The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

benefits-midage

They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

Introduction to Microfluidics Technology – June 13-17, 2016

2016 MRSEC Summer Course Announcement

Registration for our annual, one-week summer course, “Introduction to Microfluidics Technology” at Brandeis University, near Boston, MA, is now open. The application deadline is March 31, 2016.

Introduction to Microfluidics Technology is a hands-on laboratory course sponsored by the National Science Foundation’s Bioinspired Soft Materials Research Science and Engineering Center (MRSEC) at Brandeis. It will be offered during the week of June 13 ‐ 17, 2016. The course is intended for graduate students, post docs, faculty, and industrial scientists/engineers interested in utilizing microfluidic technology in their work, both in the physical and life sciences. The course does not assume any specific prerequisites.

“Introduction to Microfluidics Technology” (June 13 – 17, 2016)
will be taught by Dr. Nathan Tompkins.

The $750 fee covers course tuition, housing in double-occupancy rooms, and breakfast/lunch/coffee from Monday through Friday. Single rooms are not available. Local students who do not need housing will pay a non-resident fee of $500 (cash and check only please).

More information is available.

Gio Biosco (P’98) gets NIH Pioneer Award

Molecular and Cell Biology alum Giovanni Bosco Giovanni Bosco Ph.D. ’98, currently Associate Professor of Genetics at Dartmouth, recently received a Pioneer Award from the NIH.

Gio Bosco is a die-hard chromatin regulation guy who became interested in whether long-term changes in DNA structure are involved in long-term behavioral plasticity. Gio did his PhD work in Jim Haber’s lab and provided some of the earliest and strongest evidence for a critical DNA repair mechanism called break-induced replication, which plays an essential role in maintaining the integrity of chromosome ends when the normal end-addition of DNA by telomerase is absent.

In his postdoctoral work, Giovanni turned from using yeast as a model system to Drosophila.  In the lab of Terry Orr-Weaver at MIT he focused his attention on the role of DNA replication in regulating gene amplifications and became interested in the importance of post-translational modifications (acetylations and phosphorylations) of the histone proteins that wrap the DNA into chromatin.

Approximately 7 years ago Gio started contemplating the question of how these post-translational histone modifications change during behavior and learning. He returned to his Brandeis roots to develop tools and approaches to address this problem. He received an NIH K18 grant to fund a sabbatical in Leslie Griffith’s lab in 2010. He and his behavior group have remained connected to Brandeis since then through frequent joint group meeting visits.

We’ll be interested to hear more about the role of histone modifications in how learning and memory occurs in the context of social behavior, and in how social behavior can be inherited through multiple generations, as the result of the Bosco lab research funded by this award.

 

Putting “umpolung” to work in synthesis of nitrogen-bearing stereocenters

Professor Li Deng‘s lab in the Brandeis Chemistry Department has recently published a high-profile paper in Nature, disclosing an important advance in the chemical synthesis of organic molecules containing nitrogen. Li Deng writeup 1

A great number of important drugs contain at least one nitrogen atom connected to a “stereogenic” carbon atom. Stereogenic carbons are connected to four different groups, making possible two different configurations called “R-” or “S-”. In synthesizing a drug, it can be disastrous if the product does not have the correct R/S configuration.  For instance, the morning-sickness drug Thalidomide caused birth defects in ~10,000 children because it was a mixture of R and S molecules.Li Deng writeup 2

Selective preparation of only R or only S molecules containing nitrogen is a major challenge in organic chemistry. Many recent approaches have formed such stereocenters by use of an electron rich “nucleophile” to attack an electron poor “imine”. Deng is now the first to report an unconventional strategy in which the polarity of the reaction partners is reversed. In the presence of base and a creatively designed catalyst, the imine is converted into an electron rich nucleophile, and can attack a variety of electrophiles. Deng’s catalysts are effective in minute quantities (as low as 0.01 % of the reaction mixture), and yield products with R- or S- purities of 95-98 %.

In addition to Professor Deng, authors on the paper included former graduate student Yongwei Wu PhD ’14, current Chemistry PhD student Zhe Li, and Chemistry postdoctoral associate Lin Hu.

Wu Y, Hu L, Li Z, Deng L. Catalytic asymmetric umpolung reactions of imines. Nature. 2015;523(7561):445-50. (commentary)

Physics students win awards

The Physics Department recently held its annual Student Research Symposium in Memory of Professor Stephan Berko. At the symposium, the undergraduate speakers describe their senior thesis honors research as the final step in gaining an honors degree in physics. The graduate student speakers are in the middle of their PhD research, and describe their progress and goals.

The prize winners are nominated and chosen by the faculty for making particularly noteworthy progress in their research. Here are the Berko prize winners for 2015:

Undergraduate Prize Winners:

Adam Wang
Title: “Controlling Coupled Chemical Oscillators: Toward Synchronization Engineering and Chemical Computation”
video

Jacob Gold
Title: “Inhibitively Coupled Chemical Oscillators as a Substrate for Logic Gates and Larger Circuits”
video

Graduate Prize Winners:

Lishibanya Mohapatra
Title: “How cells control the size of their organelles?”
video

Feodor Hilitski
Title: “Measuring mechanics of active microtubule bundles, one filament at a time”
video

Other Physics Prize winners this year:

Cesar A. Agon Falkoff prize
Hannah Herde Falkoff prize
Matthew Cambria Physics Faculty prize
Stefan Stanojevic Physics Faculty prize

Odor Recognition & Brute-Force Conversions

Frontiers in Computational Neuroscience will be publishing an interesting paper written by Honi Sanders and John Lisman (with co-authors Brian E. Kolterman, Roman Shusterman, Dmitry Rinberg, Alexei Koulakov) titled, “A network that performs brute-force conversion of a temporal sequence to a spatial pattern: relevance to odor recognition“. Honi Sanders has written a preview of this paper.

by Honi Sanders

Lisman_ProvisionalPDF_BLThere are many occasions in which the brain needs to process information that is provided in a sequence. These sequences may be externally generated or internally generated. For example, in the case of understanding speech, where words that come later may affect the meaning of words that come earlier, the brain must somehow store the sentence it is receiving long enough to process the sentence as a whole. On the other hand, sequences of information also are passed from one brain area to another.  In these cases too the brain must store the sequence it is receiving long enough to process the message as a whole.

One such sequence is generated by the olfactory bulb, which is the second stage of processing of the sense of smell.  While individual cells in the olfactory bulb will fire bursts in response to many odors, the order in which they fire is specific to an individual odor. How such a sequence can be recognized as a specific odor remains unclear.  In Sanders et al, we present experimental evidence that the sequence is discrete and therefore contains a relatively small number of sequential elements; each element is represented in a given cycle of the gamma frequency oscillations that occur during a sniff. This raises the possibility of a “brute force” solution for converting the sequence into a spatial pattern of the sort that could be recognized by standard “attractor” neural networks.  We present computer simulations of model networks that have modules; each model can produce a persistent snapshot of what occurs during a given gamma cycle. In this way, the unique properties of the sequence can be determined at the end of sniff by the spatial pattern of cell firing in all modules.

The authors thank Brandeis University High Performance Computing Cluster for cluster time. This work was supported by the NSF Collaborative Research in Computational Neuroscience, NSF IGERT, and the Howard Hughes Medical Institute.

Genetics Training Grant Retreat to be held Friday, 9/26/14

The annual Genetics Training Grant seminar is being held on Friday, September 26th at the Shapiro Campus Center Auditorium at Brandeis University. Four cutting-edge synthetic biologists: Timothy Lu, Ron Weiss, William Shih and Ahmad Khalil will share their research for the Synthetic Biology: Insights and Applications” symposium.
 
Brandeis graduate students and post-docs will have the opportunity to meet the speakers and present their work in a poster session after the talks. We encourage researchers from all departments to contribute. If you are currently, or previously were on the Genetics Training Grant, presentation of a poster is expected. 

Schedule for GTG Retreat

9:30-10:30 Ron Weiss (MIT, Dept. of Biological Engineering)
“Synthetic biology: from parts to modules to therapeutic systems.”
10:30-11:00 Coffee Break
11:00-12:00 Timothy Lu (MIT, Dept. of Biology Engineering)
“Synthetic biology for human health applications.”
12:00-1:30 Break/Lunch
1:30-2:30 William Shih (Wyss Institute)
“DNA nanostructures as building blocks for molecular biophysics and future therapeutics.”
2:30-3:30 Ahmad Khalil (Boston University, Biomedical Engineering)
“Building molecular assemblies to control the flow of biological information.”
3:30-5:00 Poster session
Shapiro Science Center 2nd floor.
All life sciences students are invited to present.

Men, Women and Emotional Stress Responses

Psychoneuroendocrinology (November 2014) is publishing a fascinating paper authored by Sarah Lupis, Michelle Lerman and Jutta Wolf titled Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women.

473People can experience a wide range of emotions when under stress, including feelings of anger and fear. In recent years researchers have sought to understand how these emotion stress responses are linked to biological stress responses. In particular, some evidence suggests that anger and fear may be linked to cardiovascular changes in differential ways. It is less clear, however, how emotions during stress may predict increases in levels of the stress hormone cortisol. These deficits in our understanding are partly due to the methodological difficulties in measuring emotion in the context of stress. Much prior research has relied solely on retrospective self-report (after the stress has passed, a questionnaire asks a study participant to reflect on how he felt in the moment of stress). By this time, the participant may have forgotten how he felt, or may already be utilizing coping strategies to process those emotions. In addition, he may not feel comfortable reporting how the stressor made him feel, leading to less-than-honest responses. Unsurprisingly, prior research has not shown consistent links between these self-report measures and biological stress responses. In the current study, we therefore added facial coding of emotion expression to assess emotions occurring during stress. Our aim was to determine how expressions of anger and fear were linked to heart rate and cortisol stress responses.

We recruited 32 healthy Brandeis students and exposed them to a brief psychosocial stressor. A certified coder assessed facial expressions shown during the stressful situation. Heart rate and cortisol levels were measured throughout. After the stressor, the participants also self-reported how they felt during the stressor. A first notable finding showed that what participants self-reported feeling and the expressions they actually showed did not correlate. With regards to self-report, men who reported feeling fear showed blunted cortisol stress responses. Consistent with prior research, self-report was otherwise not associated with heart rate or cortisol stress responses. When looking at facial expressions, a consistent pattern appeared: men who showed more anger during the stressful situation also showed exaggerated heart rate and cortisol stress responses. For women, neither anger nor fear were linked to biological stress responses (see Figure).

Our findings first emphasize the importance of assessing emotion using multiple means. In this case, facial expressions revealed an emotion-stress link for males that would not be apparent using self-report alone. Facial coding may thus be a useful addition to current stress paradigms. Further, if men who react with anger in stressful situations do respond with exaggerated stress responses, it could have important down-stream health effects. Exaggerated, prolonged, or dysfunctional stress responses could, over time, lead to changes in basal stress systems. This kind of ‘allostatic load’ is associated with negative health outcomes including diabetes and cardiovascular disease. Anger and fear do not seem to drive these responses in females, and further study is needed to determine if similar relationships exist for a different set of emotions, perhaps self-conscious emotions like shame. By better understanding these relationships, more healthful ways of coping with stress can be developed, which is particularly important given that for many, stress has become an unavoidable part of daily life.

 

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