Duration judgements in patients with schizophrenia

Background. The ability to encode time cues underlies many cognitive processes. In the light of schizophrenic patients' compromised cognitive abilities in a variety of domains, it is noteworthy that there are numerous reports of these patients displaying impaired timing abilities. However, the timing intervals that patients have been evaluated on in prior studies vary considerably in magnitude (e.g. 1 s, 1 min, 1 h etc.). Method. In order to obviate differences in abilities in chronometric counting and place minimal demands on cognitive processing, we chose tasks that involve making judgements about brief durations of time (<1 s). Results. On a temporal generalization task, patients were less accurate than controls at recognizing a standard duration. The performance of patients was also significantly different from controls on a temporal bisection task, in which participants categorized durations as short or long. Although time estimation may be closely intertwined with working memory, patients' working memory as measured by the digit span task did not correlate significantly with their performance on the duration judgement tasks. Moreover, lowered intelligence scores could not completely account for the findings. Conclusions. We take these results to suggest that patients with schizophrenia are less accurate at estimating brief time periods. These deficits may reflect dysfunction of biopsychological timing processes

Discovery and characterization of potent, efficacious, orally available antimalarial Plasmepsin X inhibitors and preclinical safety assessment of UCB7362

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life

What determines the shape of a Pine-Island-like ice shelf?

Ice shelf shape directly controls ocean heat intrusions, melting near the grounding line, and buttressing. Little is known about what determines ice-shelf shape because ice-ocean coupled simulations typically aim at projecting Antarctica's contribution to sea-level rise and they do not resolve small-scale ice-ocean interactive processes. We conduct ice-ocean coupled simulations for an idealized high-resolution, Pine-Island-like model configuration. We show that ocean melting and ice stretching caused by acceleration thin the ice shelf from the grounding line toward the ice shelf front, consistent with previous studies. In the across-flow direction, ocean melting and ice advection cancel each other out and flatten the ice shelf. More than one-third of the ice thinning from grounding line to ice front can be attributed to ocean melting at depths shallower than 500 m. Our results emphasize the importance of interactive processes between the entire ice shelf and the ocean for determining the ice shelf shape. Plain Language Summary Antarctic ice flows into the ocean and forms a floating extension of land ice called an ice shelf. The ice shelf shape directly controls the amount of ocean heat intrusions, melting near the grounding line, and buttressing. However, little is understood about ice-ocean interactive processes determining ice shelf shape because (a) ocean modelers apply a constant cavity geometry, (b) ice modelers mostly assume simplified melting parameterization, and (c) ice-ocean coupled simulations typically aim at projections of Antarctica's sea-level contributions and they require long model integration. We conduct ice-ocean coupled simulations for an idealized high-resolution Pine-Island-like model configuration. Basal melting and ice stretching create a typical ice shelf shape with steep thinning near the grounding line followed by gradual thinning toward the ice shelf front. In the across-flow direction, ice divergence from the center advects ice toward edges, compensating for melt-driven thinning and flattening ice shelf shape. We also show that ice melting at shallow depths contributes to about one-third of ice-shelf thinning. Although it is thought that ice shelf melting at the grounding line dominantly controls ice shelf behavior, our results suggest the importance of ice-ocean interactive processes for the entire ice shelf cavity for determining the ice shelf shape

snoRNA, a Novel Precursor of microRNA in Giardia lamblia

An Argonaute homolog and a functional Dicer have been identified in the ancient eukaryote Giardia lamblia, which apparently lacks the ability to perform RNA interference (RNAi). The Giardia Argonaute plays an essential role in growth and is capable of binding specifically to the m7G-cap, suggesting a potential involvement in microRNA (miRNA)-mediated translational repression. To test such a possibility, small RNAs were isolated from Giardia trophozoites, cloned, and sequenced. A 26-nucleotide (nt) small RNA (miR2) was identified as a product of Dicer-processed snoRNA GlsR17 and localized to the cytoplasm by fluorescence in situ hybridization, whereas GlsR17 was found primarily in the nucleolus of only one of the two nuclei in Giardia. Three other small RNAs were also identified as products of snoRNAs, suggesting that the latter could be novel precursors of miRNAs in Giardia. Putative miR2 target sites were identified at the 3′-untranslated regions (UTR) of 22 variant surface protein mRNAs using the miRanda program. In vivo expression of Renilla luciferase mRNA containing six identical miR2 target sites in the 3′-UTR was reduced by 40% when co-transfected with synthetic miR2, while the level of luciferase mRNA remained unaffected. Thus, miR2 likely affects translation but not mRNA stability. This repression, however, was not observed when Argonaute was knocked down in Giardia using a ribozyme-antisense RNA. Instead, an enhancement of luciferase expression was observed, suggesting a loss of endogenous miR2-mediated repression when this protein is depleted. Additionally, the level of miR2 was significantly reduced when Dicer was knocked down. In all, the evidence indicates the presence of a snoRNA-derived miRNA-mediated translational repression in Giardia

A New Approach to Population Sizing for Memetic Algorithms: A Case Study for the Multidimensional Assignment Problem

Memetic algorithms are known to be a powerful technique in solving hard optimization problems. To design a memetic algorithm, one needs to make a host of decisions. Selecting the population size is one of the most important among them. Most of the algorithms in the literature fix the population size to a certain constant value. This reduces the algorithm's quality since the optimal population size varies for different instances, local search procedures, and runtimes. In this paper we propose an adjustable population size. It is calculated as a function of the runtime of the whole algorithm and the average runtime of the local search for the given instance. Note that in many applications the runtime of a heuristic should be limited and, therefore, we use this bound as a parameter of the algorithm. The average runtime of the local search procedure is measured during the algorithm's run. Some coefficients which are independent of the instance and the local search are to be tuned at the design time;we provide a procedure to find these coefficients. The proposed approach was used to develop a memetic algorithm for the multidimensional assignment problem (MAP). We show that our adjustable population size makes the algorithm flexible to perform efficiently for a wide range of running times and local searches and this does not require any additional tuning of the algorithm

Manufacturing waste disposal practices of the chemical propulsion industry

The waste production, mitigation and disposal practices of the United States chemical propulsion industry have been investigated, delineated, and comparatively assessed to the U.S. industrial base. Special emphasis has been placed on examination of ozone depleting chemicals (ODC's). The research examines present and anticipated future practices and problems encountered in the manufacture of solid and liquid propulsion systems. Information collected includes current environmental laws and regulations that guide the industry practices, processes in which ODC's are or have been used, quantities of waste produced, funding required to maintain environmentally compliant practices, and preventive efforts

Deconvoluting heme biosynthesis to target blood-stage malaria parasites

Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. DOI: http://dx.doi.org/10.7554/eLife.09143.00

fenics_ice 1.0: A framework for quantifying initialisation uncertainty for time-dependent ice-sheet models

Mass loss due to dynamic changes in ice sheets is a significant contributor to sea level rise, and this contribution is expected to increase in the future. Numerical codes simulating the evolution of ice sheets can potentially quantify this future contribution. However, the uncertainty inherent in these models propagates into projections of sea level rise is and hence crucial to understand. Key variables of ice sheet models, such as basal drag or ice stiffness, are typically initialized using inversion methodologies to ensure that models match present observations. Such inversions often involve tens or hundreds of thousands of parameters, with unknown uncertainties and dependencies. The computationally intensive nature of inversions along with their high number of parameters mean traditional methods such as Monte Carlo are expensive for uncertainty quantification. Here we develop a framework to estimate the posterior uncertainty of inversions and project them onto sea level change projections over the decadal timescale. The framework treats parametric uncertainty as multivariate Gaussian and exploits the equivalence between the Hessian of the model and the inverse covariance of the parameter set. The former is computed efficiently via algorithmic differentiation, and the posterior covariance is propagated in time using a time-dependent model adjoint to produce projection error bars. This work represents an important step in quantifying the internal uncertainty of projections of ice sheet models.</p