Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids

Inadequate immunomodulatory potency of mesenchymal stem cells (MSC) may limit their therapeutic efficacy. We report glucocorticoid steroids augment MSC expression and activity of indoleamine-2,3-dioxygenase (IDO), a primary mediator of MSC immunomodulatory function. This effect depends on signaling through the glucocorticoid receptor and is mediated through up-regulation of FOXO3. Treatment of MSCs with glucocorticoids, budesonide or dexamethasone, enhanced IDO expression following IFN-γ stimulation in multiple donors and was able to restore IDO expression in over-passaged MSCs. As IDO enhancement was most notable when cells were continuously exposed to budesonide, we engineered MSC with budesonide loaded PLGA microparticles. MSC efficiently internalized budesonide microparticles and exhibited 4-fold enhanced IDO activity compared to budesonide preconditioned and naïve MSC, resulting in a 2-fold improvement in suppression of stimulated peripheral blood mononuclear cells in an IDO-dependent manner. Thus, the augmentation of MSC immune modulation may abrogate challenges associated with inadequate potency and enhance their therapeutic efficacy

Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway

<p>Abstract</p> <p>Background</p> <p>Protein kinase CK2 is a pleiotropic serine/threonine protein kinase with hundreds of reported substrates, and plays an important role in a number of cellular processes. The cellular functions of <it>Plasmodium falciparum </it>CK2 (PfCK2) are unknown. The parasite's genome encodes one catalytic subunit, PfCK2α, which we have previously shown to be essential for completion of the asexual erythrocytic cycle, and two putative regulatory subunits, PfCK2β1 and PfCK2β2.</p> <p>Results</p> <p>We now show that the genes encoding both regulatory PfCK2 subunits (PfCK2β1 and PfCK2β2) cannot be disrupted. Using immunofluorescence and electron microscopy, we examined the intra-erythrocytic stages of transgenic parasite lines expressing hemagglutinin (HA)-tagged catalytic and regulatory subunits (HA-CK2α, HA-PfCK2β1 or HA-PfCK2β2), and localized all three subunits to both cytoplasmic and nuclear compartments of the parasite. The same transgenic parasite lines were used to purify PfCK2β1- and PfCK2β2-containing complexes, which were analyzed by mass spectrometry. The recovered proteins were unevenly distributed between various pathways, with a large proportion of components of the chromatin assembly pathway being present in both PfCK2β1 and PfCK2β2 precipitates, implicating PfCK2 in chromatin dynamics. We also found that chromatin-related substrates such as nucleosome assembly proteins (Naps), histones, and two members of the Alba family are phosphorylated by PfCK2α <it>in vitro</it>.</p> <p>Conclusions</p> <p>Our reverse-genetics data show that each of the two regulatory PfCK2 subunits is required for completion of the asexual erythrocytic cycle. Our interactome study points to an implication of PfCK2 in many cellular pathways, with chromatin dynamics being identified as a major process regulated by PfCK2. This study paves the way for a kinome-wide interactomics-based approach to elucidate protein kinase function in malaria parasites.</p

Open-ended evolution to discover analogue circuits for beyond conventional applications

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10710-012-9163-8. Copyright @ Springer 2012.Analogue circuits synthesised by means of open-ended evolutionary algorithms often have unconventional designs. However, these circuits are typically highly compact, and the general nature of the evolutionary search methodology allows such designs to be used in many applications. Previous work on the evolutionary design of analogue circuits has focused on circuits that lie well within analogue application domain. In contrast, our paper considers the evolution of analogue circuits that are usually synthesised in digital logic. We have developed four computational circuits, two voltage distributor circuits and a time interval metre circuit. The approach, despite its simplicity, succeeds over the design tasks owing to the employment of substructure reuse and incremental evolution. Our findings expand the range of applications that are considered suitable for evolutionary electronics

Bio-Inspired Multi-Layer Spiking Neural Network Extracts Discriminative Features from Speech Signals

Spiking neural networks (SNNs) enable power-efficient implementations due to their sparse, spike-based coding scheme. This paper develops a bio-inspired SNN that uses unsupervised learning to extract discriminative features from speech signals, which can subsequently be used in a classifier. The architecture consists of a spiking convolutional/pooling layer followed by a fully connected spiking layer for feature discovery. The convolutional layer of leaky, integrate-and-fire (LIF) neurons represents primary acoustic features. The fully connected layer is equipped with a probabilistic spike-timing-dependent plasticity learning rule. This layer represents the discriminative features through probabilistic, LIF neurons. To assess the discriminative power of the learned features, they are used in a hidden Markov model (HMM) for spoken digit recognition. The experimental results show performance above 96% that compares favorably with popular statistical feature extraction methods. Our results provide a novel demonstration of unsupervised feature acquisition in an SNN

SN 2015ba: A type IIP supernova with a long plateau

We present optical photometry and spectroscopy from about a week after explosion to $\sim$272 d of an atypical Type IIP supernova, SN 2015ba, which exploded in the edge-on galaxy IC 1029. SN 2015ba is a luminous event with an absolute V-band magnitude of -17.1$\pm$0.2 mag at 50 d since explosion and has a long plateau lasting for $\sim$123 d. The distance to the SN is estimated to be 34.8$\pm$0.7 Mpc using the expanding photosphere and standard candle methods. High-velocity H-Balmer components constant with time are observed in the late-plateau phase spectra of SN 2015ba, which suggests a possible role of circumstellar interaction at these phases. Both hydrodynamical and analytical modelling suggest a massive progenitor of SN 2015ba with a pre-explosion mass of 24-26 M$_\odot$. However, the nebular spectra of SN 2015ba exhibit insignificant levels of oxygen, which is otherwise expected from a massive progenitor. This might be suggestive of the non-monotonical link between O-core masses and the zero-age main-sequence mass of pre-supernova stars and/or uncertainties in the mixing scenario in the ejecta of supernovae.Comment: 42 pages, 7 pages Appendix, 20 figures, 10 tables, Accepted for publication in MNRAS, 14-June-201

C-Terminal Substitution of MDM2 Interacting Peptides Modulates Binding Affinity by Distinctive Mechanisms

The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19–26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD) and an equivalent phage optimized peptide (12/1) were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design

Does timing of decisions in a mixed duopoly matter?

We determine the endogenous order of moves in a mixed pricesetting duopoly. In contrast to the existing literature on mixed oligopolies we establish the payo equivalence of the games with an exogenously given order of moves if the most plausible equilibrium is realized in the market. Hence, in this case it does not matter whether one becomes a leader or a follower. We also establish that replacing a private firm by a public firm in the standard Bertrand-Edgeworth game with capacity constraints increases social welfare and that a pure-strategy equilibrium always exists

The effect of obesity on electrocardiographic detection of hypertensive left ventricular hypertrophy:Recalibration against cardiac magnetic resonance

Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold-standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0±15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow–Lyon voltage and product, Cornell voltage and product, Gubner–Ungerleidger voltage and Romhilt–Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2±5.7 vs 26.4±9.4 mm, P<0.05), Cornell product (2540±942 vs 3023±1185 mm • ms, P<0.05) and for Gubner–Ungerleider voltage (18.2±7.1 vs 23.3±1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow–Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension

The Fast-evolving Type Ib Supernova SN 2015dj in NGC 7371

We present the detailed optical evolution of a Type Ib SN 2015dj in NGC 7371, using data spanning up to ∼170 days after discovery. SN 2015dj shares similarity in light-curve shape with SN 2007gr and peaks at M V = -17.37 0.02 mag. Analytical modeling of the quasi bolometric light curve yields 0.06 0.01 M o˙ of 56Ni, ejecta mass M o˙, and kinetic energy erg. The spectral features show a fast evolution and resemble those of spherically symmetric ejecta. The analysis of nebular phase spectral lines indicates a progenitor mass between 13-20 M o˙, suggesting a binary scenario.K.M. acknowledges the support from the Department of Science and Technology (DST), Government of India, and Indo-US Science and Technology Forum (IUSSTF) for the WISTEMM fellowship and the Department of Physics, UC Davis, where part of this work was carried out. K.M. also acknowledges BRICS grant DST/IMRCD/BRICS/Pilotcall/ProFCheap/2017(G) for the present work. Research by S.V. is supported by NSF grant AST-1813176. NUTS is supported in part by the Instrument Center for Danish Astrophysics (IDA). E.C., N.E.R., L.T., S. B., and M.T. are partially supported by PRIN-INAF 2016 with the project “Toward the SKA and CTA era: discovery, localization, and physics of transient sources” (P.I. M. Giroletti)