Ferredoxin-NADP(+) reductase from Plasmodium falciparum undergoes NADP(+)-dependent dimerization and inactivation: functional and crystallographic analysis

The completion of the Plasmodium falciparum genome sequence has recently promoted the search for new antimalarial drugs. More specifically, metabolic pathways of the apicoplast, a key organelle for survival of the parasite, have been recognized as potential targets for the development of specific new antimalarial agents. As most apicomplexan parasites, P. falciparum displays a plant-type ferredoxin-NADP(+) reductase, yielding reduced ferredoxin for essential biosynthetic pathways in the apicoplast. Here we report a molecular, kinetic and ligand binding characterization of the recombinant ferredoxin-NADP(+) reductase from P. falciparum, in the light of current data available for plant ferredoxin-NADP(+) reductases. In parallel with the functional characterization, we describe the crystal structures of P. falciparum ferredoxin-NADP(+) reductase in free form and in complex with 2'-phospho-AMP (at 2.4 and 2.7 A resolution, respectively). The enzyme displays structural properties likely to be unique to plasmodial reductases. In particular, the two crystal structures highlight a covalent dimer, which relies on the oxidation of residue Cys99 in two opposing subunits, and a helix-coil transition that occurs in the NADP-binding domain, triggered by 2'-phospho-AMP binding. Studies in solution show that NADP(+), as well as 2'-phospho-AMP, promotes the formation of the disulfide-stabilized dimer. The isolated dimer is essentially inactive, but full activity is recovered upon disulfide reduction. The occurrence of residues unique to the plasmodial enzyme, and the discovery of specific conformational properties, highlight the NADP-binding domain of P. falciparum ferredoxin-NADP(+) reductase as particularly suited for the rational development of antimalarial compounds

Resting lateralized activity predicts the cortical response and appraisal of emotions : an fNIRS study

This study explored the effect of lateralized left-right resting brain activity on prefrontal cortical responsiveness to emotional cues and on the explicit appraisal (stimulus evaluation) of emotions based on their valence. Indeed subjective responses to different emotional stimuli should be predicted by brain resting activity and should be lateralized and valence-related (positive vs negative valence). A hemodynamic measure was considered (functional near-infrared spectroscopy). Indeed hemodynamic resting activity and brain response to emotional cues were registered when subjects (N = 19) viewed emotional positive vs negative stimuli (IAPS). Lateralized index response during resting state, LI (lateralized index) during emotional processing and self-assessment manikin rating were considered. Regression analysis showed the significant predictive effect of resting activity (more left or right lateralized) on both brain response and appraisal of emotional cues based on stimuli valence. Moreover, significant effects were found as a function of valence (more right response to negative stimuli; more left response to positive stimuli) during emotion processing. Therefore, resting state may be considered a predictive marker of the successive cortical responsiveness to emotions. The significance of resting condition for emotional behavior was discussed

Brains in Competition: Improved Cognitive Performance and Inter-Brain Coupling by Hyperscanning Paradigm with Functional Near-Infrared Spectroscopy

Hyperscanning brain paradigm was applied to competitive task for couples of subjects. Functional Near-Infrared Spectroscopy (fNIRS) and cognitive performance were considered to test inter-brain and cognitive strategy similarities between subjects (14 couples) during a joint-action. We supposed increased brain-to-brain coupling and improved cognitive outcomes due to joint-action and the competition. As supposed, the direct interaction between the subjects and the observed external feedback of their performance (an experimentally induced fictitious feedback) affected the cognitive performance with decreased Error Rates (ERs), and Response Times (RTs). In addition, fNIRS measure (oxyhemoglobin, O2Hb) revealed an increased brain activity in the prefrontal cortex (PFC) in post-feedback more than pre-feedback condition. Moreover, a higher inter-brain similarity was found for the couples during the task, with higher matched brain response in post-feedback condition than pre-feedback. Finally, a significant increased prefrontal brain lateralization effect was observed for the right hemisphere. Indeed the right PFC was more responsive with similar modalities within the couple during the post-feedback condition. The joined-task and competitive context was adduced to explain these cognitive performance improving, synergic brain responsiveness within the couples and lateralization effects (negative emotions)

Sociol Health Illn

The association between education or income and mortality has been explored in great detail. These measures capture both the effects of material disadvantage on health and the psychosocial impacts of a low socioeconomic position on health. When explored independently of educational attainment and income, occupational prestige - a purely perceptual measure - serves as a measure of the impact of a psychosocial phenomenon on health. For instance, a fire-fighter, academician or schoolteacher may carry the social benefits of a higher social status without actually having the income (in all cases) or the educational credentials (in the case of the fire-fighter) to match. We explored the independent influence of occupational prestige on mortality. We applied Cox proportional hazards models to a nationally representative sample of over 380,000 US workers who had worked at any time between 1986 and 1994 with mortality follow up through 2002. We found that occupational prestige is associated with a decrease in the risk of all-cause, cancer, cardiovascular and respiratory-related mortality after controlling for household income and educational attainment. We further investigated the question of whether the effects of prestige are moderated by sex and broader occupational groupings. Prestige effects operate in white-collar occupations for men only and within service occupations for all workers.R01 OH003915/OH/NIOSH CDC HHS/United StatesR010H003915/PHS HHS/United States2016-08-19T00:00:00Z22443309PMC499136

Event-related alpha suppression in response to facial motion

This article has been made available through the Brunel Open Access Publishing Fund.While biological motion refers to both face and body movements, little is known about the visual perception of facial motion. We therefore examined alpha wave suppression as a reduction in power is thought to reflect visual activity, in addition to attentional reorienting and memory processes. Nineteen neurologically healthy adults were tested on their ability to discriminate between successive facial motion captures. These animations exhibited both rigid and non-rigid facial motion, as well as speech expressions. The structural and surface appearance of these facial animations did not differ, thus participants decisions were based solely on differences in facial movements. Upright, orientation-inverted and luminance-inverted facial stimuli were compared. At occipital and parieto-occipital regions, upright facial motion evoked a transient increase in alpha which was then followed by a significant reduction. This finding is discussed in terms of neural efficiency, gating mechanisms and neural synchronization. Moreover, there was no difference in the amount of alpha suppression evoked by each facial stimulus at occipital regions, suggesting early visual processing remains unaffected by manipulation paradigms. However, upright facial motion evoked greater suppression at parieto-occipital sites, and did so in the shortest latency. Increased activity within this region may reflect higher attentional reorienting to natural facial motion but also involvement of areas associated with the visual control of body effectors. © 2014 Girges et al

Molecular-biology-driven treatment for metastatic colorectal cancer

Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients

Moderate aerobic exercise (brisk walking) increases bone density in cART-treated persons

Moderate intensity aerobic activity reduces the risk of cardiovascular disease, diabetes and metabolic syndrome in the general population and has a potential in preventing bone loss. We evaluated the effects of brisk walking, with or without strength exercise, on bone mineral density in HIV-infected treated persons. Twenty-eight HIV-infected, cART-treated, sedentary subjects with VL<50 c/mL were enrolled in a 12-week exercise program, consisting of 3 outdoor sessions/week of 60 min walking at 67–70% of HR (heart rate) max±30 min circuit training at 65% of 1-RM (repetition maximum). Subjects were examined at baseline (BL) and 12 weeks (W12) by 6-minute walking test (6MWT) and by counting the number of repetitions for each strength exercise; and by dual energy X-ray absorptiometry (DEXA) to evaluate lumbar spine and femoral bone mineral density with t- and z-scores - in addition to morphometric (BMI, waist, hip and leg circumference) and blood examination (cytometry, fasting total, HDL and LDL cholesterol, triglycerides, glucose, insulin; AST/ALT, ALP, gGT, creatinine, CPK, HbA1c; CD4+ and CD8+, plasma HIV-RNA). Differences over time were tested by Wilcoxon-signed rank test and between groups by Mann-Whitney test. Twenty-seven (96%) participants (19M, 8F; median 48 y-o, IQR 43–54; median CD4+624/µL, IQR 478–708; ART with PI: 13 patients, with NNRTI: 7 patients, and including TDF: 15 patients) completed the 12-week program with a median adherence of 61% (IQR 50–70): 18 in the ‘walk only’ only group and 9 in the ‘walk and strength’ group. At W12, participants showed significant improvement of distance by 6MWT (Table), and of performance in all strength exercises (crunch p=0.023, lat machine p=0.016, chest press p=0.016, leg extension p=0.016, sitting calf p=0.008, leg press p=0.016). DEXA spine z-score improved significantly in the whole group, and femoral z-scores in the ‘walk only’ group. There was no z-score difference at BL between patients with/out PIs, NNRTIs or TDF. However, spine z-score improved significantly in patients receiving TDF. At W12 BMI, waist circumference, and LDL also improved significantly in the whole group, whereas no significant changes were observed for the other variables, The above 12-week program improved fitness and bone density in HIV-infected treated subjects, in addition to some morphometric variables and serum LDL. Brisk walking, with or without strength exercise, might help control the long-term consequences of cART