Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice

Towards a structure-based exciton Hamiltonian for the CP29 antenna of photosystem II

The exciton Hamiltonian pertaining to the first excited states of chlorophyll (Chl) a and b pigments in the minor light-harvesting complex CP29 of plant photosystem II is determined based on the recent crystal structure at 2.8 Å resolution applying a combined quantum chemical/electrostatic approach as used earlier for the major light-harvesting complex LHCII. Two electrostatic methods for the calculation of the local transition energies (site energies), referred to as the Poisson–Boltzmann/quantum chemical (PBQC) and charge density coupling (CDC) method, which differ in the way the polarizable environment of the pigments is described, are compared and found to yield comparable results, when tested against fits of measured optical spectra (linear absorption, linear dichroism, circular dichroism, and fluorescence). The crystal structure shows a Chl a/b ratio of 2.25, whereas a ratio between 2.25 and 3.0 can be estimated from the simulation of experimental spectra. Thus, it is possible that up to one Chl b is lost in CP29 samples. The lowest site energy is found to be located at Chl a604 close to neoxanthin. This assignment is confirmed by the simulation of wild-type-minus-mutant difference spectra of reconstituted CP29, where a tyrosine residue next to Chl a604 is modified in the mutant. Nonetheless, the terminal emitter domain (TED), i.e. the pigments contributing mostly to the lowest exciton state, is found at the Chl a611–a612–a615 trimer due to strong excitonic coupling between these pigments, with the largest contributions from Chls a611 and a612. A major difference between CP29 and LHCII is that Chl a610 is not the energy sink in CP29, which is presumably to a large extent due to the replacement of a lysine residue with alanine close to the TED

Creatine kinase B deficient neurons exhibit an increased fraction of motile mitochondria

Contains fulltext : 69450.pdf ( ) (Open Access)BACKGROUND: Neurons require an elaborate system of intracellular transport to distribute cargo throughout axonal and dendritic projections. Active anterograde and retrograde transport of mitochondria serves in local energy distribution, but at the same time also requires input of ATP. Here we studied whether brain-type creatine kinase (CK-B), a key enzyme for high-energy phosphoryl transfer between ATP and CrP in brain, has an intermediary role in the reciprocal coordination between mitochondrial motility and energy distribution. Therefore, we analysed the impact of brain-type creatine kinase (CK-B) deficiency on transport activity and velocity of mitochondria in primary murine neurons and made a comparison to the fate of amyloid precursor protein (APP) cargo in these cells, using live cell imaging. RESULTS: Comparison of average and maximum transport velocities and global transport activity showed that CK-B deficiency had no effect on speed of movement of mitochondria or APP cargo, but that the fraction of motile mitochondria was significantly increased by 36% in neurons derived from CK-B knockout mice. The percentage of motile APP vesicles was not altered. CONCLUSION: CK-B activity does not directly couple to motor protein activity but cells without the enzyme increase the number of motile mitochondria, possibly as an adaptational strategy aimed to enhance mitochondrial distribution versatility in order to compensate for loss of efficiency in the cellular network for ATP distribution

Bandit Models of Human Behavior: Reward Processing in Mental Disorders

Drawing an inspiration from behavioral studies of human decision making, we propose here a general parametric framework for multi-armed bandit problem, which extends the standard Thompson Sampling approach to incorporate reward processing biases associated with several neurological and psychiatric conditions, including Parkinson's and Alzheimer's diseases, attention-deficit/hyperactivity disorder (ADHD), addiction, and chronic pain. We demonstrate empirically that the proposed parametric approach can often outperform the baseline Thompson Sampling on a variety of datasets. Moreover, from the behavioral modeling perspective, our parametric framework can be viewed as a first step towards a unifying computational model capturing reward processing abnormalities across multiple mental conditions.Comment: Conference on Artificial General Intelligence, AGI-1

Recommendations for Combining Action Observation and Motor Imagery Interventions in Sport

Combined action observation and motor imagery (AOMI) interventions involve observing a movement demonstration, usually via video, whilst at the same time imagining the feelings and sensations involved in executing the observed action. Research findings indicate that AOMI interventions can be effective for improving sport performance, yet no guidelines currently exist within the literature to inform applied sport psychologists how to develop and implement AOMI interventions with athletes. The aim of this article is to address this gap in the applied sport psychology literature. Accordingly, the article provides an overview of the ‘Science of AOMI’ by discussing the neurophysiological, cognitive, psychological and performance effects of AOMI interventions to introduce the concept of AOMI and potential benefits of AOMI interventions in sport. The article then covers the ‘Practice of AOMI’ by discussing practical recommendations for applied sport psychologists on how to develop and implement AOMI interventions for performance enhancement purposes. Important considerations related to filming the action observation video are discussed, such as selection of the model and choice of visual perspective. Guidelines are then provided for developing and delivering personalized kinesthetic imagery instructions for use by the athlete in synchrony with action observation

Recommendations for Combining Action Observation and Motor Imagery Interventions in Sport

Copyright © 2021 the author(s). Combined action observation and motor imagery (AOMI) interventions involve observing a movement demonstration, usually via video, whilst at the same time imagining the feelings and sensations involved in executing the observed action. Research findings indicate that AOMI interventions can be effective for improving sport performance, yet no guidelines currently exist within the literature to inform applied sport psychologists how to develop and implement AOMI interventions with athletes. The aim of this article is to address this gap in the applied sport psychology literature. Accordingly, the article provides an overview of the ‘Science of AOMI’ by discussing the neurophysiological, cognitive, psychological and performance effects of AOMI interventions to introduce the concept of AOMI and potential benefits of AOMI interventions in sport. The article then covers the ‘Practice of AOMI’ by discussing practical recommendations for applied sport psychologists on how to develop and implement AOMI interventions for performance enhancement purposes. Important considerations related to filming the action observation video are discussed, such as selection of the model and choice of visual perspective. Guidelines are then provided for developing and delivering personalized kinesthetic imagery instructions for use by the athlete in synchrony with action observation

Determinants of daily smoking in Turkish young adults in the Netherlands

BACKGROUND: As little is known about the determinants of smoking in large ethnic minorities in the Netherlands and other Western European countries, we studied the determinants of smoking young adult offspring of Turkish migrants to the Netherlands. METHODS: Cross-sectional survey of 439 Turkish adults (18–28 y) in 2003. Smokers were compared with never smokers for five groups of determinants: demographic and socioeconomic factors, behavioral and emotional problems, psychosocial factors, and cultural factors. Associations were measured by prevalence rate ratios. RESULTS: Prevalences for men were 51% for daily smoking, 12% for former smoking, and 38% for never smoking. For women they were 44%, 11%, and 47%, respectively. Without adjustment for other determinants, higher prevalence was associated with: emotional problems, boredom, life events, and being male; and, specifically among women, with low self-esteem and having children. The strongest determinants of daily smoking In multivariate models were alcohol use and demographic and socio-economic factors. Of the cultural factors only strong Muslim identification was associated with lower smoking prevalence. CONCLUSION: The high prevalence of smoking warrants action. Many of the well-known determinants of smoking in Western countries were also important among young adults from ethnic minorities. Women with children and people of a low educational level deserve special attention

Serum Dioxin-like Activity Is Associated with Reproductive Parameters in Young Men from the General Flemish Population

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented. OBJECTIVE: The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium. DESIGN: In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20–40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay. RESULTS: Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology. CONCLUSIONS: These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such

Challenges and Perspectives of Quantitative Functional Sodium Imaging (fNaI).

Brain function has been investigated via the blood oxygenation level dependent (BOLD) effect using magnetic resonance imaging (MRI) for the past decades. Advances in sodium imaging offer the unique chance to access signal changes directly linked to sodium ions (23Na) flux across the cell membrane, which generates action potentials, hence signal transmission in the brain. During this process 23Na transiently accumulates in the intracellular space. Here we show that quantitative functional sodium imaging (fNaI) at 3T is potentially sensitive to 23Na concentration changes during finger tapping, which can be quantified in gray and white matter regions key to motor function. For the first time, we measured a 23Na concentration change of 0.54 mmol/l in the ipsilateral cerebellum, 0.46 mmol/l in the contralateral primary motor cortex (M1), 0.27 mmol/l in the corpus callosum and -11 mmol/l in the ipsilateral M1, suggesting that fNaI is sensitive to distributed functional alterations. Open issues persist on the role of the glymphatic system in maintaining 23Na homeostasis, the role of excitation and inhibition as well as volume distributions during neuronal activity. Haemodynamic and physiological signal recordings coupled to realistic models of tissue function will be critical to understand the mechanisms of such changes and contribute to meeting the overarching challenge of measuring neuronal activity in vivo