1,447 research outputs found
Determination of barrier heights and prefactors from protein folding rate data
We determine both barrier heights and prefactors for protein folding by
applying constraints determined from experimental rate measurements to a
Kramers theory for folding rate. The theoretical values are required to match
the experimental values at two conditions of temperature and denaturant that
induce the same stability. Several expressions for the prefactor in the Kramers
rate equation are examined: a random energy approximation, a correlated energy
approximation, and an approximation using a single Arrhenius activation energy.
Barriers and prefactors are generally found to be large as a result of
implementing this recipe, i.e. the folding landscape is cooperative and smooth.
Interestingly, a prefactor with a single Arrhenius activation energy admits no
formal solution.Comment: 11 pages, 5 figures, 1 table, Accepted Biophys
Age-Correlated Gene Expression in Normal and Neurodegenerative Human Brain Tissues
Human brain aging has received special attention in part because of the elevated risks of neurodegenerative disorders such as Alzheimer's disease in seniors. Recent technological advances enable us to investigate whether similar mechanisms underlie aging and neurodegeneration, by quantifying the similarities and differences in their genome-wide gene expression profiles.We have developed a computational method for assessing an individual's "physiological brain age" by comparing global mRNA expression datasets across a range of normal human brain samples. Application of this method to brains samples from select regions in two diseases--Alzheimer's disease (AD, superior frontal gyrus), frontotemporal lobar degeneration (FTLD, in rostral aspect of frontal cortex ∼BA10)--showed that while control cohorts exhibited no significant difference between physiological and chronological ages, FTLD and AD exhibited prematurely aged expression profiles.This study establishes a quantitative scale for measuring premature aging in neurodegenerative disease cohorts, and it identifies specific physiological mechanisms common to aging and some forms of neurodegeneration. In addition, accelerated expression profiles associated with AD and FTLD suggest some common mechanisms underlying the risk of developing these diseases
GALEX, Optical and IR Light Curves of MQ Dra: UV Excesses at Low Accretion Rates
Ultraviolet light curves constructed from NUV and FUV detectors on GALEX
reveal large amplitude variations during the orbital period of the Low
Accretion Rate Polar MQ Dra (SDSSJ1553+55). This unexpected variation from a UV
source is similar to that seen and discussed in the Polar EF Eri during its low
state of accretion, even though the accretion rate in MQ Dra is an order of
magnitude lower than even the low state of EF Eri. The similarity in phasing of
the UV and optical light curves in MQ Dra imply a similar location for the
source of light. We explore the possibilities of hot spots and cyclotron
emission with simple models fit to the UV, optical and IR light curves of MQ
Dra. To match the GALEX light curves with a single temperature circular hot
spot requires different sizes of spots for the NUV and FUV, while a cyclotron
model that can produce the optical harmonics with a magnetic field near 60 MG
requires multipoles with fields > 200 MG to match the UV fluxes.Comment: accepted for ApJ; 15 pages, 7 tables, 8 fig
Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling
Excess of glucocorticoids (GCs) is a leading cause of bone fragility, and therapeutic targets are sorely needed. We report that genetic deletion or pharmacological inhibition of proline-rich tyrosine kinase 2 (Pyk2) prevents GC-induced bone loss by overriding GC effects of detachment-induced bone cell apoptosis (anoikis). In wild-type or vehicle-treated mice, GCs either prevented osteoclast apoptosis or promoted osteoblast/osteocyte apoptosis. In contrast, mice lacking Pyk2 [knockout (KO)] or treated with Pyk2 kinase inhibitor PF-431396 (PF) were protected. KO or PF-treated mice were also protected from GC-induced bone resorption, microarchitecture deterioration, and weakening of biomechanical properties. In KO and PF-treated mice, GC increased osteoclasts in bone and circulating tartrate-resistant acid phosphatase form 5b, an index of osteoclast number. However, bone surfaces covered by osteoclasts and circulating C-terminal telopeptides of type I collagen, an index of osteoclast function, were not increased. The mismatch between osteoclast number vs function induced by Pyk2 deficiency/inhibition was due to osteoclast detachment and anoikis. Further, GC prolongation of osteoclast lifespan was absent in KO and PF-treated osteoclasts, demonstrating Pyk2 as an intrinsic osteoclast-survival regulator. Circumventing Pyk2 activation preserves skeletal integrity by preventing GC effects on bone cell survival (proapoptotic for osteoblasts/osteocytes, antiapoptotic for osteoclasts) and GC-induced bone resorption. Thus, Pyk2/anoikis signaling as a therapeutic target for GC-induced osteoporosis
Retrospective evaluation of foot-and-mouth disease vaccineeffectiveness in Turkey
AbstractFoot-and-mouth disease (FMD) is present in much of Turkey and its control is largely based on vaccination. The arrival of the FMD Asia-1 serotype in Turkey in 2011 caused particular concern, spreading rapidly westwards across the country towards the FMD free European Union. With no prior natural immunity, control of spread would rely heavily on vaccination.Unlike human vaccines, field protection is rarely evaluated directly for FMD vaccines. Between September 2011 and July 2012 we performed four retrospective outbreak investigations to assess the vaccine effectiveness (VE) of FMD Asia-1 vaccines in Turkey. Vaccine effectiveness is defined as the reduction in risk in vaccinated compared to unvaccinated individuals with similar virus exposure in the field.The four investigations included 12 villages and 1230 cattle >4 months of age. One investigation assessed the FMD Asia-1 Shamir vaccine, the other three evaluated the recently introduced FMD Asia-1 TUR 11 vaccine made using a field isolate of the FMD Asia-1 Sindh-08 lineage that had recently entered Turkey.After adjustment for confounding, the TUR 11 vaccine provided moderate protection against both clinical disease VE=69% [95% CI: 50%–81%] and infection VE=63% [95% CI: 29%–81%]. However, protection was variable with some herds with high vaccine coverage still experiencing high disease incidence. Some of this variability will be the result of the variation in virus challenge and immunity that occurs under field conditions.In the outbreak investigated there was no evidence that the Asia-1 Shamir vaccine provided adequate protection against clinical FMD with an incidence of 89% in single vaccinated cattle and 69% in those vaccinated two to five times.Based on these effectiveness estimates, vaccination alone is unlikely to produce the high levels of herd immunity needed to control FMD without additional control measures
Epistasis not needed to explain low dN/dS
An important question in molecular evolution is whether an amino acid that
occurs at a given position makes an independent contribution to fitness, or
whether its effect depends on the state of other loci in the organism's genome,
a phenomenon known as epistasis. In a recent letter to Nature, Breen et al.
(2012) argued that epistasis must be "pervasive throughout protein evolution"
because the observed ratio between the per-site rates of non-synonymous and
synonymous substitutions (dN/dS) is much lower than would be expected in the
absence of epistasis. However, when calculating the expected dN/dS ratio in the
absence of epistasis, Breen et al. assumed that all amino acids observed in a
protein alignment at any particular position have equal fitness. Here, we relax
this unrealistic assumption and show that any dN/dS value can in principle be
achieved at a site, without epistasis. Furthermore, for all nuclear and
chloroplast genes in the Breen et al. dataset, we show that the observed dN/dS
values and the observed patterns of amino acid diversity at each site are
jointly consistent with a non-epistatic model of protein evolution.Comment: This manuscript is in response to "Epistasis as the primary factor in
molecular evolution" by Breen et al. Nature 490, 535-538 (2012
GALEX and Optical Light Curves of WX LMi, SDSSJ103100.5+202832.2 and SDSSJ121209.31+013627.7
{\it GALEX} near ultraviolet (NUV) and far-ultraviolet (FUV) light curves of
three extremely low accretion rate polars show distinct modulations in their UV
light curves. While these three systems have a range of magnetic fields from 13
to 70 MG, and of late type secondaries (including a likely brown dwarf in
SDSSJ121209.31+013627.7), the accretion rates are similar, and the UV
observations imply some mechanism is operating to create enhanced emission
zones on the white dwarf. The UV variations match in phase to the two magnetic
poles viewed in the optical in WX LMi and to the single poles evident in the
optical in SDSSJ1212109.31+013627.7 and SDSSJ103100.55+202832.2. Simple spot
models of the UV light curves show that if hot spots are responsible for the UV
variations, the temperatures are on the order of 10,000-14,000K. For the single
pole systems, the size of the FUV spot must be smaller than the NUV and in all
cases, the geometry is likely more complicated than a simple circular spot.Comment: 29 pages, 4 tables, 10 figures, Astrophysical Journal, accepte
Investigation of routes and funnels in protein folding by free energy functional methods
We use a free energy functional theory to elucidate general properties of
heterogeneously ordering, fast folding proteins, and we test our conclusions
with lattice simulations. We find that both structural and energetic
heterogeneity can lower the free energy barrier to folding. Correlating
stronger contact energies with entropically likely contacts of a given native
structure lowers the barrier, and anticorrelating the energies has the reverse
effect. Designing in relatively mild energetic heterogeneity can eliminate the
barrier completely at the transition temperature. Sequences with native
energies tuned to fold uniformly, as well as sequences tuned to fold by a
single or a few routes, are rare. Sequences with weak native energetic
heterogeneity are more common; their folding kinetics is more strongly
determined by properties of the native structure. Sequences with different
distributions of stability throughout the protein may still be good folders to
the same structure. A measure of folding route narrowness is introduced which
correlates with rate, and which can give information about the intrinsic biases
in ordering due to native topology. This theoretical framework allows us to
systematically investigate the coupled effects of energy and topology in
protein folding, and to interpret recent experiments which investigate these
effects.Comment: 12 pages, 1 figure, to appear in Proc. Natl. Acad. Sc
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