cells of interest are referred to as granule cells (GCs) (see image below).  In the investigators’ study of newly-formed GCs using the mouse animal model, they found that exposing the test animal subjects to EE accelerated the incorporation of these neurons into the microcircuits of the dentate gyrus – the apparent site for the establishment of new memories.


Granule Cells

In addition, further study demonstrated that in order for this incorporation of new GCs to proceed, the process required the participation of parvalbumin y-aminobutyric acid-releasing interneurons (PV-INs).  Inactivation of PV-INs effectively prevented the effects of EE.  Neuronal stem cells (NSC) of the adult hippocampus are the precursors of GCs of the dentate gyrus.  
  

These results further our understanding of the complex cellular and molecular mechanisms involved in incorporating new memories in the adult human brain.

Friday, October 14, 2016

Natural Killer Cells in the Treatment of Cancer

It has been well established that the human immune system has the inherent capability to recognize and eliminate aberrant tissue cells in the body that have become transformed into cancerous cells capable of metastasis.  The natural process of finding and eliminating these cells is referred to as cancer surveillance.  It is this understanding that has led to the development of clinical approaches taking advantage of this phenomenon.  The techniques employed in this regard are classified under the heading, cancer immunotherapy.

There is a particular subset of circulating immuno-competent white blood cells referred to as natural killer cells that play a significant role in the body’s response to infectious pathogens as well as in cancer surveillance (see image below).  Dr. Rizwan Rowee and is colleagues from the Department of Medicine, Oncology Division Washington University School of Medicine in St. Louis investigated the properties of natural killer cells in regard to their ability to identify and destroy cancerous cells.  They were particularly interested in their “memory” capacity.  It has long been known that subsets of immuno-competent cells retain the capacity to recognize and attack particular targets from previous encounters.  This is an indispensable feature of a normal immune system.


Natural Killer Cells Attacking a Target Cell

Following exhaustive study and analysis of these natural killer cells with human leukemic cells in culture, the investigators discovered that natural killer cells with memory-like capability actually demonstrated an anti-leukemic effect against patients with acute myeloid leukemia (AML).  In some cases, this treatment led to clinical remissions.  The investigators reported that, “Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.”


These are very important findings especially in regard to the treatment of patients with AML; since, this disease is a particularly aggressive form of leukemia.

Monday, October 10, 2016

Dr. Arnoldo Gabaldón


Malaria is one of the world’s deadliest diseases.  It is especially prevalent in the tropics.  The life cycle of the causative microbial parasite – members of the plasmodium genus i.e. Plasmodium vivax is complex involving the Anopheles mosquito as a vector (see images below).  The nature of the infection is such that it has eluded the development of an effective vaccine for many years. 


Human red cells infected by Plasmodium vivax



In light of this, it is quite surprising that Dr. Arnoldo Gabaldón, born in 1909, in Venezuela made a significant contribution to the understanding of this disease and its implications in regard to public health.
Gabaldón earned a doctorate in medical sciences at the Universidad Central de Venezuela. He continued his education internationally working in Hamburg and the United States at  the Rockefeller Foundation and ultimately received a doctorate from Johns Hopkins University in hygiene sciences with a specialty in protozoology. With this kind of medical background and expertise in infectious disease, he was asked to head the newly created Special Directorate of Malariology in his home country of Venezuela in 1936.  He held this post until 1950.
He successfully applied his understanding of the methodologies required to combat infectious disease to the rate and severity of malarial infection that gripped his country in the 1930s.  This included the emphasis on public hygiene and sanitation and the judicious application of anti-malarial drugs. His approach was so successful that mortality resulting from malarial infection was decreased significantly by 1944 and, more importantly, its control was seen as within reach.
This initial success was followed by an attempt to significantly reduce the Anopheles mosquito population.  For this purpose, the insecticide dichlorodiphenyltrichloroethane  (DDT) was used.  The historic data has revealed that “by 1950 the death rate from malaria in the country had been reduced to 9 per 100,000 inhabitants and was eradicated in an area of 132 000 km2. In 1955, 10 years after the program started the rate was lowered to 1 per 100 000 population and the eradicated area had increased to 305,414 km2.” On balance, it should be kept in mind that the discovery of the ecological burden posed by the use of DDT on the natural environment has effectively banned its application for many years.
Gabaldón is also credited with discovering a new species of malarial parasites and had focused a great deal of his efforts on further study of the Anopheles mosquito.  He was later appointed Minister of Health and Welfare between 1959 and 1964 in recognition of his premier understanding regarding issued of public health.  He died in September of 1990.

Arnoldo Gabaldón made a significant contribution to the principles and practices of public health around the area of infectious disease.  The example of his leadership has been emulated throughout the world and possibly has saved countless lives. 

Tuesday, September 20, 2016

The C9ORF72 Protein as a Suppressor of Autoimmunity

There are many chronic illnesses that are referred to as autoimmune diseases such as multiple sclerosis, amyotrophic lateral sclerosis (ALS) and pemphigus vulgaris for example; the etiology of these diseases originates from the patient’s immune system attacking normal tissue.   

ALS is a disease that presents as a progressive degeneration of the normal function of motor neurons resulting in paralysis and death.  It has been shown that mutations in the C9ORF72 gene are commonly found in ALS and frontotemporal dementia.  This gene is located on the short arm of chromosome 9 in humans.  This gene contains the information for the production of the C9orf72 protein.  Furthermore, in animal model studies using the mouse, it has been found that mutations in this gene result in Autoimmune-like symptoms.  Transplantation of normal murine bone marrow positively impacted diseased mice with this mutation and bone marrow transplantation of diseased mice into normal animals alternatively resulted in symptoms of autoimmunity.  These latter results led investigators to suspect that the C9orf72 gene is normally active in hematopoietic cells – cells residing in the bone marrow that produce circulating blood cells - in suppressing autoimmunity.

Recent findings have clearly established that mice that harbor mutations in the C9orf72 gene that result in the loss of function of the C9orf72 protein gene product develop the following symptoms –
  • splenomegaly – enlarged spleen
  • neutrophilia – increased population of neutrophils in the circulation
  • thrombocytopenia – decreased numbers of platelets
  • increased expression of inflammatory cytokines
  • severe autoimmunity.

These diseased animal suffer a high mortality rate.


These data represent strong evidence that the C9ORF72 gene plays a very important role in the suppression of autoimmunity and may prove to be of future therapeutic value.

Tuesday, September 6, 2016

What Will be Our Legacy?

The essential questions I would like to pose are the following-
  • Are we prepared to leave as our legacy not only to future generations of humans, but also the future of our fellow creatures a world whose living populations will be severely decimated by the onslaught of climate change brought on by human activity?
  • Are we prepared to jeopardize the quality of life and security of future generations of humanity on planet Earth so that we can maintain our privileged and comfortable lifestyles based upon a patent disregard for the environmental degradation that we necessarily impose upon our planet?

These questions are no longer simply philosophical in nature.  The current data is clear that we are in the midst of a major change in the global environment caused primarily by human activity.  The following statement was made within the Smithsonian Museums website – Smithsonian.com – “According to the International Union of Geological Sciences (IUGS), the professional organization in charge of defining Earth’s time scale, we are officially in the Holocene (“entirely recent”) epoch, which began 11,700 years ago after the last major ice age.

“But that label is outdated, some experts say. They argue for “Anthropocene”—from anthropo, for “man,” and cene, for “new”—because human-kind has caused mass extinctions of plant and animal species, polluted the oceans and altered the atmosphere, among other lasting impacts.”

Humanity’s response, within the 21st century, to this real crisis will determine the future that awaits the living world.  Of course, the earth has been through at least five major mass extinctions in its long geological history and will certainly survive another.  The kind of adjustments involved, however, require long stretches of time involving many thousands if not millions of years.  We do not have the luxury of waiting.  The future of the natural environment depends upon what we do, or what we fail to do now.