3,695 research outputs found
Historical contingency and entrenchment in protein evolution under purifying selection
The fitness contribution of an allele at one genetic site may depend on
alleles at other sites, a phenomenon known as epistasis. Epistasis can
profoundly influence the process of evolution in populations under selection,
and can shape the course of protein evolution across divergent species. Whereas
epistasis between adaptive substitutions has been the subject of extensive
study, relatively little is known about epistasis under purifying selection.
Here we use mechanistic models of thermodynamic stability in a ligand-binding
protein to explore the structure of epistatic interactions between
substitutions that fix in protein sequences under purifying selection. We find
that the selection coefficients of mutations that are nearly-neutral when they
fix are highly contingent on the presence of preceding mutations. Conversely,
mutations that are nearly-neutral when they fix are subsequently entrenched due
to epistasis with later substitutions. Our evolutionary model includes
insertions and deletions, as well as point mutations, and so it allows us to
quantify epistasis within each of these classes of mutations, and also to study
the evolution of protein length. We find that protein length remains largely
constant over time, because indels are more deleterious than point mutations.
Our results imply that, even under purifying selection, protein sequence
evolution is highly contingent on history and so it cannot be predicted by the
phenotypic effects of mutations assayed in the wild-type sequence.Comment: 42 pages, 13 figure
RAGE Signaling in Skeletal Biology
PURPOSE OF REVIEW:
The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease.
RECENT FINDINGS:
The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE-ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations. Recent studies have demonstrated that RAGE and its ligands play an important physiological role in the regulation of skeletal development, homeostasis, and repair/regeneration. Conversely, elevated levels of RAGE and its ligands are clearly related with various diseases associated with increased bone loss and fragility. However, despite the recent advancements in the field, many questions regarding RAGE and its ligands in skeletal biology remain unanswered
The inevitability of unconditionally deleterious substitutions during adaptation
Studies on the genetics of adaptation typically neglect the possibility that
a deleterious mutation might fix. Nonetheless, here we show that, in many
regimes, the first substitution is most often deleterious, even when fitness is
expected to increase in the long term. In particular, we prove that this
phenomenon occurs under weak mutation for any house-of-cards model with an
equilibrium distribution. We find that the same qualitative results hold under
Fisher's geometric model. We also provide a simple intuition for the surprising
prevalence of unconditionally deleterious substitutions during early
adaptation. Importantly, the phenomenon we describe occurs on fitness
landscapes without any local maxima and is therefore distinct from
"valley-crossing". Our results imply that the common practice of ignoring
deleterious substitutions leads to qualitatively incorrect predictions in many
regimes. Our results also have implications for the substitution process at
equilibrium and for the response to a sudden decrease in population size.Comment: Corrected typos and minor errors in Supporting Informatio
Minimal distance transformations between links and polymers: Principles and examples
The calculation of Euclidean distance between points is generalized to
one-dimensional objects such as strings or polymers. Necessary and sufficient
conditions for the minimal transformation between two polymer configurations
are derived. Transformations consist of piecewise rotations and translations
subject to Weierstrass-Erdmann corner conditions. Numerous examples are given
for the special cases of one and two links. The transition to a large number of
links is investigated, where the distance converges to the polymer length times
the mean root square distance (MRSD) between polymer configurations, assuming
curvature and non-crossing constraints can be neglected. Applications of this
metric to protein folding are investigated. Potential applications are also
discussed for structural alignment problems such as pharmacophore
identification, and inverse kinematic problems in motor learning and control.Comment: Submitted to J. Phys.:Condens. Matte
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Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.
Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network
Transcriptional errors and the drift barrier
Population genetics predicts that the balance between natural selection and genetic drift is determined by the population size. Species with large population sizes are predicted to have properties governed mainly by selective forces; whereas species with small population sizes should exhibit features governed by mutational processes alone. This “drift-barrier hypothesis” has been successful in explaining extensive variation in genome size, mutation rate, transposable element abundance, and other molecular features across diverse taxa (1⇓–3). However, in PNAS Traverse and Ochman (4) report a striking exception to this theory by showing that transcriptional error rates are nearly equal across several bacterial species with very different population sizes
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