PARTCH, Carrie  CIRCADIAN Clocks UCSC Mar 18 2013

a lot of work at SLAC involves phase lock loops;  
locking  resonators...

she is in Dept of Chem and Biochem at UC Santa Cruz

this is  at SLAC Colloq  at 4:15 PM in Panofsky on Monday Mar 18 2013;

title today:  Circadian clocks: how they keep 24 hour time and control your physiology

sl1:  life is synched to Earth's daily rotation

critical to be synched with the solar cycle
behavior: sleep/wake; mood; cog performance

physio: glucose metab; hormone prod; cardiovas func; and cell division

some cells divide one time per day

shift work is a known carcinogen!!!  (WHO designation)

circad rhythms helps orgs anticipate reular envior changes:

cyanobacteria:  separate 2 chemic incompatible processes:
photsyntehesis and nitrogen fixaiton

enzyme behavior is difft during light and drak:

photosyn  likes  sunlight;  taking in CO2 aqnd sunlight

multi orgs
xenobiotic detoxification peaks with expression of metabolic enzymes at predicted feeding times

animals with intacty clocks survive better in the wild
(exper verified)

master regulatory...

CELL AUTONOMOUS  molec  oscillations

Jurgen Aschoff  mid 50s and 60s  discovered this...  present in everyone of your cells

functions on its own  (even without external clues)

negative feedback loop:

Aschoff built a bunker  with volunteer Subject = S inside...

Science 1999   humans  24 hours 11 mins  + or - 5 mins...

molec clocks are temper compensated...

ie  they adapt to temper diffs  (keep TIME constant despite temp)

phase adjust to enviro cues
eg with incr day length...

Siberian hamster:   coat color changes with season...

LIGHT is the most predominant stimulus  (UV)
Colin Pittendrigh:
Zeitgeber:

Light: food: social interactions;

zeitgeber:  either delaying bedtime  in eve  or
advancing it in wee hours:

much easier to DELAY clock  (easier to go WESTWARD than Eastward)

(John did introduction)

SCN = suprachiasmatic nucleus  is the master clocksee Zhang and Kay in 2010  Nat Reviews/ Molec Cell Biol.

new class of photoreceptors... photon countr  in the eyes...
only clock in your body that synchs  outside enviro to your brain/body...

SCN  coordiantes liver/ pancreas/ heart

two proteins that act together:  Period and CRY  Cry1 and Cry2;  and Per1 and per2  from SCN

two bundles of 10,000 neurons  each pulse is  24 hours in time... movie clip from David Welsh UCSD...

we are protein biochemists:

how do protein dynamics control 24 hour timing?

clock:BMALI

Huang 2012 in SCIENCE

these proteins regulate transcription

maleable machines... will never by crystalized... too floppy

she goes thru the domains of BMALI

she worked under Joe Takahashi  her former PI...

did work with NMR  spectroscopy...

BMALI TAD  adopts two distinct conformations

a slow bio timer
switches brtwn  trans and cis around a  Proline imide bond...

so... a slow protein switch helps to control bio timing...

when you add back  BMA1  then synchronizaiton occurs...

BASS 2013  NATURE... clock timing affects your dialy life...

her  bedtime is btwn 10P and 11P  she talks abt people
who need to get to bed at 7P...

SAD = seasonal affectie disorder...

people who sleep from 4P to 4A  > 80% have clinical depression

are you a morning lark or anight owl?

most people  go to bed  at MN and get up at 8A  but next peak at 12:30A to 8:30A

owls... late  to bed  peaks  around age 22 or so...

wright K  2013  Sleep Med  (a review)  sleep and the clock...

cricadian drive for wakfulness  peaks around 9 PM

homeostatic drive for sleep  blances that out...

shift work  totally messes it up...

Roenneberg  2007  sleep
compares  free days  (sat and sunday)  vs work days  when u need to get up...

jet lag may cause stupidity...

Gibson  2010  PLOS One:  decr  adult neurogenesis!!!

clock timing affects your dialy life (and death!)

Lim  Annals of Neurology 2012

are there differences in clock genes?

GG  peak activity in eve
AA  morning activity
AG  most common  mid day...

also predicted time of death...

clockwork physio

core body temp;
uring volume
cerebr bllod flow,
sys  pres!!!
melatonin,
cortisol
thyrotrphin
growth hormone...

Hastings  2007  Endocrinology

she is a mother of a 3 year old!

cerebral blood flow  peaks  at night...

2-3  fold incr in heart attacks and strokes in the early morning! 

huge peak in growth hormone at  2AM

does it matter when u eat?

Hatori  2012 Cell Metab...

intricate link btwn   food intake and  circad rhytyms...

food can act as a zeitgeber...

mouse diet:  15%  fat  diet  vs  50% fat diet  and
ad lib  feeding vs  time-resticted...

eating high fat diet  whenever they want:  they get morbidly obese...
but if restricgted time... only sl overweight  (only at night when they nl eat)

You NEED TO HAVE A FASTING FAST!!!  
CR =caloric restriction  in C Elegans...

restrict feeding to specific time of day...

HATORI, M  et al  2012 in Cell Metab...

eating whenever you want damps your circad rhythms...

time restricgte dis much better!

get high amplitude  circ rhythms if food restr...!

a handful of proteins regulates  circ rhythm  in SCN...  they synch e verything

Bass, J  2013  in NAture...

there is acetner at UCSD for chronobio

theory:  most  DNA replication occurs at night (to escape damage:
ie DNA is unfolded at night when no exposure to UV !!)

master clock is in the SCN  = suprachiasmatic nucleus...