562 research outputs found
An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain; however, achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches for novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offer the ability to repurpose FDA-approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed, including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations and the ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms that have strong potential to determine novel and effective treatment regimens
In search of multipolar order on the Penrose tiling
Based on Monte Carlo calculations, multipolar ordering on the Penrose tiling,
relevant for two-dimensional molecular adsorbates on quasicrystalline surfaces
and for nanomagnetic arrays, has been analyzed. These initial investigations
are restricted to multipolar rotors of rank one through four - described by
spherical harmonics Ylm with l=1...4 and restricted to m=0 - positioned on the
vertices of the rhombic Penrose tiling. At first sight, the ground states of
odd-parity multipoles seem to exhibit long-range multipolar order, indicated by
the appearance of a superstructure in the form of the decagonal
Hexagon-Boat-Star tiling, in agreement with previous investigations of dipolar
systems. Yet careful analysis establishes that long-range multipolar order is
absent in all cases investigated here, and only short-range order exists. This
result should be taken as a warning for any future analysis of order in either
real or simulated arrangements of multipoles on quasiperiodic templates
Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men
<p>Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).</p>
<p>Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance
following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual
improvements in running performance in the field.</p>
<p>Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was
determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max
and 3,000 m time trial performance were measured pre, post administration and at the end of the study.</p>
<p>Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec
vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration
(10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration
(60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after
rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to
baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post
rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68,
20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration
compared to baseline (13.761.1 gNkg21, p<0.001).</p>
<p>Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after
administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and
Hbmass.</p>
Sources of pro-cyclicality in east Asian financial systems
Procyclicality is a normal feature of economic systems, but financial sector
weaknesses can exacerbate it sufficiently to pose a threat to macroeconomic and financial
stability. These include shortcomings in bank risk management and governance, in
supervision and in terms of dependence on volatile sources of funds. The paper tests
econometrically for the importance of such features leading to pro-cyclicality in the financial
systems of 11 East Asian countries. This analysis makes it possible to identify specific policy
measures for East Asian countries that could limit the extent to which financial systems
exacerbate pro-cyclicality
Impact of hiatal hernia on histological pattern of non-erosive reflux disease
BACKGROUND: Hiatus hernia (HH) has major pathophysiological effects favoring gastroesophageal reflux and hence contributing to esophageal mucosa injury, especially in patients with severe gastroesophageal disease. However, prospective studies investigating the impact of HH on the esophageal mucosa in non-erosive reflux disease (NERD) are lacking. This study evaluated the association between the presence of (HH) and the histological findings in symptomatic patients with NERD. METHODS: Fifty consecutive patients with gastroesophageal reflux disease (GERD) were enrolled. After conventional endoscopy, Lugol solution was applied and biopsy specimens were obtained. Histological parameters including basal zone hyperplasia, papillary length and cellular infiltration were evaluated. The chi-square test with Yates' correlation was used for comparing discrete parameters between groups. However, Fisher's exact probability test was used where the expected frequencies were lower than 5. Wilcoxon's test for unpaired samples was preferred in cases of semi-quantitative parameters. RESULTS: The presence of HH along with more severe findings (0.01 <P < 0.05) was confirmed in 18 patients. NERD was observed in 29 (58%) patients. Basal zone hyperplasia and loss of glycogen accompanied HH in all cases, and the correlation was significant in NERD (P < 0.001). The remaining histological patterns were similar between erosive reflux disease and NERD in the presence of HH. CONCLUSION: The presence of HH is correlated with more severe endoscopy findings, and predisposes for severe histological abnormality in cases of NERD
The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains
We have investigated the contribution to ionic
selectivity of residues in the selectivity filter and pore
helices of the P1 and P2 domains in the acid sensitive
potassium channel TASK-1. We used site directed mutagenesis
and electrophysiological studies, assisted by structural
models built through computational methods. We have
measured selectivity in channels expressed in Xenopus
oocytes, using voltage clamp to measure shifts in reversal
potential and current amplitudes when Rb+ or Na+ replaced
extracellular K+. Both P1 and P2 contribute to selectivity,
and most mutations, including mutation of residues in the
triplets GYG and GFG in P1 and P2, made channels nonselective.
We interpret the effects of these—and of other
mutations—in terms of the way the pore is likely to be
stabilised structurally. We show also that residues in the
outer pore mouth contribute to selectivity in TASK-1.
Mutations resulting in loss of selectivity (e.g. I94S, G95A)
were associated with slowing of the response of channels to
depolarisation. More important physiologically, pH sensitivity
is also lost or altered by such mutations. Mutations
that retained selectivity (e.g. I94L, I94V) also retained their
response to acidification. It is likely that responses both to
voltage and pH changes involve gating at the selectivity filter
Retuning of Inferior Colliculus Neurons Following Spiral Ganglion Lesions: A Single-Neuron Model of Converging Inputs
Lesions of spiral ganglion cells, representing a restricted sector of the auditory nerve array, produce immediate changes in the frequency tuning of inferior colliculus (IC) neurons. There is a loss of excitation at the lesion frequencies, yet responses to adjacent frequencies remain intact and new regions of activity appear. This leads to immediate changes in tuning and in tonotopic progression. Similar effects are seen after different methods of peripheral damage and in auditory neurons in other nuclei. The mechanisms that underlie these postlesion changes are unknown, but the acute effects seen in IC strongly suggest the “unmasking” of latent inputs by the removal of inhibition. In this study, we explore computational models of single neurons with a convergence of excitatory and inhibitory inputs from a range of characteristic frequencies (CFs), which can simulate the narrow prelesion tuning of IC neurons, and account for the changes in CF tuning after a lesion. The models can reproduce the data if inputs are aligned relative to one another in a precise order along the dendrites of model IC neurons. Frequency tuning in these neurons approximates that seen physiologically. Removal of inputs representing a narrow range of frequencies leads to unmasking of previously subthreshold excitatory inputs, which causes changes in CF. Conversely, if all of the inputs converge at the same point on the cell body, receptive fields are broad and unmasking rarely results in CF changes. However, if the inhibition is tonic with no stimulus-driven component, then unmasking can still produce changes in CF
Novel precoded relay-assisted algorithm for cellular systems
Cooperative schemes are promising solutions for cellular wireless systems to improve system fairness, extend coverage and increase capacity. The use of relays is of significant interest to allow radio access in situations where a direct path is not available or has poor quality. A data precoded relay-assisted scheme is proposed for a system cooperating with 2 relays, each equipped with either a single antenna or 2-antenna array. However, because of the half-duplex constraint at the relays, relaying-assisted transmission would require the use of a higher order constellation than in the case when a continuous link is available from the BS to the UT. This would imply a penalty in the power efficiency. The simple precoding scheme proposed exploits the relation between QPSK and 16-QAM, by alternately transmitting through the 2 relays, achieving full diversity, while significantly reducing power penalty. Analysis of the pairwise error probability of the proposed algorithm with a single antenna in each relay is derived and confirmed with numerical results. We show the performance improvements of the precoded scheme, relatively to equivalent distributed SFBC scheme employing 16-QAM, for several channel quality scenarios. Copyright © 2010 Sara Teodoro, et al.European project CODIVPortuguese project CADWINPortuguese project AGILEFC
Novel precoded relay-assisted algorithm for cellular systems
Cooperative schemes are promising solutions for cellular wireless systems to improve system fairness, extend coverage and increase capacity. The use of relays is of significant interest to allow radio access in situations where a direct path is not available or has poor quality. A data precoded relay-assisted scheme is proposed for a system cooperating with 2 relays, each equipped with either a single antenna or 2-antenna array. However, because of the half-duplex constraint at the relays, relaying-assisted transmission would require the use of a higher order constellation than in the case when a continuous link is available from the BS to the UT. This would imply a penalty in the power efficiency. The simple precoding scheme proposed exploits the relation between QPSK and 16-QAM, by alternately transmitting through the 2 relays, achieving full diversity, while significantly reducing power penalty. Analysis of the pairwise error probability of the proposed algorithm with a single antenna in each relay is derived and confirmed with numerical results. We show the performance improvements of the precoded scheme, relatively to equivalent distributed SFBC scheme employing 16-QAM, for several channel quality scenarios. Copyright © 2010 Sara Teodoro, et al.European project CODIVPortuguese project CADWINPortuguese project AGILEFC
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