Eggs: Fresh or Stale?
Researchers from the Carnegie Institution for Science have weighed in on the question of whether female mammals have germ-line stem cells that are capable of generating new egg cells. Recent reports have questioned the long-held notion that female mammals are born with all the eggs they will ever possess, suggesting instead that they have stem cells capable of generating new eggs. In their work, the researchers used a sensitive labeling system to see whether they could identify clusters of eggs after labeling of single cells, which would indicate the presence of stem cells. They did not find such clusters, even though their labeling system was sensitive enough to detect a single cell division every two weeks, and so concluded that "adult female mice neither require nor contain active germ-line stem cells or produce new oocytes in vivo." Their work appeared in the April 29, 2013, online issue of the Proceedings of the National Academy of Sciences.
MTOR Active Site Structure Is Solved
Scientists from Memorial Sloan-Kettering Cancer Center published structural data on the mTOR kinase, which integrates nutrient sensing with growth regulation, in complex with both specific and nonspecific inhibitors. The mTOR kinase is a key regulator of growth, and it is targeted by hundreds of agents now in preclinical and clinical development. In their paper, the authors co-crystallized mTOR with both specific and nonspecific inhibitors. The studies "reveal active-site residues and conformational changes that underlie inhibitor potency and specificity," and so should provide valuable information for the design of more specific inhibitors. They were published in the May 1, 2013, advance online edition of Nature.
How Novel Coronavirus Is Different from SARS
A team from the University of Washington has identified important differences between NCoV or HCoV-EMC, an emerging coronavirus with a high fatality rate, and the SARS-coronavirus that caused a pandemic nearly 10 years ago. Although both are coronaviruses, the scientists found that NCoV caused changes in the transcriptome of cells it infected "to a much greater extent" than SARS. NCoV also was able to suppress the expression of several genes that are important for antigen presentation, an ability that SARS does not have and that "could have an important impact on the ability of the host to mount an adaptive host response." The authors also used their data to predict several therapeutic strategies that might be successful against NCoV, including inhibitors of MAP, PI3 and other kinases, as well as glucocorticoids. The findings were published in the April 30, 2013, online issue of mBIO.
Breaching Blood-Brain Barrier, Permanently
Scientists from the Massachusetts Eye and Ear Infirmary have developed a way to create a permanent opening in the blood-brain barrier via mucosal engrafting, or the implantation of a graft within the base of the skull that allows larger-than-normal molecules to pass through the blood-brain barrier at the engraftment site. The blood-brain barrier greatly restricts the molecules that can pass into the brain, including potential pharmacological agents, and is one reason that neurological drug development is even more difficult than average. In their studies, the authors developed a mouse model of a surgery that has been successfully used to repair skull base defects in humans. They found that in such animals, molecules could pass directly into the brain that were large enough to suggest "a potential role for this technique in the treatment of Parkinson's disease." The authors said their study shows that "mucosal engrafting represents the first permanent and stable method of bypassing the [blood-brain barrier]" to deliver large drugs directly into the brain. Their findings appeared in the April 24, 2013, issue of PLoS ONE.
Seeing Autism in the Placenta
A team from Yale University has discovered that certain placental abnormalities are a possible early identification method for babies who are at high risk of developing autism. Typically, children with autism are not diagnosed until they are several years old, and earlier diagnosis and intervention might be better able to ameliorate some of the symptoms of the disorder during early brain development. In their study, the authors looked at so-called trophoblastic inclusions in the placentas of mothers who had older children with autism, and in mothers who had older children with typical neural development. They found that "the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas." Trophoblastic inclusions result when certain placental stem cells divide excessively. Such trophoblastic inclusions are unlikely to be a cause of autism, but they do offer the possibility of early identification of children at risk. The work appeared in the April 26, 2013, advance online edition of Biological Psychiatry.
Easily Transmissible Bird Flu Strain
Scientists from the Chinese Academy of Agricultural Sciences have combined different strains of flu virus and found that the H5N1 avian influenza virus can, when combined in the right way, become transmissible between mammals, presumably including humans. Influenza viruses can change their genetic makeup both through mutations and through reassortment, where large segments of virus combine in novel ways in animals that are infected with several different strains of the same virus. The authors found that combining certain segments of an H1N1 strain that is highly transmissible between humans with H5N1 resulted in viral strains that were easily transmissible between guinea pigs, though the resulting infections were not fatal to the animals. "H5N1 subtype viruses do have the potential to acquire mammalian transmissibility by reassortment in current agricultural scenarios." They published that conclusion, and the data supporting it, in the May 2, 2013, advance online issue of Science. In the same issue, researchers from the Chinese Academy of Sciences described atomic-level studies of how genetic mutations that make H5N1 more easily transmissible between mammals affect the binding of hemagglutinin to its receptor in the lungs of its victims.
How Protein Misfolding Kills Cells
A team from the Sanford Burnham Research Institute has gained new insights into how protein misfolding leads to cell death. In their study, the authors were trying to understand why phosphorylation of elF2alpha, which initiates the translation of RNA, can lead to cell death in some circumstances and promote cell survival in others. They found that in the timing of activity between elF2alpha and two other proteins, ATF4 and CHOP. ElF2alpha temporarily slows down protein production when the endoplasmic reticulum cannot keep up with its folding duties in times of stress, and later activation of ATF4 and CHOP restores protein synthesis. If protein synthesis is restored too soon, however, free radical production leads to cell death. "The findings suggest," the authors concluded, "that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the [endoplasmic reticulum]." They were published in the April 28, 2013, advance online edition of Nature Cell Biology.
Early Bird Gene Mutation Linked to Migraine
A group of scientists from the University of California at Los Angeles and the University of California at San Francisco discovered a gene mutation that is linked to both familial advanced phase sleep syndrome, in which individuals go to bed and wake up very early, and migraine. The researchers identified the mutation, in the casein kinase Idelta gene, in two families with multiple family members suffering from migraines. They then engineered transgenic mice and showed that such animals had multiple neural abnormalities that are thought to physically underlie migraines. Specifically, the animals showed increased sensitivity to pain after being treated with a migraine trigger. They also had cortical spreading depression, which may be responsible for the aura that precedes the onset of some migraines. The authors concluded that reduced activity in casein kinase Idelta is one underlying reason for migraines. Their work appeared in the May 2, 2013, issue of Science Translational Medicine.
Genomic Classification of Uterine Cancers
Scientists from the multi-institutional Cancer Genome Atlas Research Network have classified uterine cancers into four categories, based on their sequencing and proteomic study of about 375 uterine cancers. Previous studies of uterine tumors have looked at gene sequencing only, and have included tumors that differed in their histologies as well as their grades. The authors found that tumors could be classified into four groups, which they identified as "POLE ultramutated, microsatellite instability hypermutated, copy-number low and copy-number high." They also found that uterine serous carcinomas, which originate from different cells than endometroid uterine cancers, share genomic features with ovarian serous and certain breast tumors. The authors said their study "provides key molecular insights into [tumor] classification, which may have a direct effect on treatment recommendations for patients, and provides opportunities for genome-guided clinical trials and drug development." It appeared in the May 2, 2013, issue of Nature.
PI3 Kinase Resistance Explained
Researchers from Duke University and Memorial Sloan-Kettering Cancer Center have identified one mechanism by which cancers can develop resistance to PI3 kinase (PI3K) inhibitors. Such inhibitors are in clinical development, but like most targeted therapies, work only for a time until tumors mutate their way around them. In their experiments, the authors found that some tumors develop resistance to PI3K inhibitors by increasing the activity of two other kinases, RSK3 or RSK4. "The addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity," they wrote. "These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK." Their findings were published in the May 1, 2013, issue of the Journal of Clinical Investigation.
– Anette Breindl, Science Editor