116 research outputs found
Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics
Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine
Electrostatic Interactions of Asymmetrically Charged Membranes
We predict the nature (attractive or repulsive) and range (exponentially
screened or long-range power law) of the electrostatic interactions of
oppositely charged and planar plates as a function of the salt concentration
and surface charge densities (whose absolute magnitudes are not necessarily
equal). An analytical expression for the crossover between attractive and
repulsive pressure is obtained as a function of the salt concentration. This
condition reduces to the high-salt limit of Parsegian and Gingell where the
interaction is exponentially screened and to the zero salt limit of Lau and
Pincus in which the important length scales are the inter-plate separation and
the Gouy-Chapman length. In the regime of low salt and high surface charges we
predict - for any ratio of the charges on the surfaces - that the attractive
pressure is long-ranged as a function of the spacing. The attractive pressure
is related to the decrease in counter-ion concentration as the inter-plate
distance is decreased. Our theory predicts several scaling regimes with
different scaling expressions for the pressure as function of salinity and
surface charge densities. The pressure predictions can be related to surface
force experiments of oppositely charged surfaces that are prepared by coating
one of the mica surfaces with an oppositely charged polyelectrolyte
Color singlet suppression of quark-gluon plasma formation
The rate of quark-gluon plasma droplet nucleation in superheated hadronic
matter is calculated within the MIT bag model. The requirements of color
singletness and (to less extent) fixed momentum suppress the nucleation rate by
many orders of magnitude, making thermal nucleation of quark-gluon plasma
droplets unlikely in ultrarelativistic heavy-ion collisions if the transition
is first order and reasonably described by the bag model.Comment: 9 pages, 3 ps figures. To appear in PhysRevC (April 1996
The Weak Gravity Conjecture and the Viscosity Bound with Six-Derivative Corrections
The weak gravity conjecture and the shear viscosity to entropy density bound
place constraints on low energy effective field theories that may help to
distinguish which theories can be UV completed. Recently, there have been
suggestions of a possible correlation between the two constraints. In some
interesting cases, the behavior was precisely such that the conjectures were
mutually exclusive. Motivated by these works, we study the mass to charge and
shear viscosity to entropy density ratios for charged AdS5 black branes, which
are holographically dual to four-dimensional CFTs at finite temperature. We
study a family of four-derivative and six-derivative perturbative corrections
to these backgrounds. We identify the region in parameter space where the two
constraints are satisfied and in particular find that the inclusion of the
next-to-leading perturbative correction introduces wider possibilities for the
satisfaction of both constraints.Comment: 24 pages, 6 figures, v2: published version, refs added, minor
clarificatio
Weak pairwise correlations imply strongly correlated network states in a neural population
Biological networks have so many possible states that exhaustive sampling is
impossible. Successful analysis thus depends on simplifying hypotheses, but
experiments on many systems hint that complicated, higher order interactions
among large groups of elements play an important role. In the vertebrate
retina, we show that weak correlations between pairs of neurons coexist with
strongly collective behavior in the responses of ten or more neurons.
Surprisingly, we find that this collective behavior is described quantitatively
by models that capture the observed pairwise correlations but assume no higher
order interactions. These maximum entropy models are equivalent to Ising
models, and predict that larger networks are completely dominated by
correlation effects. This suggests that the neural code has associative or
error-correcting properties, and we provide preliminary evidence for such
behavior. As a first test for the generality of these ideas, we show that
similar results are obtained from networks of cultured cortical neurons.Comment: Full account of work presented at the conference on Computational and
Systems Neuroscience (COSYNE), 17-20 March 2005, in Salt Lake City, Utah
(http://cosyne.org
X-ray harmonic comb from relativistic electron spikes
X-ray devices are far superior to optical ones for providing nanometre
spatial and attosecond temporal resolutions. Such resolution is indispensable
in biology, medicine, physics, material sciences, and their applications. A
bright ultrafast coherent X-ray source is highly desirable, for example, for
the diffractive imaging of individual large molecules, viruses, or cells. Here
we demonstrate experimentally a new compact X-ray source involving high-order
harmonics produced by a relativistic-irradiance femtosecond laser in a gas
target. In our first implementation using a 9 Terawatt laser, coherent soft
X-rays are emitted with a comb-like spectrum reaching the 'water window' range.
The generation mechanism is robust being based on phenomena inherent in
relativistic laser plasmas: self-focusing, nonlinear wave generation
accompanied by electron density singularities, and collective radiation by a
compact electric charge. The formation of singularities (electron density
spikes) is described by the elegant mathematical catastrophe theory, which
explains sudden changes in various complex systems, from physics to social
sciences. The new X-ray source has advantageous scalings, as the maximum
harmonic order is proportional to the cube of the laser amplitude enhanced by
relativistic self-focusing in plasma. This allows straightforward extension of
the coherent X-ray generation to the keV and tens of keV spectral regions. The
implemented X-ray source is remarkably easily accessible: the requirements for
the laser can be met in a university-scale laboratory, the gas jet is a
replenishable debris-free target, and the harmonics emanate directly from the
gas jet without additional devices. Our results open the way to a compact
coherent ultrashort brilliant X-ray source with single shot and high-repetition
rate capabilities, suitable for numerous applications and diagnostics in many
research fields
The Evolution of Compact Binary Star Systems
We review the formation and evolution of compact binary stars consisting of
white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and
BHs are thought to be the primary astrophysical sources of gravitational waves
(GWs) within the frequency band of ground-based detectors, while compact
binaries of WDs are important sources of GWs at lower frequencies to be covered
by space interferometers (LISA). Major uncertainties in the current
understanding of properties of NSs and BHs most relevant to the GW studies are
discussed, including the treatment of the natal kicks which compact stellar
remnants acquire during the core collapse of massive stars and the common
envelope phase of binary evolution. We discuss the coalescence rates of binary
NSs and BHs and prospects for their detections, the formation and evolution of
binary WDs and their observational manifestations. Special attention is given
to AM CVn-stars -- compact binaries in which the Roche lobe is filled by
another WD or a low-mass partially degenerate helium-star, as these stars are
thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure
Dipolar cortico-muscular electrical stimulation: a novel method that enhances motor function in both - normal and spinal cord injured mice
<p>Abstract</p> <p>Background</p> <p>Electrical stimulation of the central and peripheral nervous systems is a common tool that is used to improve functional recovery after neuronal injury.</p> <p>Methods</p> <p>Here we described a new configuration of electrical stimulation as it was tested in anesthetized control and spinal cord injury (SCI) mice. Constant voltage output was delivered through two electrodes. While the negative voltage output (ranging from -1.8 to -2.6 V) was delivered to the muscle via transverse wire electrodes (diameter, 500 μm) located at opposite ends of the muscle, the positive output (ranging from + 2.4 to +3.2 V) was delivered to the primary motor cortex (M1) (electrode tip, 100 μm). The configuration was named dipolar cortico-muscular stimulation (dCMS) and consisted of 100 pulses (1 ms pulse duration, 1 Hz frequency).</p> <p>Results</p> <p>In SCI animals, after dCMS, cortically-elicited muscle contraction improved markedly at the contralateral (456%) and ipsilateral (457%) gastrocnemius muscles. The improvement persisted for the duration of the experiment (60 min). The enhancement of cortically-elicited muscle contraction was accompanied by the reduction of M1 maximal threshold and the potentiation of spinal motoneuronal evoked responses at the contralateral (313%) and ipsilateral (292%) sides of the spinal cord. Moreover, spontaneous activity recorded from single spinal motoneurons was substantially increased contralaterally (121%) and ipsilaterally (54%). Interestingly, spinal motoneuronal responses and muscle twitches evoked by the test stimulation of non-treated M1 (received no dCMS) were significantly enhanced as well. Similar results obtained from normal animals albeit the changes were relatively smaller.</p> <p>Conclusion</p> <p>These findings demonstrated that dCMS could improve functionality of corticomotoneuronal pathway and thus it may have therapeutic potential.</p
A Unique Modification of the Eukaryotic Initiation Factor 5A Shows the Presence of the Complete Hypusine Pathway in Leishmania donovani
Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (N€-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of α-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A ∼42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed ∼40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite
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Mutational heterogeneity in cancer and the search for new cancer genes
Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention
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