49,997 research outputs found
Genetics update: monogenetics, polygene disorders and the quest for modifying genes
The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions
Maternal fluoxetine exposure alters cortical hemodynamic and calcium response of offspring to somatosensory stimuli
Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (Hb
Hyperuniformity with no fine tuning in sheared sedimenting suspensions
Particle suspensions, present in many natural and industrial settings,
typically contain aggregates or other microstructures that can complicate
macroscopic flow behaviors and damage processing equipment. Recent work found
that applying uniform periodic shear near a critical transition can reduce
fluctuations in the particle concentration across all length scales, leading to
a hyperuniform state. However, this strategy for homogenization requires fine
tuning of the strain amplitude. Here we show that in a model of sedimenting
particles under periodic shear, there is a well-defined regime at low
sedimentation speed where hyperuniform scaling automatically occurs. Our
simulations and theoretical arguments show that the homogenization extends up
to a finite lengthscale that diverges as the sedimentation speed approaches
zero.Comment: 11 pages, 6 figure
The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids.
Telomerase is an enzyme that adds repetitive DNA sequences to the ends of chromosomes and consists of two main subunits: the telomerase reverse transcriptase (TERT) protein and an associated telomerase RNA (TER). The telomerase essential N-terminal (TEN) domain is a conserved region of TERT proposed to mediate DNA substrate interactions. Here, we have employed single molecule telomerase binding assays to investigate the function of the TEN domain. Our results reveal telomeric DNA substrates bound to telomerase exhibit a dynamic equilibrium between two states: a docked conformation and an alternative conformation. The relative stabilities of the docked and alternative states correlate with the number of basepairs that can be formed between the DNA substrate and the RNA template, with more basepairing favoring the docked state. The docked state is further buttressed by the TEN domain and mutations within the TEN domain substantially alter the DNA substrate structural equilibrium. We propose a model in which the TEN domain stabilizes short RNA-DNA duplexes in the active site of the enzyme, promoting the docked state to augment telomerase processivity
Molecular Lines as Diagnostics of High Redshift Objects
Models are presented for CO rotational line emission by high redshift
starburst galaxies. The influence of the cosmic microwave background on the
thermal balance and the level populations of atomic and molecular species is
explicitly included. Predictions are made for the observability of starburst
galaxies through line and continuum emission between z=5 and z=30. It is found
that the Millimeter Array could detect a starburst galaxy with ~10^5 Orion
regions, corresponding to a star formation rate of about 30 Mo yr^{-1}, equally
well at z=5 or z=30 due to the increasing cosmic microwave background
temperature with redshift. Line emission is a potentially more powerful probe
than dust continuum emission of very high redshift objects.Comment: 15 pages LaTex, uses aasms4.sty, Accepted by ApJ
Strategic Factors in Nineteenth Century American Economic History: A Volume to Honor Robert W. Fogel
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