## Sysiphus Meets our Social Brains

Get up. Go to work. Go home. Go to bed. This tropes permeates our culture — plot-lines in advertisements, movies, books, TV shows, and even conversation — it describes the mundanity of our daily existence. A woman might wake up in the morning, perform her morning routine to ready herself for work and her household for the day, commute the same route to a workplace to perform tasks that amount to the same repetitions that she did yesterday (send emails, prepare documents, perform calculations, meet with people), and then go home, perform an evening routine. And the cycle repeats itself. Continue reading

## Letting Go of the Once & Future Self

Starting my freshman year in college, I kept all of my class notes, organized in binders and arranged on shelves. They were all nearly the same: the course syllabus on the front as if it were a table of contents (with check marks as each week or assignment ticked by), followed by the the exams (as if it were an executive summary), followed by my notes in loose-leaf paper (with the dates marked in the upper right-hand corners), then handouts, then homework, then quizzes. The binders were color-coded by field: Chemistry – Black; Evolution Ecology & Organismal Biology – Green; Biochemistry and Molecular Genetics – Blue; Immunology – Red; Math/Calc – Burgundy; Non-science (general ed. curriculum) – light blue or yellow. They were not organized by date, but rather by clustered together by field. I carried this through graduate school and kept all these notes from 1999 to 2015.

I am not sure why I started doing this, I think that it started because during the first quarter, I felt like I had put a lot of effort into organizing these materials. They exist in physical form. The words, symbols, equations, and diagrams represented my newly acquired knowledge and skills … it would have felt weird or destructive to throw them away. And so I kept them from one quarter to the next. Then from freshman year to sophomore year, and so on … lugging around boxes of binders from dorm to Mom’s house to dorm to apartment to apartment from city to city and from timezone to timezone. These binders came to represent my identity as a scientist. Continue reading

## Optimizing Funding Policies and Other Strategies to Improve the Impact and Sustainability of Biomedical Research

The National Institutes of Health is requesting information from the public, specifically targeting the scientific research community. They do this by issuing RFI’s (can you get what that stands for?) as “Notices.” “Notices” have an “NOT” number, and are the official communication of the NIH with the public. Most recently, they have issued NOT-OD-15-084: RFI: Optimizing Funding Policies and Other Strategies to Improve the Impact and Sustainability of Biomedical Research. I have been encouraging my friend and colleagues on Teh Facebookz, Twitz, and other social networks to provide their feedback.

## UC San Diego MicroRNA Scientific Interest Group

I have started a new MicroRNA Scientific Interest Group, which I intend to be campus-wide and bring together researchers whose work touches these molecules, because they seem to be involved in nearly every pathway.

My Department has created as website and Google-calendar, which is linked to here: http://psychiatry.ucsd.edu/education/Pages/InterestGroups.aspx

I am very excited to get this started. As I mentioned to my Dept Chair: I have not organized any large events like this since I was a fearless grad student, so I am a little bit nervous. However, the first meeting was a success. Students and faculty were engaged, asked questions — and the discussion took the evening 40 minutes past the planned stop time!

For the first meeting, I gave a brief introduction, followed by a 10 minute research presentation (of our microRNA-138 in the aging mouse, published in Am. J. Geriatric Psychiatry), and Dr Maurizio Zanetti, Prof of Medicine at the Moore’s Cancer Center gave an incredibly interesting talk about some of the tools his lab has developed.

Since the research results and data that I presented were already published, I will go ahead and embed my presentation here.

Cheers.

## Soma to Germline Information Transfer via MicroRNA in Sperm

A few months ago, I posted about an article which  speculated that the evolution of the modern human brain was a result of Lamarckian evolution. To recap — this means that a trait is acquired during one’s life experience, and that trait is transferred to the offspring. The classic example is that giraffes have long necks because a precursor animal stretched its neck to reach high foliage, the next generation was born with longer necks because of its parents’ reaching. The next generation reached yet higher, and the next generation had yet longer necks. In humans, the example is something like a blacksmith has big muscles from working at a forge all day, he passes on his big-muscles to his son because of the use of his arms.

For something like brain development to be influenced by life experiences, I speculated that hormonal changes (e.g., corticotropin release hormone, ACTH, cortisol, norepinephrine) as a result of psychological stress or trauma would have to induce epigenetic changes in sperm.

Imagine my surprise when I directed my web browser to Nature News where researchers at the Brain Research Institute at the University of Zurich discovered that specific microRNAs were indeed increased in the sperm of male mice exposed to psychological trauma (being forced to be away from their mother during rearing, who was undergoing stressful experiences, i.e.: cold-stress or forced swimming)…. and these microRNA increases persisted for yet one more generation, and also was increased in their hypothalamus and cortex. So this is one interesting piece of the puzzle.  The Pubmed Link.

They do not yet know the mechanism of the microRNA-induced changes. But there are several steps that need to be taken to be sure that the observed effect is real, and a few grains of salt.

1. The study used high-throughput analysis, and screening-type methodologies. These should always be followed up with low-throughput analyses because the reliability of any one target in a high throughput screen of RNA quantity is low. We did this with our PLOS One study. We used a different methodology to quantitate a panel of several microRNAs from our high throughput screen which quantitated 380. We chose some that were up, some that were down and some that were not different. We plotted the signal in the single-target method vs. the high-throughput method to validate that they matched. This, in my opinion, is a must-do, if you plan to make a claim about any one transcript.
2. The mechanism is not understood. How do the microRNA’s change in the sperm? One good place to start would be to look at the promoter region for the candidate microRNAs that were altered — are these transcription factor sites or hormone response elements (e.g., that would respond to cortisol)?  Are there methylation sites?
3. The next additional step is to show that changing the concentrations of those microRNAs has some effect on prenatal CNS development.

This topic is very near and dear to my own research plans and goals. I’m going to recreate here a figure that I used to illustrate the point of the FKBP5 gene. This protein’s function is to modulate the glucocorticoid receptor nuclear translocation, it essentially inhibits it; so it serves as a feedback mechanism for particular cells to “turn off” cortisol signaling very quickly after it starts. But if FKBP5 is too high … no cortisol signaling was allowed in the first place. There are gene polymorphism in FKBP5 associated with major depression … and one of my future research plans is to determine the big how and why.  One potential way is by altering microRNA response element sequences.   …. aaaand it comes full circle. I would be interested to know of any of the microRNAs discovered to be changed in the sperm of traumatized male mice might also bind to FKBP5.  Cool stuff, huh?

## The Mysterious “Shin Splint”

When I first started running about 7 years ago, I experienced pain in my right shin, which got worse with use and exercise. Specifically, this is pain in the medial tibia, exacerbated by stress and use (running). I asked around about it, and it was explained to me like this: these are “shin splints,” which are tears in the tendon which connects the muscle to the bone, specifically the calf muscle to the bone around that area. I was told that it was caused because the tendons are not strong enough to support the stress put on by the new exercise of the muscle pushing and pulling on it. The only thing to do is to rest and let it heal. So that’s what I was told. I let it heal by doing alternative cardio exercises like elliptical machine (which uses way fewer calories than running and doesn’t strengthen many muscles, but if you employ techniques to make it more difficult, you can strengthen the gluts & thighs) and rowing machine. After the pain went  away, I incorporated calf muscle-building exercise into my routine and never had a problem since. So that’s my anecdote.

## What does the research say?

First of all the etiology (root biological cause) behind “medial tibial stress syndrome” is not known. So the story I was told, believed, and repeated, might not necessarily be true, but it is plausible. I found a pretty good review of risk factors (here). Continue reading

## Snakes on a Brain

In October, 2013 ScienceNews put out a press release describing an article published by researchers from UC Davis and U Toyama (Japan) advancing the “Snake Detection Theory.” They measured the responses of pulvinar neurons to visual stimuli, including a hand, face, geometric shape, and a snake. They report that they found a specific response to the snake as a visual stimulus, and that it supports the notion that the primate brain evolved under evolutionary pressure from living alongside snakes as competitors and predators.

The pulvinar neurons are located in the thalamus (in humans, the pulvinar nucleus, or cluster or neurons, is the largest in this structure). The thalamus is a structure that is deep in the vertebrate brain and it relays sensory and motor signals to the cerebral cortex, it regulates consciousness, sleep, alertness. This group of neurons receives input from crossed optic fibers (that is, the right part receives input from the left eye), which then relays information to the cortex of the occipital lobe. They also communicate with other regions, but that is the path of visual stimuli. Continue reading

## Basics of MicroRNA Biology

Last year, I gave a talk at the Psychoneuroimmunology Research Society (PNIRS) Annual Meeting.  Whatever the merits of the research presented at this meeting … I had a good time and I was tasked with giving a very basic talk as part of a short course. The short course was titled, “A Tutorial on 21st Century Molecular Biology.” I think the reason the conference organizers felt this course would be beneficial is that a large chunk of the researchers in this society are psychologists and psychiatrists; who do not have training in the latest and greatest in cell and molecular biology but they are trying (really, really hard!) to understand how the immune system interacts with the central nervous system, resulting in behavioral changes. In my opinion, they are trying to follow in the footsteps of Richard Sapolsky (who, it seems, has since moved on to other topics), who pioneered the study of stress & stress hormones (e.g., corticosterone), an immune suppressor, and their effects on brain signaling and brain structure, resulting in behavioral changes (e.g., depression). Though a lot of the research done now by adherents, has some serious issues on identifying causality and publish such things as “healing touch” for treatment of PTSD.

My lecture for this educational short course was titled, “The Basics of MicroRNA: A Newly Appreciated Genetic Modulator.”  I liked this presentation because it anthropomorphizes microRNA as a stick-figure with a sheriff’s badge.

## DNA Protein Kinase and T Cell Death in HIV – journal club

Embedded below is my journal club presentation from earlier this summer. I added comments in red for talking points of the take-home point for each slide.

## Use LaTeX to Write Your Grants (and other complex documents)

I’m a big fan of automating tasks and finding efficient ways of doing things. Several years ago, I discovered the $LaTeX$, a typesetting and document prepping system that has entirely improved the aesthetics of the documents I’m able to produce but also increased the speed with which I can produce them.

It is not a word processing system in which you type on page and what you type appears how the document will be (“what you see is what you get” wysiwyg – wizzeewig). The files that you work in look like plain text, so you can focus on the content and less on how they look as your working. In the file that you’re working in, you designate environments, like section{My Section} … and then go with it … and go onto maybe twenty sections (or chapters, with a zillions subsections or subsubsections [and yes, subsubsubsections]). The same with figures. Why does this matter? Well, it takes away the worry of two key things in a grant document (and any other large document) — format & order.