My research is broadly focused in circadian rhythm, and as a second year graduate student, I am still expanding my knowledge in this field. The more I read, the more I realize that everything is connected! Circadian rhythm can be described at many levels. There are transcriptional cycles, translational cycle, post-translational modification cycles, and even metabolic cycles. As it turns out, all to of these circadian rhythms are not coincidental, but rather, they are mostly a result of environmentally regulated mechanism such as light, nutrition, and hormonal stimuli. For the average animal, cycles of daylight, eating, and hormone release are set to the pace of their environment, and evolution has been selective for organisms that can anticipate their environments. Thus, circadian rhythms are highly conserved across the animal kingdoms. Although circadian regulation occurs at each level of gene expression, it all begins with transcription. The transcriptional circadian cycle can be attributed to transcription factors (CLOCK and CYCLE/BMAL) which bind to E-box elements and promote downstream gene expression. Of these genes, two of them (PERIOD and TIMELESS/CRYPTOCHROME) return to the nucleus to inhibit CLOCK and CYCLE activity and their own transcription. This negative feedback loop takes approximately 24h and defines the circadian period. One of the most important regulatory mechanism underlying this cycle is that of post-translational modifications (PTM) which establish the timing of PERIOD and TIMELESS inhibitory activity.
PTM regulation has been well defined in terms of phosphorylation, but the field of PTM regulatory mechanisms has barely scratched the surface. There are numerous ways a protein can be modified and even more ways in which this can affect protein activities. The articles I have selected provide an example for the importance of PTM in the circadian cycles of the liver. Metabolic health is a growing concern worldwide due to the number of people who suffer from metabolic diseases or malnutrition. The first article http://www.sciencedirect.com/science/article/pii/S0092867413014852 is a study from 2013 that illustrates the dramatic shift in transcriptional and metabolic outputs in response to nutritional challenges. It is compelling to consider what implications this has for people who regularly face “nutritional challenges” such as high fat diets. The second article http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00221/full is a review that discusses how high sugar and other nutritional challenges can affect enzyme activity in the liver by disrupting the PTM profile of those enzymes. Together, these articles support the notion that healthy eating is an important component of healthy protein function. There are a number of other ways that good nutrition supports healthy cells, metabolism, and hormone balance, but when it comes to my area of focus, I see it all through the lens of protein regulation by PTM. Perhaps a full profile of PTM in healthy and unhealthy people could establish new guidelines for future healthcare as a point of diagnostics and therapeutics. Then again, it might be easier to just eat a salad every now and then.
Cheers to good food and good PTM!
BMCDB Graduate Group, UC Davis
Excerpt from “New Antibiotic from Soil Bacteria” by Anna Azvolinsky
That the antibiotic can kill M. tuberclosis “is a major breakthrough because it is virtually certain to be effective for the multi-resistant strains that are now all but impossible to treat,” said Richard Novick, a microbiologist at New York University Langone Medical Center who was not involved in the work.
Although further studies are needed before the antibiotic can be tested in humans, animal efficacy models are often predictive of a drug’s effects in humans, said Gerard Wright, director of the Institute for Infectious Disease Research at McMaster University in Hamilton, Canada, who penned an accompanyingeditorial.
Teixobactin was isolated from a previously unknown Gram-negative bacterium that lives in soil and cannot be cultured in the lab using standard techniques. So the researchers applied an approach called Ichip, developed jointly by Lewis and Slava Epstein’s lab, in which a soil sample is diluted with agar, and a single bacterial cell is suspended in a chamber surrounded with semi-permeable membrane. The researchers pack 96 such chambers into a single device, which they then place in soil—allowing the bacteria access to nutrients and growth factors but not to escape. This cultivation approach is an innovative way to tap into the rich biodiversity that we are currently missing because only 1 percent of microorganisms can be cultured in the lab, said Wright. “This biodiversity is also hiding a lot of chemical diversity that may include other new antibiotics.”
Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
“We first used baker’s yeast, which is an established aging model, and noticed that the yeast treated with ibuprofen lived longer,” said Dr. Michael Polymenis, an AgriLife Research biochemist in College Station. “Then we tried the same process with worms and flies and saw the same extended lifespan. Plus, these organisms not only lived longer, but also appeared healthy.”
He said the treatment, given at doses comparable to the recommended human dose, added about 15 percent more to the species lives. In humans, that would be equivalent to another dozen or so years of healthy living.
Polymenis said the three-year project showed that ibuprofen interferes with the ability of yeast cells to pick up tryptophan, an amino acid found in every cell of every organism. Tryptophan is essential for humans, who get it from protein sources in the diet.
“We are not sure why this works, but it’s worth exploring further. This study was a proof of principle to show that common, relatively safe drugs in humans can extend the lifespan of very diverse organisms. Therefore, it should be possible to find others like ibuprofen with even better ability to extend lifespan, with the aim of adding healthy years of life in people.”
Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import
The common non-steroidal anti-inflammatory drug ibuprofen has been associated with a reduced risk of some age-related pathologies. However, a general pro-longevity role for ibuprofen and its mechanistic basis remains unclear. Here we show that ibuprofen increased the lifespan of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, indicative of conserved eukaryotic longevity effects. Studies in yeast indicate that ibuprofen destabilizes the Tat2p permease and inhibits tryptophan uptake. Loss of Tat2p increased replicative lifespan (RLS), but ibuprofen did not increase RLS when Tat2p was stabilized or in an already long-lived strain background impaired for aromatic amino acid uptake. Concomitant with lifespan extension, ibuprofen moderately reduced cell size at birth, leading to a delay in the G1 phase of the cell cycle. Similar changes in cell cycle progression were evident in a large dataset of replicatively long-lived yeast deletion strains. These results point to fundamental cell cycle signatures linked with longevity, implicate aromatic amino acid import in aging and identify a largely safe drug that extends lifespan across different kingdoms of life.
Sadly we are all reminded that life is all too short. We lost one of the best and brightest stars from our BMCDB galaxy. Words fail to express how much he meant, how his presence made us all better, and how much we will miss him.
I am putting this blog post up in the hopes that people will share not just their thoughts and condolences, but also their favorite memories and stories Nick. I know his influence will stay with me for a life time. I can’t think of much else to say other than to talk to those you care about, never take anyone for granted, and share the warmth, love, and compassion that he shared with all of us. RIP Nick
Dear BMCDB faculty and students,
It is with great sorrow that I share with you this sad news.
The graduate group has received word that Nick Mahoney, a third year Ph.D. candidate, working in Chris Fraser’s lab, passed away Saturday from a heart attack. There is no additional information at this time, but I wanted to let you all know of this tragic event. Our hearts go out to Nick’s family. I will keep you posted as to what arrangements are being made as I become aware of them.
Campus psychological services are also available if you find you or someone you know needs to reach out for confidential support. The Counseling Center for Psychological Services (CAPS) is available for students. Please call (530) 752-0871. The Academic & Staff Assistance Program (ASAP) is available to faculty and staff. Please call (530) 752-2727.
Our thoughts go out to his family, friends and colleagues,
Dear BMCDB students and faculty,
Sydney Mahoney has asked that you be informed of services for Nicholas Mahoney. She will have a visitation with family on Saturday, December 13th from 2:00-5:00 p.m. at Wiscombe Funeral Home. A Memorial Service will be at the Unitarian Church on Sunday Dec. 28th at 3:00 p.m.
Both services are open to faculty, students, and staff.
Erin C. Kent, Ph.D
Many times in life, roads lead to the unknown – however much we may think we know the destination. This can be especially true for careers in science. Reading Ranjan Mukherjee’s story in Science Careers is an inspiration to keep an open mind.
Briefly summarized, he graduated with a Masters in physics from the University of Calcutta and was accepted into a biophysics PhD program at the University of Delaware. Leaving behind family and friends in India for his unknown (otherwise called Newark, Delaware), he found his adviser-to-be had passed away some months ago and no one had notified him. Suddenly met with much more unknown than one could hope for, he adapted. While teaching physics labs to fulfill student visa requirements and heterotrophic obligations, he convinced a faculty member in biology to take him on.
After earning the PhD and getting married, a postdoctoral position in Strasbourg, France meant meeting another unknown. This led to a drug discovery position targeting metabolic disease, a field in which he would spend the next 22 years. However, after 15 years at a particular company, his position in R&D was unexpectedly eliminated.
Drawing on a love of travel and writing, he sent off fresh articles to blogs and journals. A few have been picked up by a magazine, a major newspaper, and the Indian government to advertise for tourism. He is now embarking further into the unknown, launching a new writing career. It is no wonder the title of this article is “The Winding Road.”
While career trajectory often hangs heavily above anyone starting out in science, it is important to remember that life can take us anywhere and we shouldn’t always take little discouraging things (like suddenly finding out that your adviser-to-be is no more after moving halfway across the world) as discouragement. A sharp bend in the road may not necessarily mean going off the cliff, and a winding road can take you to new, incredible places.
S.M. Theg Lab
See the article at:
Science 21 November 2014: Vol. 346 no. 6212 p. 1026 DOI: 10.1126/science.346.6212.1026 PMID: 25414316