Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease:A task-based fMRI study

Background: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. Aims: To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease. Methods: In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease. Results: Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. Conclusions: Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations

Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites

Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5′-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites

Two-photon ionization of Helium studied with the multiconfigurational time-dependent Hartree-Fock method

The multiconfigurational time-dependent Hartree-Fock method (MCTDHF) is applied for simulations of the two-photon ionization of Helium. We present results for the single- and double ionization from the groundstate for photon energies in the non-sequential regime, and compare them to direct solutions of the Schr\"odinger equation using the time-dependent (full) Configuration Interaction method (TDCI). We find that the single-ionization is accurately reproduced by MCTDHF, whereas the double ionization results correctly capture the main trends of TDCI

Gamma-Ray Lines from Asymmetric Supernovae

We present 3-dimensional SPH simulations of supernova explosions from 100 seconds to 1 year after core-bounce. By extending our modelling efforts to a 3-dimensional hydrodynamics treatment, we are able to investigate the effects of explosion asymmetries on mixing and gamma-ray line emergence in supernovae. A series of initial explosion conditions are implemented, including jet-like and equatorial asymmetries of varying degree. For comparison, symmetric explosion models are also calculated. A series of time slices from the explosion evolution are further analyzed using a 3-dimensional Monte Carlo gamma-ray transport code. The emergent hard X- and gamma-ray spectra are calculated as a function of both viewing angle and time, including trends in the gamma-ray line profiles. We find significant differences in the velocity distribution of radioactive nickel between the symmetric and asymmetric explosion models. The effects of this spatial distribution change are reflected in the overall high energy spectrum, as well as in the individual gamma-ray line profiles.Comment: 32 pages, 14 figures, LAUR-02-6114, http://qso.lanl.gov/~clf "Clumping Asymmetry" section revise

Do Water Safety Lessons Improve Water Safety Knowledge?

A person, usually a child or young adult, dies by drowning every 90 seconds around the planet. Most drowning prevention initiatives do not assess the efficacy of the intervention. In this study, thirteen- to fourteen-year-olds had their level of water safety knowledge (covering cold shock, rips and tides) assessed before, just after, and 3-6 months after one, 25-minute water safety lesson on these topics. We evaluated the knowledge gained and retained on water safety “awareness” (i.e., knowledge of risks) and “confidence” in terms of knowing what to do in an emergency. The results demonstrated that the lesson significantly increased water safety awareness and confidence in pupils, and these benefits were retained for at least six months. We accept our hypothesis that theoretical, classroom-based instruction in water safety can improve the water safety awareness and confidence of children and may represent a “lesson for life.” Given the large numbers who drown around the globe annually, a lesson on water safety should be part of every national curriculum

Conditional U1 gene silencing in Toxoplasma gondii

The functional characterisation of essential genes in apicomplexan parasites, such as Toxoplasma gondii or Plasmodium falciparum, relies on conditional mutagenesis systems. Here we present a novel strategy based on U1 snRNP-mediated gene silencing. U1 snRNP is critical in pre-mRNA splicing by defining the exon-intron boundaries. When a U1 recognition site is placed into the 3’-terminal exon or adjacent to the termination codon, pre-mRNA is cleaved at the 3’-end and degraded, leading to an efficient knockdown of the gene of interest (GOI). Here we describe a simple method that combines endogenous tagging with DiCre-mediated positioning of U1 recognition sites adjacent to the termination codon of the GOI which leads to a conditional knockdown of the GOI upon rapamycin-induction. Specific knockdown mutants of the reporter gene GFP and several endogenous genes of T. gondii including the clathrin heavy chain gene 1 (chc1), the vacuolar protein sorting gene 26 (vps26), and the dynamin-related protein C gene (drpC) were silenced using this approach and demonstrate the potential of this technology. We also discuss advantages and disadvantages of this method in comparison to other technologies in more detail

Phylogenetic patterns of foliar mineral nutrient accumulation among gypsophiles and their relatives in the Chihuahuan Desert

PREMISE OF THE STUDY: Gypsum endemism in plants (gypsophily) is common on gypsum outcrops worldwide, but little is known about the functional ecology of Chihuahuan Desert gypsophiles. We investigated whether leaf chemistry of gypsophile lineages from the northern Chihuahuan Desert are similar to leaves of related nonendemic (gypsovag) species relative to their soil chemistry. We expected widely distributed gypsophiles (hypothesized to be older lineages on gypsum) would have distinct leaf chemistry from narrowly distributed, relatively younger lineages endemic to gypsum and gypsovags, reflecting adaptation to gypsum. METHODS: We collected leaves from 23 gypsophiles and related nonendemic taxa growing on nongypsum soils. Soils and leaves were analyzed for Ca, S, Mg, K, N, and P. Leaf gypsum was assessed using Fourier transform infrared spectroscopy. KEY RESULTS: Most widespread gypsophile lineages that are hypothesized to be relatively old accumulate foliar S, Ca, and gypsum, but younger gypsophile lineages and closely related gypsovags do not. Young, narrowly distributed gypsophile lineages have leaf chemical signatures similar to nonendemic congeners and confamilials. CONCLUSIONS: Our data suggest multiple adaptive mechanisms support life on gypsum in Chihuahuan Desert gypsophiles. Most widespread gypsophiles are specialized for life on gypsum, likely due to shared abilities to accumulate and assimilate S and Ca in leaves. In contrast, narrowly distributed gypsophiles may have mechanisms to exclude excess S and Ca from their leaves, preventing toxicity. Future work will investigate the nutrient accumulation and exclusion patterns of other plant organs to determine at what level excess S and Ca uptake is restricted for young-lineage gypsophiles and gypsovags

Safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial: statistical analysis plan.

BACKGROUND: There is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE). Data on the mechanisms of B cell depletion in SLE indicate that the combination of rituximab and belimumab may be more effective than rituximab alone. The safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial aims to determine whether belimumab is superior to placebo, when given 4-8 weeks after treatment with rituximab. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: BEAT-LUPUS is a randomised, double-blind, phase II trial of 52 weeks of belimumab versus placebo, initiated 4-8 weeks after rituximab treatment. The primary outcome is anti-dsDNA antibodies at 52 weeks post randomisation. Secondary outcomes include lupus flares and damage, adverse events, doses of concomitant medications, quality of life, and clinical biomarkers. We describe the trial's clinical context, outcome measures, sample size calculation, and statistical modelling strategy, and the supportive analyses planned to evaluate for mediation of the treatment effect through changes in concomitant medication doses and bias from missing data. DISCUSSION: The analysis will provide detailed information on the safety and effectiveness of belimumab. It will be implemented from July 2020 when patient follow-up and data collection is complete. TRIAL REGISTRATION: ISRCTN: 47873003 . Registered on 28 November 2016. EudracT: 2015-005543-14 . Registered on 19 November 2018

Adaptive evolution of molecular phenotypes

Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.Comment: Figures are not optimally displayed in Firefo

The efficacy and safety of adrenergic blockade post burn injury: a systematic review and meta-analysis

BACKGROUND The hypermetabolic state after severe burns is a major problem that can lead to several pathophysiologic changes and produce multiple sequelae. Adrenergic blockade has been widely used to reverse these changes and improve outcomes in burned patients but has not been rigorously evaluated. The aim of this systematic review was to investigate the efficacy and safety of the use of adrenergic blockade after burn injury