Antibiotics: Foresight not like hindsight

Gram-negative bacteria are protected from many antibiotics by their outer cell membranes. Studies attempting to understand what allows compounds to rapidly cross that cell membrane have focused on known antibiotics. Now, a team from the University of Illinois at Urbana-Champaign has screened a more chemically diverse set of compounds to identify additional characteristics of compounds that could get across the outer membrane. The results of the analysis were used to design derivatives of the gram-positive antibiotic deoxynybomycin that were effective against gram-negative bacteria as well. “We anticipate that these findings will aid in the discovery and development of antibiotics against gram-negative bacteria,” the authors wrote. That work appeared in the May 11, 2017, issue of Nature.

Why lithium works

About a third of all cases of bipolar disorder respond to lithium, but despite the fact that lithium has been used for decades to treat bipolar disorder, to date its molecular mechanism has been unknown, and there is no way to predict responders. By generating induced pluripotent stem cells (iPSCs) from lithium-responsive patients with bipolar disorder, researchers from Sanford Burnham Prebys Medical Discovery Institute, Yokohama City University, Massachusetts General Hospital and Harvard Medical School have found that lithium worked by affecting the activity of the cytoskeletal regulator CRMP2, which affected synaptic connections. The authors concluded that bipolar disorder “is a disorder not of a gene but of the posttranslational regulation of a developmentally critical molecule. Such knowledge should enable better mechanistically based treatments and bioassays.” The results appeared in the May 8, 2017, online issue of the Proceedings of the National Academy of Sciences.

Size matters for amyloid beta oligomers

Oligomers, or protein aggregates consisting of relatively few subunits, are thought to be the main damage-causing agents in many neurodegenerative diseases. In Alzheimer’s disease (AD), the oligomers are made up of amyloid beta and Abeta*56, an oligomer named for its molecular weight of 56 kilodaltons, is associated with neuronal damage and tau misprocessing. Researchers at the University of Minnesota have demonstrated that Abeta*56 interacted with the NMDA receptor, a receptor that allows calcium to enter neurons and set off a variety of cellular processes. In neuronal cell cultures and transgenic AD mouse models, Abeta*56 but not other oligomers of different weights led to the missorting of tau protein. “Our results indicate that distinct Ab assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies,” the authors wrote. Their findings appeared in the May 9, 2017, issue of Science Signaling.

HLAs in health and disease

By combining human leukocyte antigen (HLA) typing with anonymized electronic health records (EHRs), researchers have created a phenomewide association catalog between HLAs and more than 1,350 different traits, including diseases, disease severity, the presence of specific symptoms in diseases and others. HLA molecules present antigens to the immune system. They exist as multiple different types, and different types have been associated with different susceptibility to diseases, especially autoimmune diseases. Researchers from Vanderbilt University used DNA biobanks and EHRs to look at the association between HLA type and physiology more generally, and identified more than 200 such associations, including more than a dozen that had not been previously described. The results, which are openly available at www.phewascatalog.org, “provide a comprehensive set of HLA risk loci for additional research, allowing an in-depth evaluation of the underlying genetic architectures for a range of diseases,” the authors wrote. Their findings appeared in the May 10, 2017, issue of Science Translational Medicine.

Predicting Entyvio success

Inflammatory bowel disease (IBD) patients were more likely to respond to treatment with Entyvio (vedolizumab, Takeda Pharmaceutical Co. Ltd.) if they had high levels of specific gut microbiome species and high activity in specific metabolic pathways at the beginning of treatment. The composition of the gut microbiome plays an important role in IBD, and researchers from Massachusetts General Hospital investigated whether it could also predict the response to treatments. They analyzed disease activity and the fecal microbiome four times over the course of a year in patients treated with Entyvio for Crohn’s disease or ulcerative colitis. Patients who were in remission after 14 weeks of treatment had higher levels of Roseburia inulinivorans and a Burkholderiales species, and 13 pathways, including branched chain amino acid synthesis, were also more active in the microbiomes of patients who went into remission. The authors concluded that “the pathways and microbes thus identified could potentially serve as targets for newer therapies and shed further light on the pathogenesis and progression of these complex diseases.” They reported their findings in the May 10, 2017, issue of Cell Host & Microbe.

Artificial bone marrow makes blood cells

Researchers have engineered artificial bone marrow that was able to both form bone and support the production of blood cells from blood-forming stem cells when it was transplanted into mice. Bone marrow transplant is the standard of care for a number of life-threatening diseases, but the procedure is itself life-threatening because it requires harsh chemotherapy to “condition” the bone marrow by killing off the cells that are present. The authors developed a two-compartment chamber that supported the survival of blood stem cells and responded to mobilizing agents that stimulate the formation of blood cells. The engineered marrow was also able to support the formation of bone. The team wrote their marrow “could potentially be used as ectopic BM surrogates to treat various nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.” The results appeared in the May 8, 2017, online issue of the Proceedings of the National Academy of Sciences.

Rapid deep sequencing of metastatic tumors

Prospective next-generation sequencing with a turnaround time of less than 21 days was able to identify tumor alterations that were invisible to current standard methods in patients with advanced cancers. The mutational landscape of such tumors, especially if they are pretreated, may differ significantly from those of untreated tumors that are biopsied at diagnosis. But rapid deep sequencing has been a technical challenge. A team from Memorial Sloan-Kettering Cancer Center used their MSK-IMPACT sequencing method to look at matched tumor and normal tissues from more than 10,000 patients with metastatic tumors to identify multiple molecular alterations in several 100 cancer genes. “Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types,” the authors wrote. Furthermore, patients were enrolled on genomically matched clinical trials at a rate of 11 percent.” The findings appeared in the May 8, 2017, issue of Nature Medicine.

Motor restoration without dopamine

The death of dopamine-using neurons in the substantia nigra leads to motor dysfunction in Parkinson’s disease, and restoring dopamine signaling has been a core goal of therapies for Parkinson’s. Now, a team from Carnegie Mellon University has been able to restore motor function in mice with dopamine depletion via an alternate approach. The researchers used optogenetics to stimulate a subset of neurons in the globus pallidus, a midbrain region that projects to the substantia nigra and is important for inhibiting movement. The researchers showed that while nonspecific stimulation of the globus pallidus did not improve motor function in dopamine-depleted mice, stimulating only a subset of cells that expressed parvalbumin restored their motor abilities, though they were still lacking dopamine. They published their findings in the May 8, 2017, issue of Nature Neuroscience.

Thanks for the memories

Chronic treatment with tetrahydrocannabinol (THC), which is the active ingredient in marijuana, improved the memory performance of old mice. The aging process is modulated, in part, by the endocannabinoid system, and previous research had shown that expression levels of the cannabinoid receptor 1 (CB1) as well as its major ligand, 2-arachidonoylglycerol, declined with age. Researchers from the German University of Bonn tested whether that decline was responsible for cognitive declines in aging by treating middle-age and old mice with low levels of THC for four weeks. “THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months,” the authors wrote. “Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.” Also in accordance with known research, treating young mice with THC worsened instead of improved their cognitive abilities. The team published its results in the May 8, 2017, issue of Nature Medicine.

What makes vaccines work

How effective a vaccine is can be predicted both by its immune and its metabolic consequences. Researchers from Emory University in Atlanta have taken a detailed look at the response to Zostavax (Merck & Co. Inc.) in individuals vaccinated at different ages. Zostavax is a shingles vaccine that is licensed for individuals over the age of 50. It is much less effective in individuals over the age of 70 than in those ages 60 to 69, and the team compared both immune and metabolic responses between the two age groups for up to half a year following vaccination. They wrote that their analysis revealed “striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and [identified] immune and metabolic correlates of vaccine immunity. . . . Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.” The work appeared in the May 11, 2017, online issue of Cell.