86 research outputs found
Fast Poisson Noise Removal by Biorthogonal Haar Domain Hypothesis Testing
Methods based on hypothesis tests (HTs) in the Haar domain are widely used to
denoise Poisson count data. Facing large datasets or real-time applications,
Haar-based denoisers have to use the decimated transform to meet limited-memory
or computation-time constraints. Unfortunately, for regular underlying
intensities, decimation yields discontinuous estimates and strong "staircase"
artifacts. In this paper, we propose to combine the HT framework with the
decimated biorthogonal Haar (Bi-Haar) transform instead of the classical Haar.
The Bi-Haar filter bank is normalized such that the p-values of Bi-Haar
coefficients (pBH) provide good approximation to those of Haar (pH) for
high-intensity settings or large scales; for low-intensity settings and small
scales, we show that pBH are essentially upper-bounded by pH. Thus, we may
apply the Haar-based HTs to Bi-Haar coefficients to control a prefixed false
positive rate. By doing so, we benefit from the regular Bi-Haar filter bank to
gain a smooth estimate while always maintaining a low computational complexity.
A Fisher-approximation-based threshold imple- menting the HTs is also
established. The efficiency of this method is illustrated on an example of
hyperspectral-source-flux estimation
Chronic Renal Allograft Dysfunction: Risk Factors, Immunology and Prevention
Introduction: Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Despite great progress in surgical aspects and immunosupression therapy, long-term graft survival has not been consistent. Chronic allograft dysfunction (CAD) remains a major cause of late grafts failure.
Review: CAD is a generic term of all causes of chronic renal allograft dysfunction associated with fibrosis. It is clinically characterized by a gradual worsening of renal function in the presence of arterial hypertension and low-grade proteinuria. Histological changes of CAD usually precede functional deterioration and include interstitial fibrosis/tubular atrophy accompanied by vascular changes and glomerulosclerosis. Both immunological and non immunological factors can be responsible for CAD. Immunological causes include chronic active antibody-mediated and T cell-mediated rejection. Non immunological factors include brain death in the donor, increasing donor age, ischemia-reperfusion injury, calcineurin inhibitor nephrotoxicity, hypertension, diabetes mellitus, hyperlipidemia, chronic obstruction and chronic viral infections. Even if the contributing factors to CAD can be identified, not all of them can be interrupted prior to and after grafting. Preventive strategies include improvements in medical and surgical strategies to reduce ischemia-reperfusion injury, strategies to minimize acute rejection and strategies aiming for HLA-matched transplants. Additional measures include tight control of blood pressure, proteinuria, lipids and glucose. Antivirus treatment, appropriate diet, weight control, no smoking and good compliance are also suggested in certain settings.
Conclusion: Evidence-based treatment strategies for CAD are lacking, but several prevention and management strategies are recommended in clinical practice.
Keywords: Calcineurin Inhibitor Toxicity; Chronic Rejection; Ischemia-Reperfusion; Transplantatio
A review of fMRI simulation studies
Simulation studies that validate statistical techniques for fMRI data are challenging due to the complexity of the data. Therefore, it is not surprising that no common data generating process is available (i.e. several models can be found to model BOLD activation and noise). Based on a literature search, a database of simulation studies was compiled. The information in this database was analysed and critically evaluated focusing on the parameters in the simulation design, the adopted model to generate fMRI data, and on how the simulation studies are reported. Our literature analysis demonstrates that many fMRI simulation studies do not report a thorough experimental design and almost consistently ignore crucial knowledge on how fMRI data are acquired. Advice is provided on how the quality of fMRI simulation studies can be improved
Wavelet penalized likelihood estimation in generalized functional models
The paper deals with generalized functional regression. The aim is to
estimate the influence of covariates on observations, drawn from an exponential
distribution. The link considered has a semiparametric expression: if we are
interested in a functional influence of some covariates, we authorize others to
be modeled linearly. We thus consider a generalized partially linear regression
model with unknown regression coefficients and an unknown nonparametric
function. We present a maximum penalized likelihood procedure to estimate the
components of the model introducing penalty based wavelet estimators.
Asymptotic rates of the estimates of both the parametric and the nonparametric
part of the model are given and quasi-minimax optimality is obtained under
usual conditions in literature. We establish in particular that the LASSO
penalty leads to an adaptive estimation with respect to the regularity of the
estimated function. An algorithm based on backfitting and Fisher-scoring is
also proposed for implementation. Simulations are used to illustrate the finite
sample behaviour, including a comparison with kernel and splines based methods
Nonlinear complexity analysis of brain fMRI signals in schizophrenia
Peer reviewedPublisher PD
<i>Trypanosoma brucei</i> DHRF-TS revisited:characterisation of a bifunctional and highly unstable recombinant dihydrofolate reductase-thymidylate synthase
<div><p>Bifunctional dihydrofolate reductase–thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA<sup>-</sup> <i>Escherichia coli</i>, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (<i>K</i><sub>i</sub> 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (<i>K</i><sub>i</sub> 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.</p></div
Multiple Mutations in Heterogeneous Miltefosine-Resistant Leishmania major Population as Determined by Whole Genome Sequencing
Leishmania spp. are parasitic protozoa responsible for a spectrum of diseases known as leishmaniasis. There are few drugs available for the treatment of these diseases, and miltefosine is the first oral drug used in treatment of visceral leishmaniasis, a form of the disease that can be lethal if not treated. In this study, we seek to understand the mechanism of action and identify targets of the drug by generating promastigote mutants highly resistant to miltefosine. Two independent mutants were submitted to short read whole genome sequencing. Genome analysis of these mutants has permitted us to identify point mutations in three genes (P-type ATPase, pyridoxal kinase and α-adaptin like protein) that were also present in other independent miltefosine resistant mutants. Some of the new genes identified here could be useful as potential markers for miltefosine resistance in Leishmania. Moreover, our approach has permitted us to highlight that resistance can be highly heterogeneous at the population level with individual clones derived from this population differing both in terms of genotypes but also susceptibility phenotypes. This may have practical applications while studying resistance
Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death.
Activation of proteolytic cell death pathways may circumvent drug resistance in deadly protozoan parasites such as Plasmodium falciparum and Leishmania. To this end, it is important to define the cell death pathway(s) in parasites and thus characterize proteases such as metacaspases (MCA), which have been reported to induce cell death in plants and Leishmania parasites. We, therefore, investigated whether the cell death function of MCA is conserved in different protozoan parasite species such as Plasmodium falciparum and Leishmania major, focusing on the substrate specificity and functional role in cell survival as compared to Saccharomyces cerevisae. Our results show that, similarly to Leishmania, Plasmodium MCA exhibits a calcium-dependent, arginine-specific protease activity and its expression in yeast induced growth inhibition as well as an 82% increase in cell death under oxidative stress, a situation encountered by parasites during the host or when exposed to drugs such as artemisins. Furthermore, we show that MCA cell death pathways in both Plasmodium and Leishmania, involve a z-VAD-fmk inhibitable protease. Our data provide evidence that MCA from both Leishmania and Plasmodium falciparum is able to induce cell death in stress conditions, where it specifically activates a downstream enzyme as part of a cell death pathway. This enzymatic activity is also induced by the antimalarial drug chloroquine in erythrocytic stages of Plasmodium falciparum. Interestingly, we found that blocking parasite cell death influences their drug sensitivity, a result which could be used to create therapeutic strategies that by-pass drug resistance mechanisms by acting directly on the innate pathways of protozoan cell death
Drug Resistance in Eukaryotic Microorganisms
Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies
Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications
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