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Atomic resolution experimental phase information reveals extensive disorder and bound 2-methyl-2,4-pentanediol in Ca(2+)-calmodulin. - Acta crystallographica. Section D, Structural biology
Calmodulin (CaM) is the primary calcium signaling protein in eukaryotes and has been extensively studied using various biophysical techniques. Prior crystal structures have noted the presence of ambiguous electron density in both hydrophobic binding pockets of Ca(2+)-CaM, but no assignment of these features has been made. In addition, Ca(2+)-CaM samples many conformational substates in the crystal and accurately modeling the full range of this functionally important disorder is challenging. In order to characterize these features in a minimally biased manner, a 1.0â€…Ã… resolution single-wavelength anomalous diffraction data set was measured for selenomethionine-substituted Ca(2+)-CaM. Density-modified electron-density maps enabled the accurate assignment of Ca(2+)-CaM main-chain and side-chain disorder. These experimental maps also substantiate complex disorder models that were automatically built using low-contour features of model-phased electron density. Furthermore, experimental electron-density maps reveal that 2-methyl-2,4-pentanediol (MPD) is present in the C-terminal domain, mediates a lattice contact between N-terminal domains and may occupy the N-terminal binding pocket. The majority of the crystal structures of target-free Ca(2+)-CaM have been derived from crystals grown using MPD as a precipitant, and thus MPD is likely to be bound in functionally critical regions of Ca(2+)-CaM in most of these structures. The adventitious binding of MPD helps to explain differences between the Ca(2+)-CaM crystal and solution structures and is likely to favor more open conformations of the EF-hands in the crystal.
Regulation of DJ-1 by glutaredoxin 1 in vivo - implications for Parkinson's disease. - Biochemistry
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH; and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. elegans, however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx-/- mice we provide evidence that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents; and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homolog in a C. elegans in vivo model of PD. Therefore; our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.
Incorporating Mobility in Growth Modeling for Multilevel and Longitudinal Item Response Data. - Multivariate behavioral research
Multilevel data often cannot be represented by the strict form of hierarchy typically assumed in multilevel modeling. A common example is the case in which subjects change their group membership in longitudinal studies (e.g., students transfer schools; employees transition between different departments). In this study, cross-classified and multiple membership models for multilevel and longitudinal item response data (CCMM-MLIRD) are developed to incorporate such mobility, focusing on students' school change in large-scale longitudinal studies. Furthermore, we investigate the effect of incorrectly modeling school membership in the analysis of multilevel and longitudinal item response data. Two types of school mobility are described, and corresponding models are specified. Results of the simulation studies suggested that appropriate modeling of the two types of school mobility using the CCMM-MLIRD yielded good recovery of the parameters and improvement over models that did not incorporate mobility properly. In addition, the consequences of incorrectly modeling the school effects on the variance estimates of the random effects and the standard errors of the fixed effects depended upon mobility patterns and model specifications. Two sets of large-scale longitudinal data are analyzed to illustrate applications of the CCMM-MLIRD for each type of school mobility.
Walking the tightrope: Proteostasis and neurodegenerative disease. - Journal of neurochemistry
A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-Î², Î±-synuclein or SOD1, many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration and location to be functional. In this review we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways and the active formation of inclusion, in neurodegenerative diseases associated with protein aggregation. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Methylammonium Bismuth Iodide as a Lead-Free, Stable Hybrid Organic-Inorganic Solar Absorber. - Chemistry (Weinheim an der Bergstrasse, Germany)
Methylammonium lead halide (MAPbX3 ) perovskites exhibit exceptional carrier transport properties. But their commercial deployment as solar absorbers is currently limited by their intrinsic instability in the presence of humidity and their lead content. Guided by our theoretical predictions, we explored the potential of methylammonium bismuth iodide (MBI) as a solar absorber through detailed materials characterization. We synthesized phase-pure MBI by solution and vapor processing. In contrast to MAPbX3 , MBI is air stable, forming a surface layer that does not increase the recombination rate. We found that MBI luminesces at room temperature, with the vapor-processed films exhibiting superior photoluminescence (PL) decay times that are promising for photovoltaic applications. The thermodynamic, electronic, and structural features of MBI that are amenable to these properties are also present in other hybrid ternary bismuth halide compounds. Through MBI, we demonstrate a lead-free and stable alternative to MAPbX3 that has a similar electronic structure and nanosecond lifetimes.Â© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
HelexKids: A word frequency database for Greek and Cypriot primary school children. - Behavior research methods
In this article, we introduce HelexKids, an online written-word database for Greek-speaking children in primary education (Grades 1 to 6). The database is organized on a grade-by-grade basis, and on a cumulative basis by combining Grade 1 with Grades 2 to 6. It provides values for Zipf, frequency per million, dispersion, estimated word frequency per million, standard word frequency, contextual diversity, orthographic Levenshtein distance, and lemma frequency. These values are derived from 116 textbooks used in primary education in Greece and Cyprus, producing a total of 68,692 different word types. HelexKids was developed to assist researchers in studying language development, educators in selecting age-appropriate items for teaching, as well as writers and authors of educational books for Greek/Cypriot children. The database is open access and can be searched online at www.helexkids.org .
Effect of molecular chaperones on aberrant protein oligomers in vitro: super- versus sub-stoichiometric chaperone concentrations. - Biological chemistry
Living systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 Î¼M, of two molecular chaperones, namely Î±B-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. Î±B-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasises the efficiency and versatility of these protein molecules.
Intramuscular diaphragmatic stimulation for patients with traumatic high cervical injuries and ventilator dependent respiratory failure: A systematic review of safety and effectiveness. - Injury
Intramuscular diaphragmatic stimulation using an abdominal laparoscopic approach has been proposed as a safer alternative to traditional phrenic nerve stimulation. It has also been suggested that early implementation of diaphragmatic pacing may prevent diaphragm atrophy and lead to earlier ventilator independence. The aim of this study was therefore to systematically review the safety and effectiveness of intramuscular diaphragmatic stimulators in the treatment of patients with traumatic high cervical injuries resulting in long-term ventilator dependence, with particular emphasis on the affect of timing of insertion of such stimulators.The Cochrane database and PubMed were searched between January 2000 and June 2015. Reference lists of selected papers were also reviewed. The inclusion criteria used to select from the pool of eligible studies were: (1) reported on adult patients with traumatic high cervical injury, who were ventilator-dependant, (2) patients underwent intramuscular diaphragmatic stimulation, and (3) commented on safety and/or effectiveness.12 articles were included in the review. Reported safety issues post insertion of intramuscular electrodes included pneumothorax, infection, and interaction with pre-existing cardiac pacemaker. Only one procedural failure was reported. The percentage of patients reported as independent of ventilatory support post procedure ranged between 40% and 72.2%. The mean delay of insertion ranged from 40 days to 9.7 years; of note the study with the average shortest delay in insertion reported the greatest percentage of fully weaned patients.Although evidence for intramuscular diaphragmatic stimulation in patients with high cervical injuries and ventilator dependent respiratory failure is currently limited, the technique appears to be safe and effective. Earlier implantation of such devices does not appear to be associated with greater surgical risk, and may be more effective. Further high quality studies are warranted to investigate the impact of delay of insertion on ventilator weaning.Copyright Â© 2016 Elsevier Ltd. All rights reserved.
T-cell-intrinsic Tif1Î±/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy. - Proceedings of the National Academy of Sciences of the United States of America
There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting Î±Î²(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1Î±)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)Î±Î²(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1Î²-mediated activation in vitro and in vivo, and fail to respond to IL-1Î²-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.
Social status drives social relationships in groups of unrelated female rhesus macaques. - Animal behaviour
Strong social relationships confer health and fitness benefits in a number of species, motivating the need to understand the processes through which they arise. In female cercopithecine primates, both kinship and dominance rank are thought to influence rates of affiliative behaviour and social partner preference. Teasing apart the relative importance of these factors has been challenging, however, as female kin often occupy similar positions in the dominance hierarchy. Here, we isolated the specific effects of rank on social relationships in female rhesus macaques by analysing grooming patterns in 18 social groups that did not contain close relatives, and in which dominance ranks were experimentally randomized. We found that grooming was asymmetrically directed towards higher-ranking females and that grooming bouts temporarily decreased the likelihood of aggression between grooming partners, supporting the idea that grooming is associated with social tolerance. Even in the absence of kin, females formed the strongest grooming relationships with females adjacent to them in rank, a pattern that was strongest for the highest-ranking females. Using simulations, we show that three rules for allocating grooming based on dominance rank recapitulated most of the relationships we observed. Finally, we evaluated whether a female's tendency to engage in grooming behaviour was stable across time and social setting. We found that one measure, the rate of grooming females provided to others (but not the rate of grooming females received), exhibited modest stability after accounting for the primary effect of dominance rank. Together, our findings indicate that dominance rank has strong effects on social relationships in the absence of kin, suggesting the importance of considering social status and social connectedness jointly when investigating their health and fitness consequences.
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