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Biomedical research published in September

Oct 07, 2016

In this edition of our monthly science round-up, we feature interesting discoveries aimed at improving the treatment of diseases such as obesity, Dengue fever and cancer. Keep reading to discover how scientists around the world are improving our understanding of biology and addressing unmet clinical needs.

Happy Reading- Enjoy the September edition of our monthly science round  up

Neuroscience - Discovery of a neuronal protein that regulates obesity

Scientists now know that the central nervous system (CNS) contributes to the development of obesity and metabolic diseases. However, the neurobiological mechanisms involved remain poorly understood. Specifically, how a high fat diet changes the brain to promote the accumulation of body fat is still unclear. Scientists at Baylor and Texas Children's Hospital led by Dr Makota Fukuda have recently shown that a small GTPase called Rap 1 plays a central role in dietary obesity.

The Rap 1 gene is expressed in a variety of tissues including the brain. However, its principal function in the brain is associated with memory and learning. Using a mouse model of dietary obesity, the researchers examined how Rap 1 deletion affected weight gain on a high fat diet compared to control mice with intact Rap 1. While control mice gained weight, Rap1-deficient mice had comparatively less body weight and fat. Similar effects were observed with pharmacological inhibition of neuronal Rap-1.

Loss of Rap-1 not only provided protection against diet-induced obesity, but also from glucose imbalance, insulin resistance in other parts of the body and neuropathological changes elicited by a high-fat diet. The researchers also demonstrated that Rap-1 regulates neural sensitivity to the satiety hormone leptin, which regulates body weight by inhibiting appetite. Mice that lacked Rap-1 and consumed a high-fat diet did not develop leptin resistance, compared to their obese counterparts who demonstrated an inability to respond to signals of satiety produced by leptin. These findings indicate that Rap-1 could be a possible therapeutic target for treating dietary obesity.

Kaneko K et al. (2016). Neuronal Rap1 regulates energy balance, glucose homeostasis and leptin actions. Cell Rep 16, 3003-3015.

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Cancer - New strategy for treating acute myeloid leukemia

Patients with acute myeloid leukemia (AML) currently has a 5-year survival rate of approximately 27%. AML comprises many different genetic subtypes; however all subtypes share the hallmark of arrested development of myeloblasts at an immature and self-renewing stage. This leads to the proliferation of immature cells that crowd out and suppress the growth of mature myeloid cells. Previous studies have shown that most AML cases, despite their heterogeneity, express the HoxA9 gene, which is downregulated during differentiation of myeloblasts to mature myeloid cells.

Building on this information, a multi-institutional team of scientists led by Dr David Scadden from the Massachusetts General Hospital and the Harvard Stem Cell Institute designed a conditional HoxA9 mouse model to test a series of defined compounds that could overcome the aberrant cell differentiation observed in AML. In the model, myeloid cells that developed normally to maturity would fluoresce green. The scientists applied this model to test a series of defined compounds and determined that those that inhibited the enzyme dihydroorotate dehydrogenase (DHODH) enabled proper differentiation of myeloid cells.

DHOH was not previously known to play a role in myeloid differentiation and thus represents a novel therapeutic target for treating AML. Additional studies in mice showed that targeting DHOH led to reduced leukemic cell burden, decreased levels of leukemia-initiating cells and improved survival. Further investigation of the mechanism underlying the favorable effects of DHOH inhibition in AML is needed before this strategy can be tested in humans.

Sykes DB et al. (2016). Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockage in acute myeloid leukemia. Cell 167, 171-186.

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Immunology - The composition of microbes in the gut of infants determines their susceptibility to allergy and asthma later in life

The prevalence of asthma in the western world has doubled in the past six decades. Determining why some children develop asthma and allergies when others do not has been a key research focus of Dr Christine Cole Johnson of the Henry Ford Health System for over a decade. In a recent study published in the journal Nature Medicine, Dr Cole Johnson and Dr Susan Lynch from the University of California, San Francisco, led a multi-institutional group of researchers to the discovery that the composition of the gut microbiota in infants can predict later allergy and asthma.

The research team used high-throughput genetic analysis of the stool of 130 one-month old infants to determine the gut microbial composition. They later conducted two-year and four-year follow up studies to determine the incidence of allergy or asthma. This is the first study to examine the bacterial and fungal composition of the gut of infants.

The findings demonstrated that infants (11 out of 130) with a particular microbial composition demonstrate a three-fold higher risk of developing allergies and asthma by age two and four, respectively. Specifically having reduced bacteria such as Bifidobacterium, Akkermansia and Faecalibacterium as well as increased abundance of fungi such as Candida and Rhodotorula were associated with the observed susceptibility. The researchers also showed dysfunction of the anti-inflammatory cell type T-regulatory cells in this group of infants.

These findings present an opportunity to develop treatments to prevent these diseases at an early stage before they become established. To learn more about how microbiota in the gut influences immunity, read our latest mini-review on mucosal immunology.

Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med doi: 10.1038/nm.4176. [Epub ahead of print].

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Veterinary Research - Maternally-derived antibodies are not protective against swine influenza A virus

The so-called "protective" effect of maternally-derived antibodies (MDAs) has been described in many ways. MDAs are proposed to reduce the susceptibility to virus infection or reduce virus shedding. Recently, a research team led by Dr Charlie Cador at the French Agency for Food, Environmental and Occupational Health and Safety tested the impact of MDAs on the dynamics of swine Influenza A virus (swIAV) infection in 5-week old piglets. They evaluated both the transmission and the duration of infection by quantifying and comparing swIAV spread in piglets with and without MDAs under experimental conditions.

The results showed that piglets with MDAs had reduced susceptibility to infection compared to those without MDAs. However, virus reproduction in these animals was higher than 1, indicating that MDAs conferred very little protection against the spread of the virus. In addition, shedding of the virus was much slower in piglets with MDA protection compared to those without; suggesting longer public exposure to the virus from shedding as well as increased potential for airborne transmission. The airborne transmission rate of swIAV was also quantified and reported for the first time in this study.

These findings demonstrate that such an extended spread of swIAV even in the presence of MDAs could contribute to swIAV persistence on farms. These results will therefore facilitate better management of pigs during swIAV outbreaks, which often lead to major economic consequences in the food industry.

Cador C et al. (2016). Maternally-derived antibodies do not prevent transmission of swine influenza A virus between pigs. Vet Res 47, 86.

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Cell Biology - Scientists discover how the lncRNA Braveheart exerts its functions in the heart

Long noncoding RNA (lncRNA) describes transcripts longer than 200 nucleotides that do not code for proteins. These transcripts are copied from regions of the genome once thought to be "junk DNA". However, studies have shown that lncRNAs are involved in a number of cellular processes including guiding cell fate during embryonic development. Yet, their mechanisms of action remain poorly understood.

In 2013, MIT biologists led by Dr Laurie Boyer discovered a mouse lncRNA called Braveheart, which is expressed at high levels in the heart compared to other tissues. They demonstrated that Braveheart was essential for normal development of heart muscles, but how it functioned to induce its effect was unexplored. Boyer and her research team hypothesized that determining the structure could reveal new clues into its function. This was therefore the aim of a recent study by the research group published in the journal Molecular Cell on September 1, 2016.

Using chemical probing methods, the researchers demonstrated that Braveheart has a modular fold, and that deletion of 11 nucleotides in a G-rich internal loop of the lncRNA inhibited its function. They also discovered that a transcription factor called cellular nucleic acid binding protein (CNBP) binds strongly to this region of Braveheart. It is known that mutations in CNBP can lead to heart defects in mice and humans, since it blocks cardiac development. Braveheart was shown to release CNBP so that cardiac development can proceed normally.

Scientists have not yet identified the human counterpart of Braveheart; however, identification of the structure of the mouse homolog should facilitate the discovery of human lncRNAs with similar functions.

Xue Z et al. (2016). A G-rich motif in the lncRNA Braveheart interacts with a zinc-finger transcription factor to specify the cardiovascular lineage. Mol Cell doi: 10.1016/j.molcel.2016.08.010. [Epub ahead of print]

Klattenhoff CA et al. (2013). Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152, 570-583.

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Infectious Diseases - A salivary protein from the mosquito that transmits the Dengue virus inhibits its infection

The Aedes aegypti mosquito transmits viruses such as Dengue, Chikungunya and Zika. To transmit the Dengue virus, the mosquito injects virus-infected saliva into the skin of the host during probing and feeding. This saliva contains several proteins including members of the D7 family. In contrast to other proteins in the saliva, researchers led by Dr Michael Conway at the Central Michigan University College of Medicine recently discovered that D7 proteins in fact inhibit infection by the Dengue virus.

D7 proteins were previously shown to facilitate the blood feeding process but their role in blocking Dengue virus infection was previously unknown. Dr Conway and his research team determined that Dengue virus infected mosquitos had elevated levels of D7 proteins compared to uninfected mosquitos. They also found that D7 could block Dengue virus infection both in vitro and in vivo, and that they do this by binding directly to the virus.

Individuals exposed to the Dengue virus often have high levels of anti-D7 antibodies. Although these antibodies may prevent effective blood feeding, they can also enhance viral transmission and disease progression. These findings will undoubtedly promote the development of new therapeutics and vaccines for treating Dengue fever.

Conway MJ et al. (2016). Aedes aegypti D7 Saliva protein inhibits Dengue virus infection. Plos Negl Trop Dis 10, e0004941.

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Science News - Scientific community meets to discuss antibody validation

Two recent meetings united scientists, publishers, antibody manufacturers, grant agencies, and science communicators to discuss the increasingly popular topic of antibody validation. The first of these meetings took place at the University of Bath in the UK on September 15-16 and the second on September 25-27 in California, USA. An article in the journal Nature Medicine was published ahead of the meetings as a basis for discussion. Members of the international working group for antibody validation co-authored the publication, which provided suggested approaches for validating antibodies in common research applications.

The primary focus of the article, as well as the meetings, was to identify the role of the antibody manufacturer in providing quality antibodies to scientists. However, the role of journals, funding bodies and end-users was also discussed. Bio-Rad was present at both of these meetings and we will be posting a related blog post that features the key concerns discussed. Stay tuned to our blog for that upcoming post.

Uhlen M et al. (2016). A proposal for validation of antibodies. Nat Med 13, 823-827.

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