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Archive - Feb 2015

February 14th

The Neural Basis of “Being in the Mood”

What determines receptivity or rejection towards potential sexual partners? For people, there are many factors that play a part, appearance, culture, age, are all taken into account. But what part does the internal state of the individual play? The functioning of our bodies is maintained through a complicated system of hormonal signals. Some of these signals vary along different physiological rhythms, such as the menstrual cycle. How do changes in hormone levels affect the activity of individuals' brains and their behavior? "It is well known that the behavior of female mice changes dramatically during the different phases of their reproductive cycle, called the estrous cycle," says Dr. Susana Lima (, a Principal Investigator at the Champalimaud Centre for the Unknown in Lisbon, Portugal. "Responses to brief social interactions with males can result in radically different outcomes, ranging from receptivity to aggression. In this study, we investigated the question--what is the neural basis that underlies these polar behaviors?" The study results were published online on Februay 12, 2015 in Current Biology. The article is entitled, “Enhanced Male-Evoked Responses in the Ventromedial Hypothalamus of Sexually Receptive Female Mice.” The researchers chose to focus their research on the hypothalamus. "The hypothalamus regulates many instinctive behaviors, including feeding, sleeping, and sexual behavior", says Dr. Kensaku Nomoto, a post-doctoral researcher in the laboratory of Susana Lima. "We recorded the activity of neurons in an area within the hypothalamus dedicated to socio-sexual behavior. The activity of the neurons was observed while the females interacted with males or with other females."

Romantic Reunion of Two Fern Species After 60 Million Years Apart Stuns Plant Geneticists

A delicate woodland fern discovered in the mountains of France is the “love child” of two distantly-related groups of plants that haven't interbred in 60 million years, genetic analyses show. For most plants and animals, reuniting after such a long hiatus is thought to be impossible due to genetic and other incompatibilities between species that develop over time. Reproducing after such a long evolutionary breakup is akin to an elephant hybridizing with a manatee, or a human with a lemur, said co-author Kathleen Pryer, who directs the Duke University Herbarium. Led by Dr. Pryer and Dr. Carl Rothfels of the University of California, Berkeley, the study appears online on February 14, 2015 in the American Naturalist. The pale green fern was found growing wild on a forest floor in the Pyrenees and eventually made its way to a nursery, where researchers plucked several fronds and extracted the DNA to pinpoint its parentage. To their surprise, genetic analyses revealed that the fern was the result of a cross between an oak fern and a fragile fern -- two distantly related groups that co-occur across much of the northern hemisphere, but stopped exchanging genes and split into separate lineages some 60 million years ago. "To most people they just look like two ferns, but to fern researchers these two groups look really different," Dr. Rothfels said. Other studies have documented instances of tree frog species that proved capable of producing offspring after going their separate ways for 34 million years, and sunfish who hybridized after nearly 40 million years, but until now, those were the most extreme reunions ever recorded. "For most plant and animal species, reproductive incompatibility takes only a few million years at the most," Dr. Rothfels said.

Proteomics Analysis Reveals New Alzheimer’s Targets; Beyond Beta-Amyloid and Tau

Allan Levey, M.D, Ph.D, Chair of Neurology at Emory University School of Medicine and Director of the Emory Alzheimer's Disease Research Center, gave a a talk titled "Proteomics Discovery of New Alzheimer's Disease Targets," as part of the Dementia: Research Milestones and Policy Priorities session on Friday, Feb. 13, at the 2015 annual AAAS convention taking place in San Jose, California, February 12-16, 2015, The theme of this year’s AAAS meeting is “Innovations, Information, and Imaging.” Dr. Levey described a "beyond the usual suspects" approach to probing for proteins involved in Alzheimer's disease pathology. "Usual suspects" refers to beta-amyloid and tau, two proteins that accumulate in the brains of Alzheimer's patients. Some experimental approaches to Alzheimer's treatment aim at curbing beta-amyloid, but have not proven effective. Taking their proteomics approach, Dr. Levey and his team have already identified a previously unrecognized type of pathology in the brains of Alzheimer's patients, seen at early stages of the disease. They found tangle-like structures that sequester proteins critical for RNA splicing, a discovery that may have implications for the disease mechanism. A related article, entitled “U1 Small Nuclear Ribonucleoprotein Complex and RNA Splicing Alterations in Alzheimer’s Disease,” was published in the February 10, 2015 issue of PNAS. Last year, Emory was awarded a five-year, $7.2 million grant from the National Institute on Aging to extend this work in collaboration with five other Alzheimer's Disease Research Centers around the country.The image depicts the U1 small nuclear ribonucleoprotein complex.

[Press release] [PNAS articlet]

February 13th

Structure-Based Design Used to De-Immunize Proteins to Enable Efficient Epitope Detection at High Mutational Loads for the Enhanced Development of Effective and Safe Biotherapeutics

In the first experimental use of algorithms that employ structure-based molecular modeling to optimize de-immunized drug candidates, Karl Griswold, Ph.D., and co-investigator Christopher Bailey-Kellogg, Ph.D., of Dartmouth College complement their prior sequence-based de-immunizing algorithms and expand the tool kit of protein engineering technologies to use in next-generation drug development. Their paper, "Protein Deimmunization via Structure-Based Design Enables Efficient Epitope Deletion at High Mutational Loads," was published online on February 5, 2015 in Biotechnology and Bioengineering. "This work is part of our larger collaborative initiative to develop performance-enhanced protein drugs that are invisible to the human immune system," explained Dr. Griswold. "Biotherapeutics offer potent treatment options for a wide range of diseases but, due to their biological origins, these powerful therapies can elicit detrimental immune responses in humans." Development of biotherapeutic agents is a time-consuming and costly endeavor, and there exists a substantial risk that deleterious immunogenicity issues will undermine otherwise promising drug candidates late in the development process. While methods for identifying immunogenic hotspots, or epitopes, are evolving rapidly, technologies to redesign the hotspots, while maintaining biotherapeutic activity and stability are far less developed. The current study employed P99 betalactamase, a component of Antibody-Directed Enzyme Prodrug Therapy, to show that structure-based de-immunization resulted in highly-active and stable biotherapeutic designs that were different from those generated with earlier sequence-based algorithms. In particular, the structure-based designs remodeled a putative immunogenic hotspot that was not readily addressed with other methods.

Klotho May Be Key to Boosting Cognition

Scientists from the Gladstone Institutes and the University of California, San Francisco report in the February 11, 2015 issue of the Journal of Neuroscience that raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer’s disease. Remarkably, this boost in cognition occurred despite the accumulation of Alzheimer-related toxins in the brain, such as amyloid-beta and tau. Klotho decreases naturally with aging, which also leads to a decline in cognitive ability. An earlier study from these researchers revealed that having a genetic variant that increases klotho levels is associated with better cognition in normal, healthy individuals, and experimentally elevating klotho in mice enhances learning and memory. However, klotho’s influence in the face of aging-related cognitive disorders like Alzheimer’s disease was unclear. To test klotho’s protective capacity, the scientists created a mouse model of Alzheimer’s disease that produced higher levels of this protein throughout the body. Ordinarily, Alzheimer’s-model mice have cognitive deficits, abnormal brain activity, and premature death, but raising klotho levels meliorated these problems. The cognition-enhancing effects of the protein were powerful enough to counteract the effects of Alzheimer-related toxins, whose levels were unchanged. “It’s remarkable that we can improve cognition in a diseased brain despite the fact that it’s riddled with toxins,” says lead author Dena Dubal, M.D., Ph.D, ( Assistant Professor of Neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. “In addition to making healthy mice smarter, we can make the brain resistant to Alzheimer-related toxicity.

Innovative Statistical Analyses of Microbiome May Better Explain Connections Among Gut Bacteria, Metabolism, and Body-Mass Index (BMI)

Several recent science studies have claimed that the gut microbiome, the diverse array of bacteria that live in the stomach and intestines, may be to blame for obesity. But Katherine Pollard (photo), Ph.D., a Senior Investigator at the Gladstone Institutes in San Francisco, says it is not that simple. Dr. Pollard presented her work at the Obesity and Microbiome symposium at the AAAS Annual Meeting in San Jose, California, on Friday, February 13, 2015 at 3:00 pm PT. Using powerful computational tools, Dr. Pollard and her team have re-analyzed several previous studies and revealed that there is no significant relationship between body mass index (BMI) and the types of microbes in one's gut. In fact, her lab found that there was greater variability in gut bacteria between the different studies than between the lean and obese individuals within each study. Instead, Dr. Pollard thinks that it is the genetic make-up of the different strains of bacteria that is most important. This is because the DNA in bacteria can vary wildly. For example, while the genomes of two humans may only differ by 0.1%, two strains of the same bacteria can vary by to 30%--similar to the variation between human and mice genomes! What's more, the differences in the bacterial genomes are often important pieces that are involved in metabolism or the processing of sugar and fat. Besides reflecting important functional changes in bacterial genomes, losses and gains of genes also affect genome size. When microbiomes are studied using metagenomics--sequencing their total DNA--differences in bacterial genome size can bias the estimation of the proportion of each gene in the sample. By developing a computational shortcut to rapidly estimate genome size using statistical modeling, Dr.

Merck & Lilly Enter Collaboration to Research Combination Cancert Treatments Involving Merck’s Recently Approved Keytruda Anti-PD-1 Drug for Melanoma

As reported by PMLive on Janurary 15, 2015, Merck & Co. has agreed to a deal with Eli Lilly & Co. to research combination cancer treatments involving Merck's promising immunotherapy Keytruda, approved by the FDA in September 4, 2014. “The two companies will investigate several different regimens that put Keytruda (pembrolizumab), part of the highly anticipated anti-PD-1 (anti-programmed death receptor 1) class of cancer immunotherapies, together with a cancer compound in Lilly's portfolio. The companies confirmed three study programs that will take place as part of the collaboration, including a phase II study combining Keytruda and Lilly's Alimta (pemetrexed) in lung cancer,” PMLive reported. Furthermore, acccording to PMLive, “a second lung cancer study, this time phase I/II, will combine Keytruda with the investigational drug necitumumab, while the pairing of Keytruda and Cyramza (ramucirumab) will be investigated in multiple cancers in phase I/II trials.” PMLive said that additional details, including financial terms of the deal, had not disclosed. According to PMLive, the Merck-Lilly collaboration highlights the importance of Keytruda to Merck's growth plans. The drug is one of the most advanced drugs in the anti-PD-1 class, and became the first such product approved in the U.S., when it received FDA backing for the treatment of melanoma patients in September 2014 (see more on this below).

HPV Vaccine Highly Effective Against Multiple Cancer-Causing Strains; Positive Effects Most Obvious in 15-17 Age Group; Study Leader Suggests Boys Also Be Vaccinated

According to a multi-national, clinical trial involving nearly 20,000 young women, the human papilloma virus (HPV) vaccine Cervarix, not only has the potential to prevent cervical cancer, but was effective against other common cancer-causing human papillomaviruses, aside from just the two HPV types, 16 and 18, which are responsible for about 70 percent of all cases. That effectiveness endured for the study's entire follow-up length of up to four years. The research was published on February 4, 2015 in Clinical and Vaccine Immunology, a journal of the American Society for Microbiology. "The study confirms that targeting young adolescent girls before sexual debut for prophylactic HPV vaccination has a substantial impact on the incidence of high-grade cervical abnormalities," said corresponding author, Dr. Dan Apter, Director, The Sexual Health Clinic, Family Federation of Finland, Helsinki. The vaccine was extremely effective in young women who had never been infected with HPV. It protected nearly all from HPV-16 and -18, and protected 50-100 percent against different grades of pre-cancerous transformation of cervical cells caused by other strains of HPV, including up to 100 percent of those with the immediate precursor grade to cancer. The women were followed for up to four years post-vaccination. The vaccine was distinctly more effective among ages 15-17 than ages18-25, underscoring the value of vaccinating young adolescents, said Dr. Apter. The lower efficacy in the oldest age group may result from a larger proportion of women in that age group having had persistent infections at the time of vaccination, he said

Brain Abnormality in Broca’s Area Persists with Age in People Who Stutter

A region of the brain thought to control speech production develops abnormally in children who stutter--a pattern that persists into adulthood, according to new University of Alberta (Canada) research. In the first study to use MRI imaging to examine brain development in both children and adults who stutter, researchers at the U of A's Institute for Stuttering Treatment and Research (ISTAR) found abnormal development of grey matter in Broca's area, the region of the frontal lobe responsible for speech. It was the only abnormality found in the 30 regions of the brain the research team investigated. "In every other region of the brain we studied, we saw a typical pattern of brain matter development. These findings implicate Broca's area as a crucial region associated with stuttering," said Dr. Deryk Beal, ISTAR executive director and an assistant professor in the Faculty of Rehabilitation Medicine. Dr. Beal's team, which included collaborators from the University of Toronto, studied MRI images of the brains of 116 males between the ages of six and 48 years--both the largest group and widest age range –ever --for such a study. Roughly half the participants stuttered; the rest served as a control group. The research team observed a steady, and expected, decline in the cortical thickness of grey matter in the control group--a decline not observed in people who stutter. This decline in thickness, Dr. Beal explained, is actually a good thing because it reflects how the brain gets more efficient as we age, requiring fewer neural resources. "One interpretation of this finding could be that this area, in people who stutter, does not operate as efficiently within the brain network for speech production," Dr. Beal said.

Karolinska Scientists Report Promising Alzheimer Results in Small Group of Patients Receiving New Cell Therapy with NGF

Scientists at the Karolinska Institute in Swedne in have evaluated a new Alzheimer’s therapy in which the patients receive an implant that stimulates the growth of a certain type of nerve cell. The results, which were published online on February 9, 2015 in the scientific journal Alzheimer's & Dementia, suggest that the introduction of a nerve growth factor (NGF) can prevent neuronal degradation in Alzheimer’s patients. The title of the new article is, “Changes in CSF Cholinergic Biomarkers in Response to Cell Therapy with NGF in Patients with Alzheimer’s Disease.” Patients with Alzheimer’s disease are known to suffer a selective and early breakdown of so-called cholinergic nerve cells, which require a specific NGF to function. [Nerve growth factors (NGFs) are, essentially a group of proteins necessary for nerve cell growth and survival]. As NGF levels decline, the cholinergic nerve cells begin to degrade and the patient’s condition slowly deteriorates. In an attempt to curb the breakdown of the cholinergic nerve cells, researchers at the Karolinska Institute’s Centre for Alzheimer’s Research, and their colleagues at Karolinska University Hospital’s neurosurgery clinic, and at the Danish biotech company NsGene introduced NGF directly into the brains of Alzheimer’s patients. To do this, they used NGF-producing cell capsules, placing them in the basal fore-brain, where the cholinergic cells reside, using precision stereotactic surgery. There, the capsules, which can easily be removed, release NGF to the surrounding cells in order to prevent their degradation. The study, now published in Alzheimer’s & Dementia, is based on data from six Alzheimer’s patients.