Memory for past events may be based on retrieval accompanied by specific contextual details (recollection) or on the feeling that an item is old (familiarity) or new (novelty) in the absence of ...contextual details. There are indications that recollection, familiarity, and novelty involve different medial temporal lobe subregions, but available evidence is scarce and inconclusive. Using functional magnetic resonance imaging (MRI), we isolated retrieval-related activity associated with recollection, familiarity, and novelty by distinguishing between linear and nonlinear oldness functions derived from recognition confidence levels. Within the medial temporal lobes (MTLs), we found a triple dissociation among the posterior half of the hippocampus, which was associated with recollection, the posterior parahippocampal gyrus, which was associated with familiarity, and anterior half of the hippocampus and rhinal regions, which were associated with novelty. Furthermore, multiple regression analyses based on individual trial activity showed that all three memory signals, i.e., recollection, familiarity, and novelty, make significant and independent contributions to recognition memory performance. Finally, functional dissociations among recollection, familiarity, and novelty were also found in posterior midline, left parietal cortex, and prefrontal cortex regions. This is the first study to reveal a triple dissociation within the MTL associated with distinct retrieval processes. This finding has direct implications for current memory models.
There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in ...major depressive episodes.
We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model.
Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD). Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h OR 7.06, number needed to treat (NNT) = 5, 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches.
Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment ...of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.
Chemoresistant ovarian cancers grow in suspension within the ascites fluid. To screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we ...developed a 3D hanging drop spheroid platform.
We initiated spheroids with primary aldehyde dehydrogenase-positive (ALDH
) CD133
ovarian cancer stem cells (OvCSC) from different patient samples and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immunodeficient mice. Drug responses to cisplatin and ALDH-targeting compound or JAK2 inhibitor determined whether the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor reemergence in a personalized manner.
OvCSC spheroids from different patients exhibited varying and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with a single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression, whereas those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH
cells.
Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating
and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology and model tumor reemergence to identify new targeted therapeutics from an effective personalized medicine standpoint.
.
Abstract Background Exercise is a potential treatment for depression. However, few studies have evaluated the role of adjunct exercise in the treatment of severely major depressed inpatients. The ...goal of this study was to evaluate the effects of add-on exercise on the usual treatment of severely depressed inpatients. Methods Fifty participants were randomized to an exercise (exercise + usual treatment) or a control (usual treatment) group. Twenty-five patients were randomly allocated to each group. The participants in the exercise group performed three sessions per week throughout the hospitalization period, with a goal dose of 16.5 kcal/kg/week plus the usual pharmacological treatment. Depressive symptoms and the Quality of Life (QoL) of the participants were assessed at the baseline, the second week, and discharge. Results A significant group × time interaction was found for depressive symptoms and the physical and psychological domains of QoL. Differences between groups occurred at the second week and discharge with respect to depressive symptoms and the physical and psychological domains of QoL. There was no difference in the remission rate at discharge (48% and 32% for the exercise and control group, respectively). An NNT of 6.25 was found. No significant baseline characteristics predict remission at discharge. Conclusion Add-on exercise is an efficacious treatment for severely depressed inpatients, improving their depressive symptoms and QoL. Initial acceptance of exercise remains a challenge.
Abstract
Cooling of particles to mK-temperatures is essential for a variety of experiments with trapped charged particles. However, many species of interest lack suitable electronic transitions for ...direct laser cooling. We study theoretically the remote sympathetic cooling of a single proton with laser-cooled
9
Be
+
in a double-Penning-trap system. We investigate three different cooling schemes and find, based on analytical calculations and numerical simulations, that two of them are capable of achieving proton temperatures of about 10 mK with cooling times on the order of 10 s. In contrast, established methods such as feedback-enhanced resistive cooling with image-current detectors are limited to about 1 K in 100 s. Since the studied techniques are applicable to any trapped charged particle and allow spatial separation between the target ion and the cooling species, they enable a variety of precision measurements based on trapped charged particles to be performed at improved sampling rates and with reduced systematic uncertainties.
The ASACUSA antihydrogen and hydrogen program: results and prospects Malbrunot, C.; Amsler, C.; Arguedas Cuendis, S. ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
03/2018, Letnik:
376, Številka:
2116
Journal Article
Recenzirano
Odprti dostop
The goal of the ASACUSA-CUSP collaboration at the Antiproton Decelerator of CERN is to measure the ground-state hyperfine splitting of antihydrogen using an atomic spectroscopy beamline. A milestone ...was achieved in 2012 through the detection of 80 antihydrogen atoms 2.7 m away from their production region. This was the first observation of 'cold' antihydrogen in a magnetic field free region. In parallel to the progress on the antihydrogen production, the spectroscopy beamline was tested with a source of hydrogen. This led to a measurement at a relative precision of 2.7×10−9 which constitutes the most precise measurement of the hydrogen hyperfine splitting in a beam. Further measurements with an upgraded hydrogen apparatus are motivated by CPT and Lorentz violation tests in the framework of the Standard Model Extension. Unlike for hydrogen, the antihydrogen experiment is complicated by the difficulty of synthesizing enough cold antiatoms in the ground state. The first antihydrogen quantum states scan at the entrance of the spectroscopy apparatus was realized in 2016 and is presented here. The prospects for a ppm measurement are also discussed.
This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.
Abstract Introduction Exercise have antidepressant effects in people with Major Depressive Disorder (MDD). However, about to half of patients do not respond to exercise. The identification of factors ...that moderates the antidepressant effects of exercise in people with MDD may help researchers and health professionals to identify sub-groups of patients that would benefit more from exercise. Methods A systematic review was carried out using Medline(PubMed), EMBASE and psycINFO up to April 2015. Individual and composite moderators were summarized and the strength of the evidence was assessed. Results Eleven studies were included for review resulting in the identification of potential individual (two biological, three clinical, two psychological and two social individual) and two potential composite moderators (the interaction between BDNF and Body Mass Index (BMI) and between family history of mental illness and gender). Only the two biological features and the BDNF x BMI interaction provided confirmatory evidence. Limitations Due the different statistical approaches used in the studies, it was not possible to perform meta-analyses. The small number of studies and the exploratory nature of the evidence limits a wider generalization of the findings. Conclusion Potential clinical, psychological, social or biological moderators were identified. However, the small number of studies and the limited strength of the evidence requires further studies before drawn definitive results. Further trials should consider the inclusion of moderators analysis using an a-priori , theoretical/evidence based hypothesis in order to provide high quality evidence for the use of personalized medicine in exercise for depression.
A consistent finding from functional neuroimaging studies of cognitive aging is an age-related reduction in occipital activity coupled with increased frontal activity. This posterior–anterior shift ...in aging (PASA) has been typically attributed to functional compensation. The present functional magnetic resonance imaging sought to 1) confirm that PASA reflects the effects of aging rather than differences in task difficulty; 2) test the compensation hypothesis; and 3) investigate whether PASA generalizes to deactivations. Young and older participants were scanned during episodic retrieval and visual perceptual tasks, and age-related changes in brain activity common to both tasks were identified. The study yielded 3 main findings. First, inconsistent with a difficulty account, the PASA pattern was found across task and confidence levels when matching performance among groups. Second, supporting the compensatory hypothesis, age-related increases in frontal activity were positively correlated with performance and negatively correlated with the age-related occipital decreases. Age-related increases and correlations with parietal activity were also found. Finally, supporting the generalizability of the PASA pattern to deactivations, aging reduced deactivations in posterior midline cortex but increased deactivations in medial frontal cortex. Taken together, these findings demonstrate the validity, function, and generalizability of PASA, as well as its importance for the cognitive neuroscience of aging.
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