Probing polyoxometalate-protein interactions using molecular dynamics simulations

The molecular interactions between the Ce(IV)-substituted Keggin anion [PW11O39Ce(OH2)4]3- (CeK) and hen egg white lysozyme (HEWL), was investigated by molecular dynamics (MD) simulations. We compared the analysis of CeK with the Ce(IV)-substituted Keggin dimer [(PW11O39)2Ce]10- (CeK2) and the Zr(IV)-substituted Lindqvist anion [W5O18Zr(OH2)(OH)]3- (ZrL) in order to understand how POM features such as the shape, the size, the charge or the type of incorporated metal ion influence the POM···protein interactions. Simulations revealed two regions of the protein, in which the CeK anion interacts strongly: the cationic sites formed by Arg21 on one hand and by Arg45 and Arg68 on the other. The two sites can be related with the observed selectivity in the hydrolytic cleavage of HEWL. The POMs chiefly interact with the side chains of the positively charged (arginines and lysines) and the polar uncharged (tyrosines, serines and aspargines) residues via electrostatic attraction and hydrogen bonding with the oxygens of the POM framework. The CeK anion shows higher protein affinity than the CeK2 and ZrL anions, because it is less hydrophilic and it has the right size and shape for stablishing interactions with several residues simultaneously. The larger and more negatively charged CeK2 anion has a high solvent-accessible surface, which is sub-optimal for the interaction, while the smaller ZrL anion is highly hydrophilic and it cannot interact simultaneously with several residues so efficiently

Gross-Neveu Models, Nonlinear Dirac Equations, Surfaces and Strings

Recent studies of the thermodynamic phase diagrams of the Gross-Neveu model (GN2), and its chiral cousin, the NJL2 model, have shown that there are phases with inhomogeneous crystalline condensates. These (static) condensates can be found analytically because the relevant Hartree-Fock and gap equations can be reduced to the nonlinear Schr\"odinger equation, whose deformations are governed by the mKdV and AKNS integrable hierarchies, respectively. Recently, Thies et al have shown that time-dependent Hartree-Fock solutions describing baryon scattering in the massless GN2 model satisfy the Sinh-Gordon equation, and can be mapped directly to classical string solutions in AdS3. Here we propose a geometric perspective for this result, based on the generalized Weierstrass spinor representation for the embedding of 2d surfaces into 3d spaces, which explains why these well-known integrable systems underlie these various Gross-Neveu gap equations, and why there should be a connection to classical string theory solutions. This geometric viewpoint may be useful for higher dimensional models, where the relevant integrable hierarchies include the Davey-Stewartson and Novikov-Veselov systems.Comment: 27 pages, 1 figur

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Atomistic dynamics of sulfur-deficient high-symmetry grain boundaries in molybdenum disulfide

As a common type of structural defect, grain boundaries (GBs) play an important role in tailoring the physical and chemical properties of bulk crystals and their two-dimensional (2D) counterparts such as graphene and molybdenum disulfide (MoS2). In this study, we explore the atomic structures and dynamics of three kinds of high-symmetry GBs (α, β and γ) in monolayer MoS2. Atomic-resolution transmission electron microscopy (TEM) is used to characterize their formation and evolutionary dynamics, and atomistic simulation based analysis explains the size distribution of α-type GBs observed under TEM and the inter-GB interaction, revealing the stabilization mechanism of GBs by pre-existing sulfur vacancies. The results elucidate the correlation between the observed GB dynamics and the migration of sulfur atoms across GBs via a vacancy-mediated mechanism, offering a new perspective for GB engineering in monolayer MoS2, which may be generalized to other transition metal dichalcogenides

Reducing the rate and duration of Re-ADMISsions among patients with unipolar disorder and bipolar disorder using smartphone-based monitoring and treatment -- the RADMIS trials: study protocol for two randomized controlled trials

Abstract Background Unipolar and bipolar disorder combined account for nearly half of all morbidity and mortality due to mental and substance use disorders, and burden society with the highest health care costs of all psychiatric and neurological disorders. Among these, costs due to psychiatric hospitalization are a major burden. Smartphones comprise an innovative and unique platform for the monitoring and treatment of depression and mania. No prior trial has investigated whether the use of a smartphone-based system can prevent re-admission among patients discharged from hospital. The present RADMIS trials aim to investigate whether using a smartphone-based monitoring and treatment system, including an integrated clinical feedback loop, reduces the rate and duration of re-admissions more than standard treatment in unipolar disorder and bipolar disorder. Methods The RADMIS trials use a randomized controlled, single-blind, parallel-group design. Patients with unipolar disorder and patients with bipolar disorder are invited to participate in each trial when discharged from psychiatric hospitals in The Capital Region of Denmark following an affective episode and randomized to either (1) a smartphone-based monitoring system including (a) an integrated feedback loop between patients and clinicians and (b) context-aware cognitive behavioral therapy (CBT) modules (intervention group) or (2) standard treatment (control group) for a 6-month trial period. The trial started in May 2017. The outcomes are (1) number and duration of re-admissions (primary), (2) severity of depressive and manic (only for patients with bipolar disorder) symptoms; psychosocial functioning; number of affective episodes (secondary), and (3) perceived stress, quality of life, self-rated depressive symptoms, self-rated manic symptoms (only for patients with bipolar disorder), recovery, empowerment, adherence to medication, wellbeing, ruminations, worrying, and satisfaction (tertiary). A total of 400 patients (200 patients with unipolar disorder and 200 patients with bipolar disorder) will be included in the RADMIS trials. Discussion If the smartphone-based monitoring system proves effective in reducing the rate and duration of re-admissions, there will be basis for using a system of this kind in the treatment of unipolar and bipolar disorder in general and on a larger scale. Trial registration ClinicalTrials.gov, ID: NCT03033420 . Registered 13 January 2017. Ethical approval has been obtained

Degradation behaviors and mechanisms of MoS2 crystals relevant to bioabsorbable electronics

Monolayer molybdenum disulfide (MoS2) exhibits unique semiconducting and bioresorption properties, giving this material enormous potential for electronic/biomedical applications, such as bioabsorbable electronics. In this regard, understanding the degradation performance of monolayer MoS2 in biofluids allows modulation of the properties and lifetime of related bioabsorbable devices and systems. Herein, the degradation behaviors and mechanisms of monolayer MoS2 crystals with different misorientation angles are explored. High-angle grain boundaries (HAGBs) biodegrade faster than low-angle grain boundaries (LAGBs), exhibiting degraded edges with wedge and zigzag shapes, respectively. Triangular pits that formed in the degraded grains have orientations opposite to those of the parent crystals, and these pits grow into larger pits laterally. These behaviors indicate that the degradation is induced and propagated based on intrinsic defects, such as grain boundaries and point defects, because of their high chemical reactivity due to lattice breakage and the formation of dangling bonds. High densities of dislocations and point defects lead to high chemical reactivity and faster degradation. The structural cause of MoS2 degradation is studied, and a feasible approach to study changes in the properties and lifetime of MoS2 by controlling the defect type and density is presented. The results can thus be used to promote the widespread use of two-dimensional materials in bioabsorption applications

Readthrough of Premature Termination Codons in the Adenomatous Polyposis Coli Gene Restores Its Biological Activity in Human Cancer Cells

The APC tumor suppressor gene is frequently mutated in human colorectal cancer, with nonsense mutations accounting for 30% of all mutations in this gene. Reintroduction of the WT APC gene into cancer cells generally reduces tumorigenicity or induces apoptosis. In this study, we explored the possibility of using drugs to induce premature termination codon (PTC) readthrough (aminoglycosides, negamycin), as a means of reactivating endogenous APC. By quantifying the readthrough of 11 nonsense mutations in APC, we were able to identify those giving the highest levels of readthrough after treatment. For these mutations, we demonstrated that aminoglycoside or negamycin treatment led to a recovery of the biological activity of APC in cancer cell lines, and showed that the level of APC activity was proportional to the level of induced readthrough. These findings show that treatment with readthrough inducers should be considered as a potential strategy for treating cancers caused by nonsense mutations APC gene. They also provide a rational basis for identifying mutations responsive to readthrough inducers

Biocleavable Polycationic Micelles as Highly Efficient Gene Delivery Vectors

An amphiphilic disulfide-containing polyamidoamine was synthesized by Michael-type polyaddition reaction of piperazine to equimolar N, N′-bis(acryloyl)cystamine with 90% yield. The polycationic micelles (198 nm, 32.5 mV), prepared from the amphiphilic polyamidoamine by dialysis method, can condense foreign plasmid DNA to form nanosized polycationic micelles/DNA polyelectrolyte complexes with positive charges, which transfected 293T cells with high efficiency. Under optimized conditions, the transfection efficiencies of polycationic micelles/DNA complexes are comparable to, or even higher than that of commercially available branched PEI (Mw 25 kDa)