Monday, June 19, 2017

Computational model uncovers progression of HIV infection in brain

University of Alberta research team successfully uncovered the progression of HIV infection in the brain using a new mathematical model. The team is utilizing this model to develop a nasal spray to administer  antiretroviral medication effectively. Their research is published in Journal of Neurovirology.

Research was done by PhD student Weston Roda and Prof. Michael Li. They used data from patients who died five to 15 years after they were infected, as well as known biological processes for the HIV virus to build the model that predicts the growth and progression of HIV in the brain, from the moment of infection onward. It is the first model of an infectious disease in the brain.

"The nature of the HIV virus allows it to travel across the blood-brain barrier in infected macrophage--or white blood cell--as early as two weeks after infection. Antiretroviral drugs, the therapy of choice for HIV, cannot enter the brain so easily," said Roda. This creates what is known as a viral reservoir, a place in the body where the virus can lay dormant and is relatively inaccessible to drugs.

Prior to this study, scientists could only study brain infection at autopsy. The new model allows scientists to backtrack, seeing the progression and development of HIV infection in the brain. Using this information, researchers can determine what level of effectiveness is needed for antiretroviral therapy in the brain to decrease active infection.

"The more we understand and can target treatment toward viral reservoirs, the closer we get to developing total suppression strategies for HIV infection," said Roda. A research team led by Chris Power, Roda's co-supervisor who is a professor in the Division of Neurology, is planning clinical trials for a nasal spray that would get the drugs into the brain faster, with critical information on dosage and improvement rate provided by Roda's model.

"Our next steps are to understand other viral reservoirs, like the gut, and develop models similar to this one, as well as understand latently infected cell populations in the brain," said Roda. "With the antiretroviral therapy, infected cells can go into a latent stage. The idea is to determine the size of the latently infected population so that clinicians can develop treatment strategies"

Citation: Roda, Weston C., Michael Y. Li, Michael S. Akinwumi, Eugene L. Asahchop, Benjamin B. Gelman, Kenneth W. Witwer, and Christopher Power. "Modeling brain lentiviral infections during antiretroviral therapy in AIDS." Journal of NeuroVirology, 2017.
doi:10.1007/s13365-017-0530-3.
Adapted from press release by University of Alberta.

Thursday, June 15, 2017

Delaying aging process by selective removal of senescent cells

A recent study, led by an international team of researchers confirms that targeted removal of senescent cells (SnCs), accumulated in many vertebrate tissues as we age, contribute significantly in delaying the onset of age-related pathologies.

Credit: Baker et al., Nature 
This breakthrough research has been led by Dr. Chaekyu Kim and Dr. Ok Hee Jeon. In the study, the research team presented a novel pharmacologic candidate that alleviates age-related degenerative joint conditions, such as osteoarthritis (OA) by selectively destroying SnCs. Their findings, published in Nature Medicine, suggest that the selective removal of old cells from joints could reduce the development of post-traumatic OA and allow new cartilage to grow and repair joints.

To test the idea that SnCs might play a causative role in OA, the research team took both younger and older mice and cut their anterior cruciate ligaments (ACL) to minic injury. They, then, administered injections of an experimental drug, named UBX0101 to selectively remove SnCs after anterior cruciate ligament transection (ACLT) surgery.

Preclinical studies in mice and human cells suggested that the removal of SnCs significantly reduced the development of post-traumatic OA and related pain and created a prochondrogenic environment for new cartilage to grow and repair joints. Indeed, the research team reported that aged mice did not exhibit signs of cartilage regeneration after treatment with UBX0101 injections,

According to the research team, the relevance of their findings to human disease was validated using chondrocytes isolated from arthritic patients. The research team notes that their findings provide new insights into therapies targeting SnCs for the treatment of trauma and age-related degenerative joint disease.

Citation: Jeon, Ok Hee, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P. Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J. Baker, Jan M Van Deursen, Judith Campisi, and Jennifer H. Elisseeff. "Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment." Nature Medicine 23, no. 6 (2017): 775-81.
doi:10.1038/nm.4324.
Adapted from press release by the Uslan National Institute of Science and Technology.

Friday, June 2, 2017

Metformin influences gut microbiome

A recent study at Sahlgrenska Academy and University of Girona indicates thatcontrol of blood glucose by metformin is achieved partly through modulation of the gut microbiota. Results of the study are published in journal Nature Medicine.

Fredrik Bäckhed's research group at Sahlgrenska Academy has previously shown that the gut microbiota is altered in patients with type 2 diabetes and after bariatric surgery. By conducting a clinical study in patients with new onset diabetes, the group could clarify how the gut microbiomeis affected by metformin.

Sequencing of the microbiome of 22 patients before and after treatment compared with a placebo treated group of patients showed that the gut microbiome was altered dramatically within two months of treatment. Through experiments in the laboratory, the researchers demonstrated that metformin increases the growth of several bacterial species that are linked to improved metabolism.

Citation: Wu, Hao, Eduardo Esteve, Valentina Tremaroli, Muhammad Tanweer Khan, Robert Caesar, Louise Mannerås-Holm, Marcus Ståhlman, Lisa M. Olsson, Matteo Serino, Mercè Planas-Fèlix, Gemma Xifra, Josep M. Mercader, David Torrents, Rémy Burcelin, Wifredo Ricart, Rosie Perkins, José Manuel Fernàndez-Real, and Fredrik Bäckhed. "Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug." Nature Medicine, 2017.
doi:10.1038/nm.4345.
Adapted from press release by  the University of Gothenburg.

Tuesday, May 16, 2017

ResistoMap developed to track world wide microbial drug resistance

Scientists from the Federal Research and Clinical Center of Physical-Chemical Medicine, the Moscow Institute of Physics and Technology, and Data Laboratory have created the ResistoMap, an interactive visualization of gut resistome. Gut resistome is human gut microbiota potential to resist antibiotics and includes the set of all antibiotic resistance genes in the genomes of human gut microbes. Their ResistoMap will help identify national trends in antibiotic use and control antibiotic resistance on the global scale. This research is published in journal Bioinformatics.

Resistomap - interactive world map of human gut resistome
Resistomap -  an interactive world map of human gut microbiota potential to resist antibiotics.
Credit: Bioinformatics
Microbial drug resistance is caused by the extensive uncontrolled use of antibiotics in medicine and agriculture. It has been predicted that by 2050 around 10 million people will die annually due to reasons associated with drug resistance.

The ResistoMap has two main interactive work fields: a geographic map and a heat map. A user can choose the antibiotic group or country of interest to be displayed on the heat map and obtain a resistome cross section. The data can be filtered by the country of origin, gender, age, and diagnosis. The current version of the interactive map developed by the authors draws on a dataset that includes over 1600 individuals from 12 studies covering 15 countries. However, the dataset can be expanded by additional input from users reflecting the findings of new published studies in a unified format.

Using the ResistoMap, researchers fee that it is possible to estimate the global variation of the resistance to different groups of antibiotics and explore the associations between specific drugs and clinical factors or other metadata. For example, the Danish gut metagenomes tend to demonstrate the lowest resistome among the European groups, whereas the French samples have the highest levels, particularly of the fluoroquinolones, a group of broad-spectrum anti-bacterial drugs. This is in agreement with the fact that France has the highest total antibiotic use across Western Europe, while the use of antimicrobial drugs in Denmark and Germany is moderate, both in health care and agriculture. At the opposite end of the spectrum, Chinese and Russian populations appear to have increased levels of resistome, which is likely due to looser regulation policies, frequent prescription of broad-spectrum antibiotics, and their over-the-counter availability without prescription. The lowest levels of microbiota resistome are observed in the native population of Venezuela who have no documented contacts with populations of the developed countries. ResistoMap-informed analysis reveals certain novel trends that await further interpretation from the clinical standpoint.

Konstantin Yarygin, one of the creators of the visualization tool, says, "We anticipate that the exploratory analysis of global gut resistome enabled by the ResistoMap will provide new insights into how the use of antibiotics in medicine and agriculture could be optimized."

Citation: Yarygin, Konstantin S., Boris A. Kovarsky, Tatyana S. Bibikova, Damir S. Melnikov, Alexander V. Tyakht, and Dmitry G. Alexeev. "ResistoMap—online visualization of human gut microbiota antibiotic resistome." Bioinformatics, 2017.
doi:10.1093/bioinformatics/btx134.
Research funding: Russian Scientific Foundation.
Adapted from press release by the Moscow Institute of Physics and Technology.


Monday, May 15, 2017

Brain changes in diabetic patients

A new study published in Diabetologia reveals that overweight and obese individuals with early stage type 2 diabetes (T2D) had more severe and progressive abnormalities in brain structure and cognition compared to normal-weight study participants.

The research conducted by Dr Sunjung Yoon and Dr In Kyoon Lyoo (Ewha Brain Institute, Ewha Womens University, Seoul, South Korea), Hanbyul Cho (The Brain Institute, University of Utah, Salt Lake City, UT, USA), and colleagues in Korea and the USA looked into the effects of being overweight or obese on the brains and cognitive functions of people with early stage type 2 diabetes.

The study found that grey matter was significantly thinner in clusters in the temporal, prefrontoparietal, motor and occipital cortices of the brains of diabetic study participants when compared to the non-diabetic control group. Further thinning of the temporal and motor cortices was also observed in the overweight/obese diabetic group, compared to normal-weight diabetics. The team also discovered region-specific changes which suggested that the temporal lobe has a particular vulnerability to the combined effects of having type 2 diabetes and being overweight or obese.

Citation: Yoon, Sujung, Hanbyul Cho, Jungyoon Kim, Do-Wan Lee, Geon Ha Kim, Young Sun Hong, Sohyeon Moon, Shinwon Park, Sunho Lee, Suji Lee, Sujin Bae, Donald C. Simonson, and In Kyoon Lyoo. "Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus." Diabetologia, 2017.
doi:10.1007/s00125-017-4266-7.
Adapted from press release by Diabetologia.

Friday, May 12, 2017

Hinokitiol, molecule from Japanese cypress tree shows promise in iron related disorders

Researchers find key molecule that could lead to new therapies for anemia and other iron disorders. New findings reported in journal Science by a multi-institutional team, including researchers from University of Illinois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Brigham and Women's Hospital and Northeastern University, could impact whole range of diseases related to iron metabolism.

The team has discovered a small molecule hinokitiol, found naturally in Japanese cypress tree leaves  has shown to promote gut iron absorption in rats and mice, as well as hemoglobin production in zebrafish. Researchers observed that hinokitiol molecules can bind to iron atoms and move them across cell membranes and into/out of mitochondria, despite an absence of the native proteins that would usually carry out these functions.

Burke's team initially found that hinokitiol could transport iron across cell membranes in vitro before reaching out to Paw and other collaborators to test its efficacy in animal models. Paw, co-senior author on the new Science paper and physician at Dana-Farber/Boston Children's, and members of his lab demonstrated that hinokitiol can successfully reverse iron deficiency and iron overload in zebrafish disease models.

Based on the findings in animal studies hinokitiol does seem to have big therapeutic potential in treating disorders related to iron metabolism. However further research is needed to elucidate its utility in humans.

Citation: Grillo, Anthony S., Anna M. Santamaria, Martin D. Kafina, Alexander G. Cioffi, Nicholas C. Huston, Murui Han, Young Ah Seo, Yvette Y. Yien, Christopher Nardone, Archita V. Menon, James Fan, Dillon C. Svoboda, Jacob B. Anderson, John D. Hong, Bruno G. Nicolau, Kiran Subedi, Andrew A. Gewirth, Marianne Wessling-Resnick, Jonghan Kim, Barry H. Paw, and Martin D. Burke. "Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals." Science 356, no. 6338 (2017): 608-16.
doi:10.1126/science.aah3862.
Adapted from press release by Boston Children's Hospital.

Thursday, May 11, 2017

New tissue-engineered platform for islet cell transplantation found effective in type 1 diabetic patients

Researchers from the Diabetes Research Institute (DRI) have produced the clinical results demonstrating that pancreatic islet cells transplanted within a tissue-engineered platform can achieve insulin independence in type 1 diabetes. The research findings are published in the New England Journal of Medicine.
Islet cell transplantation omentum minipancreas
Fluorescence microscopy of islets in the omentum transplanted within the biologic scaffold. In red (insulin staining) and blue (DAPI nuclear staining). Credit: Diabetes Research Institute/University of Miami Miller School of Medicine
Islet transplantation is an emerging technology. It has demonstrated the ability to restore natural insulin production and eliminate severe hypoglycemia in people with type 1 diabetes. Traditionally the cells are transplanted into the liver, however, this site poses some limitations so researchers used omentum.

This was the first successful tissue-engineered islet transplantation that has achieved long-term insulin independence in a patient with type 1 diabetes. The biological platform was made by combining donor islets with the patient's own (autologous) blood plasma, which was laparoscopically layered onto the omentum. Clinical-grade thrombin was then layered over the islet/plasma mixture. The technique has been designed to minimize the inflammatory reaction that is normally observed when islets are implanted in the liver or in other sites with immediate contact to blood.

"The results thus far have shown that the omentum appears to be a viable site for islet implantation using this new platform technique," said lead author David Baidal, M.D., Assistant Professor of Medicine and member of the DRI's Clinical Cell Transplant team. "Data from our study and long-term follow-up of additional omental islet transplants will determine the safety and feasibility of this strategy of islet transplantation, but we are quite excited about what we are seeing now."

Citation: Baidal, David A., Camillo Ricordi, Dora M. Berman, Ana Alvarez, Nathalia Padilla, Gaetano Ciancio, Elina Linetsky, Antonello Pileggi, and Rodolfo Alejandro. "Bioengineering of an Intraabdominal Endocrine Pancreas." New England Journal of Medicine 376, no. 19 (2017): 1887-889. doi:10.1056/nejmc1613959.
Research funding: Diabetes Research Institute Foundation, JDRF, The Leona M. and Harry B. Helmsley Charitable Trust, National Institutes of Health, University of Miami.
Adapted from press release by Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine.