Membrane-Active Peptides and the Clustering of Anionic Lipids

AbstractThere is some overlap in the biological activities of cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs). We compared nine AMPs, seven CPPs, and a fusion peptide with regard to their ability to cluster anionic lipids in a mixture mimicking the cytoplasmic membrane of Gram-negative bacteria, as measured by differential scanning calorimetry. We also studied their bacteriostatic effect on several bacterial strains, and examined their conformational changes upon membrane binding using circular dichroism. A remarkable correlation was found between the net positive charge of the peptides and their capacity to induce anionic lipid clustering, which was independent of their secondary structure. Among the peptides studied, six AMPs and four CPPs were found to have strong anionic lipid clustering activity. These peptides also had bacteriostatic activity against several strains (particularly Gram-negative Escherichia coli) that are sensitive to lipid clustering agents. AMPs and CPPs that did not cluster anionic lipids were not toxic to E. coli. As shown previously for several types of AMPs, anionic lipid clustering likely contributes to the mechanism of antibacterial action of highly cationic CPPs. The same mechanism could explain the escape of CPPs from intracellular endosomes that are enriched with anionic lipids

Measurement of the electron electric dipole moment using GdIG

A new method for the detection of the electron edm using a solid is described. The method involves the measurement of a voltage induced across the solid by the alignment of the samples magnetic dipoles in an applied magnetic field, H. A first application of the method to GdIG has resulted in a limit on the electron edm of 5E-24 e-cm, which is a factor of 40 below the limit obtained from the only previous solid-state edm experiment. The result is limited by the imperfect discrimination of an unexpectedly large voltage that is even upon the reversal of the sample magnetization.Comment: 10 pages, 5 figures, v2:references corrected, submitted to PRL, v3:added labels to figure

Self-similar solution of a nonsteady problem of nonisothermal vapour condensation on a droplet growing in diffusion regime

This paper presents a mathematically exact self-similar solution to the joint nonsteady problems of vapour diffusion towards a droplet growing in a vapour-gas medium and of removal of heat released by a droplet into a vapour-gas medium during vapour condensation. An equation for the temperature of the droplet is obtained; and it is only at that temperature that the self-similar solution exists. This equation requires the constancy of the droplet temperature and even defines it unambiguously throughout the whole period of the droplet growth. In the case of strong display of heat effects, when the droplet growth rate decreases significantly, the equation for the temperature of the droplet is solved analytically. It is shown that the obtained temperature fully coincides with the one that settles in the droplet simultaneously with the settlement of its diffusion regime of growth. At the obtained temperature of the droplet the interrelated nonsteady vapour concentration and temperature profiles of the vapour-gas medium around the droplet are expressed in terms of initial (prior to the nucleation of the droplet) parameters of the vapour-gas medium. The same parameters are used to formulate the law in accordance with which the droplet is growing in diffusion regime, and also to define the time that passes after the nucleation of the droplet till the settlement of diffusion regime of droplet growth, when the squared radius of the droplet becomes proportionate to time. For the sake of completeness the case of weak display of heat effects is been studied.Comment: 12 pages, 4 figure

Critical and Non-Critical Einstein-Weyl Supergravity

We construct N=1 supersymmetrisations of some recently-proposed theories of critical gravity, conformal gravity, and extensions of critical gravity in four dimensions. The total action consists of the sum of three separately off-shell supersymmetric actions containing Einstein gravity, a cosmological term and the square of the Weyl tensor. For generic choices of the coefficients for these terms, the excitations of the resulting theory around an AdS_4 background describe massive spin-2 and massless spin-2 modes coming from the metric; massive spin-1 modes coming from a vector field in the theory; and massless and massive spin-3/2 modes (with two unequal masses) coming from the gravitino. These assemble into a massless and a massive N=1 spin-2 multiplet. In critical supergravity, the coefficients are tuned so that the spin-2 mode in the massive multiplet becomes massless. In the supersymmetrised extensions of critical gravity, the coefficients are chosen so that the massive modes lie in a "window" of lowest energies E_0 such that these ghostlike fields can be truncated by imposing appropriate boundary conditions at infinity, thus leaving just positive-norm massless supergravity modes.Comment: 29 page

Generic meta-modelling with concepts, templates and mixin layers

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-16145-2_2Proceedings of 13th International Conference, MODELS 2010, Oslo, Norway, October 3-8, 2010.Meta-modelling is a key technique in Model Driven Engineering, where it is used for language engineering and domain modelling. However, mainstream approaches like the OMG’s Meta-Object Facility provide little support for abstraction, modularity, reusability and extendibility of (meta-)models, behaviours and transformations. In order to alleviate this weakness, we bring three elements of generic programming into meta-modelling: concepts, templates and mixin layers. Concepts permit an additional typing for models, enabling the definition of behaviours and transformations independently of meta-models, making specifications reusable. Templates use concepts to express requirements on their generic parameters, and are applicable to models and meta-models. Finally, we define functional layers by means of meta-model mixins which can extend other meta-models. As a proof of concept we also report on MetaDepth, a multi-level meta-modelling framework that implements these ideas.Work sponsored by the Spanish Ministry of Science, project TIN2008-02081 and mobility grants JC2009-00015 and PR2009-0019, and by the R&D programme of the Community of Madrid, project S2009/TIC-165

Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression

Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulation of HOXA and HOXB homeobox genes and myeloid ecotropic virus insertion site 1 (MEIS1). Aberrant HOXA/MEIS1 expression is associated with genotypes such as rearrangements in Histone-lysine N-methyltransferase 2A (KMT2A-r), nucleoporin 98 (NUP98-r) and mutated nucleophosmin (NPM1c) that are found in approximately one third of children with AML. AML with upregulated HOXA/MEIS1 shares a number of molecular vulnerabilities amenable to recently developed molecules targeting the assembly of protein complexes or transcriptional regulators. The interaction between the nuclear scaffold protein menin and KMT2A has gained particular interest and constitutes a molecular dependency for maintenance of the HOXA/MEIS1 transcription program. Menin inhibitors disrupt the menin-KMT2A complex in preclinical models of KMT2A-r, NUP98-r and NPM1c acute leukemias and its occupancy at target genes leading to leukemic cell differentiation and apoptosis. Early-phase clinical trials are either ongoing or in development and preliminary data suggests tolerable toxicities and encouraging efficacy of menin inhibitors in adults with relapsed or refractory KMT2A-r and NPM1c AML. The Pediatric Acute Leukemia/European Pediatric Acute Leukemia (PedAL/EUPAL) project is focused to advance and coordinate informative clinical trials with new agents and constitute an ideal framework for testing of menin inhibitors in pediatric study populations. Menin inhibitors in combination with standard chemotherapy or other targeting agents may enhance anti-leukemic effects and constitute rational treatment strategies for select genotypes of childhood AML, and provide enhanced safety to avoid differentiation syndrome. In this review, we discuss the pathophysiological mechanisms in KMT2A-r, NUP98-r and NPM1c AML, emerging molecules targeting the HOXA/MEIS1 transcription program with menin inhibitors as the most prominent examples and future therapeutic implications of these agents in childhood AML.</p

Managing Nonmetastatic Castration-resistant Prostate Cancer.

CONTEXT:Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation. OBJECTIVE:To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients. EVIDENCE ACQUISITION:A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse. EVIDENCE SYNTHESIS:Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed. CONCLUSIONS:nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future. PATIENT SUMMARY:Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately

Analysis of the Lactobacilluscasei supragenome and its influence in species evolution and lifestyle adaptation

The broad ecological distribution of L. casei makes it an insightful subject for research on genome evolution and lifestyle adaptation. To explore evolutionary mechanisms that determine genomic diversity of L. casei, we performed comparative analysis of 17 L. casei genomes representing strains collected from dairy, plant, and human sources. Results Differences in L. casei genome inventory revealed an open pan-genome comprised of 1,715 core and 4,220 accessory genes. Extrapolation of pan-genome data indicates L. casei has a supragenome approximately 3.2 times larger than the average genome of individual strains. Evidence suggests horizontal gene transfer from other bacterial species, particularly lactobacilli, has been important in adaptation of L. casei to new habitats and lifestyles, but evolution of dairy niche specialists also appears to involve gene decay. Conclusions Genome diversity in L. casei has evolved through gene acquisition and decay. Acquisition of foreign genomic islands likely confers a fitness benefit in specific habitats, notably plant-associated niches. Loss of unnecessary ancestral traits in strains collected from bacterial-ripened cheeses supports the hypothesis that gene decay contributes to enhanced fitness in that niche. This study gives the first evidence for a L. casei supragenome and provides valuable insights into mechanisms for genome evolution and lifestyle adaptation of this ecologically flexible and industrially important lactic acid bacterium. Additionally, our data confirm the Distributed Genome Hypothesis extends to non-pathogenic, ecologically flexible species like L. casei