717 research outputs found
RNA splicing: disease and therapy
The majority of human genes that encode proteins undergo alternative pre-mRNA splicing and mutations that affect splicing are more prevalent than previously thought. The mechanism of pre-mRNA splicing is highly complex, requiring multiple interactions between pre-mRNA, small nuclear ribonucleoproteins and splicing factor proteins. Regulation of this process is even more complicated, relying on loosely defined cis-acting regulatory sequence elements, trans-acting protein factors and cellular responses to varying environmental conditions. Many different human diseases can be caused by errors in RNA splicing or its regulation. Targeting aberrant RNA provides an opportunity to correct faulty splicing and potentially treat numerous genetic disorders. Antisense oligonucleotide therapies show particular promise in this area and, if coupled with improved delivery strategies, could open the door to a multitude of novel personalized therapies
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective
Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS
Defining the need for surgical intervention following a snakebite still relies heavily on clinical assessment: The experience in Pietermaritzburg, South Africa
Background. This audit of snakebites was undertaken to document our experience with snakebite in the western part of KwaZulu-Natal (KZN) Province, South Africa (SA).Objective. To document our experience with snakebite in the western part of KZN, and to interrogate the data on patients who required some form of surgical intervention.Methods. A retrospective study was undertaken at the Pietermaritzburg Metropolitan Trauma Service, Pietermaritzburg, SA. The Hybrid Electronic Medical Registry was reviewed for the 5-year period January 2012 - December 2016. All patients admitted to the service for management of snakebite were included.Results. The offending snake is rarely identified, and the syndromic approach is now the mainstay of management. Most envenomations seen during the study period were cytotoxic, presenting with painful progressive swelling (PPS). We did not see any purely neurotoxic or haemotoxic envenomations. Antivenom is required for a subset of patients. The indications are essentially PPS that increases by >15 cm over an hour, PPS up to the elbow or knee after 4 hours, PPS of the whole limb after 8 hours, threatened airway, shortness of breath, associated clotting abnormalities and compartment syndrome. If no symptoms have manifested within 1 hour of a snakebite, clinically significant envenomation is unlikely to have occurred. Antivenom is associated with a high rate of anaphylaxis and should only be administered when absolutely indicated, preferably in a high-care setting under continuous monitoring. The need for surgery is less well defined. Urgent surgery is indicated for compartment syndrome of the limb, which is a potentially life- and limb-threatening condition. Its diagnosis is usually made clinically, but this is difficult in snakebites. Morbidity and cost increase dramatically once fasciotomy is required, as evidenced by much longer hospital stay. There is frequently a degree of cross-over between cytotoxicity and haemotoxicity in envenomations that require fasciotomy, which means that fasciotomy may result in catastrophic bleeding and should be preceded by the administration of antivenom, especially in patients with a low platelet count or a high international normalised ratio. Physiological and biochemical markers are unhelpful in assessing the need for fasciotomy. Objective methods include measurement of compartment pressures and ultrasound.Conclusion. The syndromic management of snakebite is effective and safe. There is a high incidence of anaphylactic reactions to antivenom, and its administration must be closely supervised. In our area we overwhelmingly see cytotoxic snakebites with PPS. Surgery is often needed, and we need to refine our algorithms in terms of deciding on surgery
Neutrino oscillation parameters from MINOS, ICARUS and OPERA combined
We perform a detailed analysis of the capabilities of the MINOS, ICARUS and
OPERA experiments to measure neutrino oscillation parameters at the atmospheric
scale with their data taken separately and in combination. MINOS will determine
and to within 10% at the 99% C.L. with
10 kton-years of data. While no one experiment will determine with much precision, if its value lies in the combined
sensitivity region of the three experiments, it will be possible to place a
lower bound of O(0.01) at the 95% C.L. on this parameter by combining the data
from the three experiments. The same bound can be placed with a combination of
MINOS and ICARUS data alone.Comment: Version to appear in PR
Implications of the HERA Events for the R-Parity Breaking SUSY Signals at Tevatron
The favoured R-parity violating SUSY scenarios for the anomalous HERA events
correspond to top and charm squark production via the and
couplings. In both cases the corresponding electronic
branching fractions of the squarks are expected to be . Consequently the
canonical leptoquark signature is incapable of probing these scenarios at the
Tevatron collider over most of the MSSM parameter space. We suggest alternative
signatures for probing them at Tevatron, which seem to be viable over the
entire range of MSSM parameters.Comment: 20 pages Latex file with 4 ps files containing 4 figure
Experimental Study of the Shortest Reset Word of Random Automata
In this paper we describe an approach to finding the shortest reset word of a
finite synchronizing automaton by using a SAT solver. We use this approach to
perform an experimental study of the length of the shortest reset word of a
finite synchronizing automaton. The largest automata we considered had 100
states. The results of the experiments allow us to formulate a hypothesis that
the length of the shortest reset word of a random finite automaton with
states and 2 input letters with high probability is sublinear with respect to
and can be estimated as $1.95 n^{0.55}.
Ablation plasma ion implantation using a dc power supply
Experiments are reported in which ablation plasma ion implantation (APII) has been demonstrated using a dc power supply. The ability to use a dc power supply for APII has been accomplished by using a perpendicular orientation between the target and the substrate. This perpendicular orientation significantly reduces the arcing between the target and the substrate, in contrast to previous experiments using a parallel target–substrate orientation. With this new technique a KrF laser may be fired during the dc high voltage, accelerating full-energy ions. Initial experiments using dc APII have shown that Ti is deposited and implanted onto the Si substrate, with the highest concentration of Ti located beneath the surface of the film. The deposition/implantation of Ti ions onto Si was verified by X-ray photoelectron spectroscopy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47038/1/339_2004_Article_2585.pd
Two-proton correlations from 158 AGeV Pb+Pb central collisions
The two-proton correlation function at midrapidity from Pb+Pb central
collisions at 158 AGeV has been measured by the NA49 experiment. The results
are compared to model predictions from static thermal Gaussian proton source
distributions and transport models RQMD and VENUS. An effective proton source
size is determined by minimizing CHI-square/ndf between the correlation
functions of the data and those calculated for the Gaussian sources, yielding
3.85 +-0.15(stat.) +0.60-0.25(syst.) fm. Both the RQMD and the VENUS model are
consistent with the data within the error in the correlation peak region.Comment: RevTeX style, 6 pages, 4 figures, 1 table. More discussion are added
about the structure on the tail of the correlation function. The systematic
error is revised. To appear in Phys. Lett.
Event-by-event fluctuations of average transverse momentum in central Pb+Pb collisions at 158 GeV per nucleon
We present first data on event-by-event fluctuations in the average
transverse momentum of charged particles produced in Pb+Pb collisions at the
CERN SPS. This measurement provides previously unavailable information allowing
sensitive tests of microscopic and thermodynamic collision models and to search
for fluctuations expected to occur in the vicinity of the predicted QCD phase
transition. We find that the observed variance of the event-by-event average
transverse momentum is consistent with independent particle production modified
by the known two-particle correlations due to quantum statistics and final
state interactions and folded with the resolution of the NA49 apparatus. For
two specific models of non-statistical fluctuations in transverse momentum
limits are derived in terms of fluctuation amplitude. We show that a
significant part of the parameter space for a model of isospin fluctuations
predicted as a consequence of chiral symmetry restoration in a non-equilibrium
scenario is excluded by our measurement.Comment: 6 pages, 2 figures, submitted to Phys. Lett.
Observing the First Stars and Black Holes
The high sensitivity of JWST will open a new window on the end of the
cosmological dark ages. Small stellar clusters, with a stellar mass of several
10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun
should be directly detectable out to redshift z=10, and individual supernovae
(SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible
beyond this redshift. Dense primordial gas, in the process of collapsing from
large scales to form protogalaxies, may also be possible to image through
diffuse recombination line emission, possibly even before stars or BHs are
formed. In this article, I discuss the key physical processes that are expected
to have determined the sizes of the first star-clusters and black holes, and
the prospect of studying these objects by direct detections with JWST and with
other instruments. The direct light emitted by the very first stellar clusters
and intermediate-mass black holes at z>10 will likely fall below JWST's
detection threshold. However, JWST could reveal a decline at the faint-end of
the high-redshift luminosity function, and thereby shed light on radiative and
other feedback effects that operate at these early epochs. JWST will also have
the sensitivity to detect individual SNe from beyond z=10. In a dedicated
survey lasting for several weeks, thousands of SNe could be detected at z>6,
with a redshift distribution extending to the formation of the very first stars
at z>15. Using these SNe as tracers may be the only method to map out the
earliest stages of the cosmic star-formation history. Finally, we point out
that studying the earliest objects at high redshift will also offer a new
window on the primordial power spectrum, on 100 times smaller scales than
probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and
Concurrent Facilities", Astrophysics & Space Science Library, Eds. H.
Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008
- …