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February 25th, 2016

PCSK9-Inhibitor Drug Class Proves Game-Changer for Patient with Extremely High Cholesterol

A 59-year-old heart patient with dangerously high levels of cholesterol that could not be adequately reduced by statin drugs now has near-normal cholesterol levels, thanks to a new class of drugs that grew out of work done by UT Southwestern Medical Center researchers. Two of these drugs, in a category known as PCSK9 inhibitors, were approved by the Food and Drug Administration last summer for use by some individuals with extremely high cholesterol levels. “If you take the core patients who are at highest risk, it makes you appreciate how important this drug class is,” said Dr. Amit Khera (at right in photo), Director of the Preventive Cardiology Program and Associate Professor of Internal Medicine at UT Southwestern. Frank Brown (at left in photo) of Dallas, grandfather of six and the owner of Frank’s Wrecker Service in Dallas, has familial hypercholesterolemia, an inherited condition that causes high levels of cholesterol, especially of low-density-lipoprotein (LDL) cholesterol or “bad cholesterol.” High levels of LDL cholesterol are strongly associated with heart disease. Mr. Brown, with a history of two heart attacks, had been aggressively treated with multiple drugs to reduce his cholesterol levels, but they remained stubbornly high. “When I first met Mr. Brown, he had a strong family history of heart disease, he had a cholesterol level that was ridiculously high with an LDL of 384, and he was having chest pains,” said Dr. Khera, who is Mr. Brown’s cardiologist. Dr. Khera, who holds the Dallas Heart Ball Chair in Hypertension and Heart Disease at UT Southwestern, was treating Mr.

Newly Developed Substance Inhibits Beta-Secretase Specifically in Endosomes Where Harmful Beta-Amyloid of Alzheimer’s Is Formed

For decades, intensive research has been conducted on drugs all over the world to treat Alzheimer's patients. Although major progress has been made in diagnostics (the disease can be detected increasingly early and accurately), the therapeutic options remain limited. Together with researchers in Switzerland, Germany and India, a team headed by Professor Lawrence Rajendran from the Systems and Cell Biology of Neurodegeneration at the Institute of Regenerative Medicine of the University of Zurich has now developed a targeted substance that blocks the pathogenic function of an enzyme (beta-secretase) in cells without affecting the enzyme’s other vital functions. The new work was published online on February 25, 2016 in the journal Cell Reports. The open-access article is titled “Specific Inhibition of β-Secretase Processing of the Alzheimer’s Disease Amyloid Precursor Protein.” Protein deposits in the brain are hallmarks of Alzheimer's disease and are partly responsible for the chronically progressive necrosis of the brain cells. Nowadays, these plaques can be detected at very early stages, long before the first symptoms of dementia appear. The protein clumps mainly consist of the β amyloid peptide (Aβ), a protein fragment that forms when two enzymes, β and γ secretase, cleave the amyloid precursor protein (APP) into three parts, including Aβ, which is toxic. If β or γ secretase is blocked, this also inhibits the production of any more harmful Aβ peptide. Consequently, for many years, biomedical research has concentrated on these two enzymes as therapeutic points of attack. To date, however, the results of clinical studies using substances that block γ secretase have been sobering. The problem is that the enzyme is also involved in other key cell processes.

Smallest of the World’s Giant Parasitic Flowers

Some of the world's giant flowers, those of the parasitic plant genus Rafflesia, can reach up to a meter and a half in diameter. Therefore, what could be more impressive about them than relative “dwarves” such as the record-breaking one that was recently discovered by scientists from the University of the Philippines Diliman and the University of the Philippines Los Baños. Its average diameter is only 9.73 cm and it has been named Rafflesia consueloae. The study was published online on February 25, 2016 in the open-access journal PhytoKeys. Curiously enough, the discovery happened after a field assistant accidentally tripped over a pile of forest litter to expose a decayed flower. Later on, lead researcher Professor Perry S. Ong would describe the novel finding as "serendipitous." The research article is titled “Rafflesia consueloae (Rafflesiaceae), the Smallest Among Giants; A New Species from Luzon Island, Philippines” "Rafflesia flowers are unique in that they are entirely parasitic on roots and stems of specific vines in the forests and have no distinct roots, stems, or leaves of their own," explains co-author Professor Edwino S. Fernando. "Thus, they are entirely dependent on their host plants for water and nutrients." In Sumatra and Borneo, another species of the same genus, Rafflesia arnoldi, holds the record for being the largest single flower in the world, with a diameter of up to 1.5 meters. In the Philippines, Rafflesia schadenbergiana, found only in Mindanao, is still large, with a flower diameter of 0.8 meters. Professor Fernando, added that Rafflesia consueloae is the 6th Rafflesia species from Luzon Island and the 13th for the entire Philippine archipelago.

Y-Chromosome Genetics Reveals 50,000 Years of Independent History of Aboriginal Australian People

The first complete sequences of the Y chromosomes of aboriginal Australian men have revealed a deep indigenous genetic history tracing all the way back to the initial settlement of the continent 50.000 years ago, according to a study published online in the journal Current Biology on February 25, 2016. The open-access article is titled “Deep Roots for Aboriginal Australian Y Chromosomes.” The study, by researchers from the Wellcome Trust Sanger Institute and collaborators at La Trobe University in Melbourne and several other Australian institutes, challenges a previous theory that suggested an influx of people from India into Australia around 4,000 to 5,000 years ago. This new DNA sequencing study focused on the Y chromosome, which is transmitted only from father to son, and found no support for such a prehistoric migration. The results instead show a long and independent genetic history in Australia. Modern humans arrived in Australia about 50,000 years ago, forming the ancestors of present-day aboriginal Australians. They were amongst the earliest settlers outside Africa. They arrived in an ancient continent made up of today's Australia, Tasmania, and New Guinea, called Sahul, probably thousands of years before modern humans arrived in Europe. 5,000 years ago, dingos, the native dogs, somehow arrived in Australia, and changes in stone tool use and language around the same time raised the question of whether there were also associated genetic changes in the Australian aboriginal population. At least two previous genetic studies, one of which was based on the Y chromosome, had proposed that these changes could have coincided with mixing of aboriginal and Indian populations about 5,000 ago.

Unexpected Property in Organic Semiconductor Molecule Could Lead to More Efficient & Cost-Effective Materials for Solar & Opto-Electronic Devices

On February 25, 2016, chemists and polymer scientists collaborating at the University of Massachusetts Amherst (U-Mass Amherst) reported in Nature Communications that they have identified an unexpected property in an organic semiconductor molecule that could lead to more efficient and cost-effective materials for use in cell phone and laptop displays, for example, and in opto-electronic devices such as lasers, light-emitting diodes, and fiber optic communications. Physical chemist Michael Barnes, Ph.D., and polymer scientist Alejandro Briseño, Ph.D., with doctoral students Sarah Marques, Hilary Thompson, Nicholas Colella and postdoctoral researcher Joelle Labastide, Ph.D., discovered the property, called “directional intrinsic charge separation,” in crystalline nanowires of an organic semiconductor known as 7,8,15,16-tetraazaterrylene (TAT). The open-access Nature Communications article reporting the finding is titled “Directional Charge Separation in Isolated Organic Semiconductor Crystalline Nanowires.” The researchers saw not only efficient separation of charges in TAT, but a very specific directionality that Dr. Barnes says "is quite useful. It adds control, so we're not at the mercy of random movement, which is inefficient. Our paper describes an aspect of the nanoscopic physics within individual crystals, a structure that will make it easier to use this molecule for new applications such as in devices that use polarized light input for optical switching. We and others will immediately exploit this directionality.” He adds, "Observing the intrinsic charge separation doesn't happen in polymers; so far as we know, it only happens in this family of small organic molecule crystalline assemblies or nanowires.

February 24th

Genome Sequencing Reveals Link Between Chlamydia-Caused Sexually Transmitted Infections (STIs) and Chlamydia-Caused Infectious Blindness; Transfer of Gene Variants Can Give STI Chlamydia Ability to Infect Eye

For the first time, genome sequencing has been carried out on Chlamydia trachomatis (C. trachomatis), a bacterium responsible for the disease trachoma - the world's leading infectious cause of blindness, according to a study published online on February 25, 2016 in Nature Communications. The open-access article is titled “Chlamydia trachomatis from Australian Aboriginal People with Trachoma Are Polyphyletic Composed of Multiple Distinctive Lineages.” Researchers at the Wellcome Trust Sanger Institute (UK) and Menzies School of Health Research (Australia) have discovered that genes can move from chlamydia strains in the eye to sexually transmitted strains of chlamydia, allowing them to then infect the eye and cause trachoma, a neglected tropical disease. C. trachomatis is the major cause of sexually transmitted infections (STIs) worldwide and is also responsible for trachoma. Trachoma affects about 2.2 million people worldwide, and is still present in some indigenous communities in the Northern Territory of Australia. The clinical impact of the results is that trachoma re-emergence may be more likely than previously thought, particularly if Chlamydia STI remains common. Dr. Patiyan Andersson, Senior Research Officer at the Menzies School of Health Research (Menzies) and lead author of the paper, said: "This work came about from the analysis of frozen isolates that had been collected in the 1980s and 1990s. We were able to resuscitate chlamydia bacteria that had been frozen for 30 years, and study their genomes to find out how they had evolved."

Researchers Build Powerful 3-D Microscope, Create Images of Cancer Cells in Controlled Microenvironments

University of Texas (UT) Southwestern Medical Center researchers have designed and built a microscope capable of creating high-resolution, 3-D images of living cancer cells in realistic, controllable microenvironments. “There is no microscope that allows us to look at living cells with this resolution and precision in a controlled microenvironment. We can now create 3-D images of cancer cells and record how they interact with their microenvironment via signaling,” said Dr. Gaudenz Danuser, Chair of the Lyda Hill Department of Bioinformatics at UT Southwestern and corresponding author of a study detailing the project in the February 22, 2016 issue of Developmental Cell. The open-access article is titled “Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments.” This approach enables researchers to study cells in controlled microenvironments at a level of detail that should accelerate the pace of discovery in many fields of biology, Dr. Danuser explained. “It’s a two-photon, light-sheet microscope that allows 3-D time-lapse imaging of cells deep within physiologically realistic microenvironments,” said Dr. Reto Fiolka, an Instructor of Cell Biology at UT Southwestern and fellow corresponding author of the study. Using the new microscope and software, the researchers created 3-D images of the detailed shapes that skin and lung cancer cells develop as they move through tissue. They also created images and movies of the dynamic activation of a key signaling molecule (PI3-kinase) that is involved in many cellular processes. The new microscope was designed to solve a long-standing problem in biology: the need to artificially constrain cells – usually by flattening them onto glass plates in two dimensions – in order to image them clearly.

Molecular Medicine Tri-Conference in San Francisco March 6-11; BioQuick News Is a Media Sponsor

The Molecular Medicine Tri-Conference 2016 is scheduled to take place in San Francisco from March 6 to March 11. If you are working in diagnostics and drug discovery, this is perhaps the must-attend event of the year. Attracting over 3,300 drug discovery and development professionals from over 40 countries in 2015, the Tri-Conference has grown into a diverse event, focusing on Molecular Medicine, specifically on Discovery, Genomics, Diagnostics, and Information Technology. With a 23-year history, this year’s expanded coverage includes additional programs on Molecular Diagnostics for Infectious Disease, Precision Medicine, and Cancer Immunotherapy, as well as new symposia on Companion Diagnostics and on the Commercialization of Molecular Diagnostics. You will have the opportunity to listen to many of the over-500 speakers from across all industries, all research fields, and from all over the world. A link to the registration page for the Molecular Medicine Tri-Conference is provided below, as are links to the current speaker list and to the Event-at-a-Glance brochure. BioQuick News is an official media sponsor of the Molecular Medicine Tri-Conference 2016. Other media sponsors of Tri-Conference 2016 include Science, Genetic Engineering & Biotechnology News, The Scientist, and BioIT World. A link to the list of media sponsors is also provided below.

[Registration] [Speaker List] [Event-at-a-Glance] [Media Sponsors]

Oncogenic Herpes Virus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication; “Stress-Sensor” Proteins Slow Down Cell Proliferation Stimulating Virus Lytic Gene Expression

Researchers have now found an important link between cellular stress responses, cell cycle regulation, and the reactivation of an oncogenic herpes virus. While looking for cellular factors involved in the reactivation of a particular oncogenic human herpes virus, the Kaposi's-sarcoma-associated herpes virus (KSHV), the research group of Dr. Päivi Ojala at the University of Helsinki, Finland, and collaborators, have identified a mechanism by which stress conditions favor the lytic reactivation and ensure the efficient production of progeny viruses. KSHV is the etiological agent for Kaposi’s sarcoma and for primary effusion lymphoma (PEL), an aggressive form of lymphoma with reported median survival time shorter than six months after diagnosis. Results of the new study, which combined the most advanced microscopy technologies with genetic manipulation techniques, show that a variety of chemical stresses all lead to the activation of a set of cellular "stress-sensor" proteins – like p53 and p21clip – that, in the attempt to rescue the cell from the exogenous stress slow down cell proliferation. This process seems to create a cellular environment that favors the expression of viral lytic genes, which a few hours after reactivation leads to massive damage of the cellular DNA and arrest of the cell division cycle in a stage known as Gap-2 phase or G2. In this state, cells are kept alive by viral proteins and all cellular nutrients and resources are redirected to the assembly of thousands of new virions. The p21clip protein has a critical role in maintaining cells in the G2-arrested state, the research shows, as removal of this protein by genetic manipulation restored cell division in cells undergoing lytic replication.

February 23rd

Cocaine Reward Controlled by Dopamine-Activated Rap1 Signaling Pathway in Striatal Neurons

A Nagoya University (Japan) research team, together with colleagues from other institutions, has discovered how dopamine controls the brain’s response to cocaine in a mouse model. A new report shows that cocaine administration increases dopamine levels in the striatum, activating a signaling pathway that was previously unknown—the Rap1 signaling pathway. The research was published in the February 3, 2016 issue of Neuron. The article is titled “Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation As a Reward Signal In Vivo.” Dopamine is known to activate a protein called PKA in striatal neurons, which, in turn, activates many additional substrates to regulate neuronal excitability and control behavior. However, the identities of the PKA substrates were not previously known. The Nagoya-led research team has now uncovered some answers. “We stimulated PKA in mouse brain slices to activate these unknown substrates,” explains corresponding author Kozo Kaibuchi, Ph.D., of the University of Nagoya’s Department of Cell Pharmacology. His research team was able to extract these activated proteins from brain slices and to identify them. “Using this screening approach, we identified more than 100 candidate substrates of PKA,” continues Dr. Kaibuchi. One of these novel candidates was Rasgrp2, a protein that is highly expressed in striatal neurons. Rasgrp2 positively regulates another protein called Rap1 and the authors were intrigued to find out whether Rap1 was activated by Rasgrp2 in striatal neurons as a result of cocaine administration. Through a range of experiments, the Nagoya-led research group found the answer; the scientists demonstrated that cocaine treatment increased the phosphorylation of Rasgrp2 by PKA, and phosphorylated Rasgrp2, in turn, activated Rap1 in striatal neurons.