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

Effects of dexamethasone on renal and systemic acid-base metabolism

Effects of dexamethasone on renal and systemic acid-base metabolism. We carried out long-term balance studies in adrenalectomized (ADX) dogs to evaluate the effects of small amounts of a glucocorticoid steroid with minimal mineralocorticoid potency (dexamethasone; DEX) on renal and systemic acid-base metabolism under conditions of constant mineralocorticoid replacement and both normal and increased systemic acid loads. We investigated the effects of low and high dosages of dexamethasone (0.2 mg/day [normal-DEX] vs. 0.8 mg/day [high-DEX]) before and during hydrochloric acid feeding (5 mmol/kg/day) in paired studies on ADX dogs (N = 7) maintained on constant mineralocorticoid replacement (deoxycorticosterone, corticosterone, aldosterone). Prior to hydrochloric acid feeding, no differences in plasma acid-base composition were observed between the two dosages despite greater endogenous acid production with the higher dosage of DEX, evidenced by greater rates of both net acid excretion (NAE) and the excretion of urinary anions other than chloride, bicarbonate, and phosphate (urine anion gap). During hydrochloric acid feeding, mean plasma bicarbonate (PHCO3) decreased from 21.2 ± 0.4 to 13.7 ± 0.5 (normal-DEX) and from 21.1 ± 0.4 to 15.8 ± 0.4 mEq/liter (high-DEX). The difference in the decrements in PHCO3 between groups was significant (P < 0.05). With continued hydrochloric acid feeding in both groups, increasing the DEX dosage from 0.2 to 0.8 mg/day in the normal-DEX group resulted in a. significant increase in NAE (ΣΔNAE, +161 mEq, P < 0.02) and in PHCO3 (+3.6 ± 0.5 mEq/liter, P < 0.01) to steady-state levels by day 10, which were values not significantly different from those in high-DEX. The DEX dose-related increase in NAE was greater than the corresponding increase in endogenous acid production estimated from the change in urine anion gap, and was due largely to an increase in ammonium excretion, which, because urine pH did not decrease, could not be attributed to increased intraluminal trapping of ammonia as a result of more acidic tubular fluid. These studies indicate that the severity of hydrochloric acid-induced metabolic acidosis in mineralocorticoid-replete ADX dogs can be mitigated by increasing the dosage of exogenous glucocorticoid and suggest that this acidosis mitigating effect is mediated in part by the increased NAE associated with the stimulation of renal ammonia production. These studies further indicate that the rate of production of fixed acids of metabolism increases with an increased dosage of exogenous glucocorticoid, but that this acidosis-producing effect is more than offset by independent stimulation of renal net acid excretion, such that metabolic acidosis is prevented (basal condition) or if present (hydrochloric acid feeding) is significantly ameliorated.Effets de la dexaméthasone sur le métabolisme acido-basique rénal et systémique. Les études de bilan qui sont rapportées ont été réalisées chez des chiens surrénalectomisés (ADX) pour évaluer les effets de faibles quantités d'un stéroïde glucocorticoïde, ayant une activité minéralocorticoïde faible (dexaméthasone; DEX), sur le métabolisme acido-basique rénal et systémique dans des conditions de traitement substitutif permanent de minéralocorticoïdes et de charge acide soit normale soit élevée. Nous avons étudié les effets de doses de dexaméthasone (0,2 mg/jour; normale-DEX) ou 0,8 mg/jour (élevée-DEX) avant et pendant l'administration d'acide chlorhydrique à raison de 5 mmol/kg/jour dans des études appariées chez des chiens ADX (N = 7) recevant un traitement substitutif par les minéralocorticoïdes (deoxycorticosterone acetate, corticosterone, aldosterone). Avant l'administration d'acide chlorhydrique, il n'y avait pas de différence dans la composition acido-basique du plasma selon les doses de DEX malgré l'augmentation de production endogène d'acide sous l'effet de la dose la plus élevée de DEX, augmentation traduite par une élévation de l'état stationnaire d'excrétion nette d'acide (NAE) et de la somme des débits d'excrétion des anions urinaires autres que le chlore, le bicarbonate et le phosphate (trou anionique urinaire). Au cours de l'administration d'acide chlorhydrique la concentration plasmatique moyenne de bicarbonate (PHCO3) a diminué de 21,2 ± 0,4 à 13,7 ± 0,5 (normale-DEX) et de 21,1 ± 0,4 à 15,8 ± 0,4 mEq/litre (élevée-DEX). La différence des diminutions de bicarbonate était significative (P < 0,05). Au cours de l'administration prolongée d'acide chlorhydrique aux deux groupes l'augmentation de la dose de DEX de 0,2 à 0,8 mg/jour dans le groupe normale-DEX a eu pour résultat une augmentation significative de NAE (ΣΔNAE, +161 mEq, P < 0,02) et de PHCO3 (+ 3,6 ± 0,5 mEq/litre, P < 0,01), jusqu'à de nouveaux états stationnaires, le jour 10, non sigmficativement différents de ceux observés dans le groupe élevée-DEX. L'augmentation de NAE dépendant de la dose de DEX a été plus grande que l'augmentation correspondante de la production endogène d'acide estimée à partir de la modification du trou anionique urinaire, elle était principalement due à une augmentation de l'excrétion d'ammonium qui, du fait que le pH de l'urine n'a pas diminué, ne peut pas être attribuée à une augmentation de la captation intraluminale d'ammonia. Ces résultats indiquent que la sévérité de l'acidose métabolique déterminée par acide chlorhydrique chez les chiens ADX recevant des minéralocorticoïdes peut être atténuée par l'augmentation de la dose de glucocorticoïdes exogènes et suggère que cet effet d'atténuation a pour médiateur partiel l'augmentation de NAE associée à la stimulation de la production rénale d'ammonia. Ces résultats indiquent, de plus, que le débit de production des acides fixes augmente en même temps que la dose de glucocorticoïdes exogènes mais que cet effet de production d'acidose est plus que compensé par la stimulation indépendante de l'excrétion rénale nette d'acide, de telle sorte que l'acidose métabolique est empêchée (conditions basales) ou significativement améliorée au cours de l'administration acide chlorhydrique

Acetylcholine induces fibrogenic effects via M2/M3 ACh receptors in NASH and in primary human hepatic stellate cells

BACKGROUND: The parasympathetic nervous system (PNS), via neurotransmitter Acetylcholine (ACh), modulates fibrogenesis in animal models. However, the role of ACh in human hepatic fibrogenesis is unclear. AIMS: We aimed to determine the fibrogenic responses of human hepatic stellate cells (hHSC) to ACh and the relevance of the PNS in hepatic fibrosis in patients with non-alcoholic steatohepatitis (NASH). METHODS: Primary hHSC were analysed for synthesis of endogenous ACh and acetylcholinesterase (AChE), and gene expression of choline acetyltransferase (ChAT) and muscarinic acetylcholine receptors (mAChR). Cell proliferation and fibrogenic markers were analysed in hHSC exposed to ACh, Atropine (Atrop), Mecamylamine (Mec), methoctramine and 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP). MAChR expression was analysed in human NASH scored for fibrosis. RESULTS: We observed that hHSC synthesise ACh and AChE, and express ChAT and M1-M5 mAChR. We also show that M2 was increased during NASH progression, while both M2 and M3 were found upregulated in activated hHSC. Furthermore, endogenous ACh is required for hHSC basal growth. Exogenous ACh resulted in hHSC hyperproliferation via mAChR and PI-3 K and MEK signalling pathways, as well as increased fibrogenic markers. CONCLUSION: We show that ACh regulates hHSC activation via M2 and M3 mAChR involving the PI-3 K and MEK pathways in vitro. Finally, we provide evidence that the PNS may be involved in human NASH fibrosis

Dynamics of trimming the content of face representations for categorization in the brain

To understand visual cognition, it is imperative to determine when, how and with what information the human brain categorizes the visual input. Visual categorization consistently involves at least an early and a late stage: the occipito-temporal N170 event related potential related to stimulus encoding and the parietal P300 involved in perceptual decisions. Here we sought to understand how the brain globally transforms its representations of face categories from their early encoding to the later decision stage over the 400 ms time window encompassing the N170 and P300 brain events. We applied classification image techniques to the behavioral and electroencephalographic data of three observers who categorized seven facial expressions of emotion and report two main findings: (1) Over the 400 ms time course, processing of facial features initially spreads bilaterally across the left and right occipito-temporal regions to dynamically converge onto the centro-parietal region; (2) Concurrently, information processing gradually shifts from encoding common face features across all spatial scales (e.g. the eyes) to representing only the finer scales of the diagnostic features that are richer in useful information for behavior (e.g. the wide opened eyes in 'fear'; the detailed mouth in 'happy'). Our findings suggest that the brain refines its diagnostic representations of visual categories over the first 400 ms of processing by trimming a thorough encoding of features over the N170, to leave only the detailed information important for perceptual decisions over the P300

Effective connectivity reveals strategy differences in an expert calculator

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material

Evaluando el progreso de la eficiencia con tecnología en una cadena de hoteles española

This paper analyzes the changes in the total factor productivity index of a Spanish hotel chain in the period from 2007 to 2010 with the purpose of identifying efficiency patterns for the chain in a period of financial crisis. The data envelopment analysis (DEA) Malmquist productivity index was used to estimate productivity change in 38 hotels of the AC chain. Results reveal AC hotels’ efficiency trends and, therefore, their competitiveness in the recession period; they also show the changes experienced in these hotels’ total productivity and its components: technological and efficiency changes. Positive efficiency changes were due to positive technical efficiency rather than technological efficiency. The recession period certainly influenced the performance of AC Hotels, which focused on organizational changes rather than investing in technology.Este artigo analisa as mudanças no fator total de produtividade de uma cadeia de hotéis na Espanha, no período de 2007-2010, com o propósito de identificar os padrões da cadeia em um período de crise financeira. O índice data envelopment analysis (DEA) Malmquist de produtividade foi usado para estimar a mudança da produtividade nos 38 hotéis da AC Cadeia de Hotéis. Os resultados revelaram as tendências de eficiência e competitividade da AC Hotéis em um período de recessão, bem como as mudanças vivenciadas na produtividade total e, consequentemente, em seus componentes de eficiência e tecnológicos. O período de recessão influenciou, sem dúvida, o comportamento da AC Hotéis, que buscou mais mudanças organizacionais do que tecnológicas.Este artículo analiza los cambios del índice de productividad del factor total de una cadena de hoteles españoles en el periodo de 2007 hasta 2010, con el propósito de identificar patrones de eficiencia para la cadena en un periodo de crisis financiera. El índice de productividad data envelopment analysis (DEA) Malmquist fue utilizado para estimar el cambio de productividad en 38 hoteles de la cadena AC. Los resultados revelan las tendencias de la eficiencia de los hoteles AC y, por lo tanto, su competitividad en el periodo de recisión; ellos también demuestran los cambios experimentados en la productividad total de eses hoteles y sus componentes: cambios de eficiencia y tecnológicos. Cambios de eficiencia positivos se debieron más bien a eficiencias técnicas positivas que a eficiencias tecnológicas. El periodo de recesión ciertamente ha influenciado los Hoteles AC, que enfocaron más en los cambios organizacionales que en invirtiendo en tecnología

Labor Productivity - The Use of Staffing Guides and Other Productivity Methods in U.S. Hotels: A Survey Study

This paper examines the issue of labor productivity in hotels. It elaborates on various measurement methods used by American hoteliers including staffing guides, with a special focus on productivity standards. Advantages of physical, financial and mixed methods such as percentage methods, revenue per employee, value-added, Data Envelope Analysis and Stochastic Frontier Analysis are discussed. While the use of percentages and staffing guides were found to be commonplace, results revealed that some fairly stable standards were already in place in the surveyed hotels. Results also revealed that at least in the surveyed companies, few hoteliers attempted to monitor or improve revenue per employee, focusing instead on physical labor inputs and outputs or simple labor percentages

Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis

Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions

The `Parahippocampal Place Area' Responds Selectively to High Spatial Frequencies

Defining the exact mechanisms by which the brain processes visual objects and scenes remains an unresolved challenge. Valuable clues to this process have emerged from the demonstration that clusters of neurons (“modules”) in inferior temporal cortex apparently respond selectively to specific categories of visual stimuli, such as places/scenes. However, the higher-order “category-selective” response could also reflect specific lower-level spatial factors. Here we tested this idea in multiple functional MRI experiments, in humans and macaque monkeys, by systematically manipulating the spatial content of geometrical shapes and natural images. These tests revealed that visual spatial discontinuities (as reflected by an increased response to high spatial frequencies) selectively activate a well-known place-selective region of visual cortex (the “parahippocampal place area”) in humans. In macaques, we demonstrate a homologous cortical area, and show that it also responds selectively to higher spatial frequencies. The parahippocampal place area may use such information for detecting object borders and scene details during spatial perception and navigation.National Institutes of Health (U.S.) (NIH Grant R01 MH6752)National Institutes of Health (U.S.) (grant R01 EY017081)Athinoula A. Martinos Center for Biomedical ImagingNational Center for Research Resources (U.S.)Mind Research Institut