Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide

Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. Given the conservation in CGRP sequence between monkeys and humans, addressing this question in monkeys is ideal as it allows dosing at super-therapeutic levels. To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101.     

GhKLCR1, a kinesin light chain-related gene,induces drought-stress sensitivity in Arabidopsis

Drought stress results in significant losses in agricultural production, and especially that of cotton. The molecular mechanisms that coordinate drought tolerance remain elusive in cotton. Here, we isolated a drought-response gene GhKLCR1, which is a close homolog of AtKLCR1, which encodes a kinesin light chain-related protein enriched with a tetratrico peptide-repeat region.A subcellular localization assay showed that GhKLCR1 is associated with the cell membrane. A tissue-specific expression profile analysis demonstrated that GhKLCR1 is a cotton root-specific gene. Further abiotic and hormonal stress treatments showed that GhKLCR1 was upregulated during abiotic stresses, especially after polyethylene glycol treatments. In addition, the glucuronidase(GUS) staining activity increased as the increment of mannitol concentration in transgenic Arabidopsis plants harboring the fusion construct PGhKLCR1::GUS. The root lengths of 35 S::GhKLCR1 lines were significantly reduced compared with that of wild type. Additionally, seed germination was strongly inhibited in 35 S::GhKLCR1 lines after 300-mmol L~(-1) mannitol treatments as compared with Columbia-0, indicating the sensitivity of GhKLCR1 to drought. These findings provide a better understanding of the structural, physiological and functional mechanisms of kinesin light chain-related proteins.     

A New Trigonometric Spline Approach to Numerical Solution of Generalized Nonlinear Klien-Gordon Equation

The generalized nonlinear Klien-Gordon equation plays an important role in quantum mechanics. In this paper, a new three-time level implicit approach based on cubic trigonometric B-spline is presented for the approximate solution of this equation with Dirichlet boundary conditions. The usual finite difference approach is used to discretize the time derivative while cubic trigonometric B-spline is applied as an interpolating function in the space dimension. Several examples are discussed to exhibit the feasibility and capability of the approach. The absolute errors and error norms are also computed at different times to assess the performance of the proposed approach and the results were found to be in good agreement with known solutions and with existing schemes in literature.     

T lymphocyte-mediated suppression of myeloma function in vitro. I. Suppression by allogeneically activated T lymphocytes.

Alloreactive cells generated by in vitro stimulation of C57BL/6 (H-2b) spleen lymphocytes with irradiated MOPC 315 or MOPC 104E(H-2d) cells were shown to lyse 51Cr-labeled myeloma targets at high effector:target ratios under conditions of inefficient cell contact, the alloreactive cells cause variable and frequently minimal lysis of myeloma targets but markedly suppress antibody secretion even by viable myeloma cells. The suppressor cells are radioresistant T cells lacking I-J subregion-encoded surface determinants; their precursors are insensitive to cyclophosphamide; suppression is H-2 specific and not mediated by secreted factors; and the suppression is blocked by Cytochalasin B, a known inhibitor of T cell-mediated cytolysis. These properties are typical of cytolytic T lymphocytes (CTL) and not of defined suppressor T cells, suggesting that inhibition of myeloma function probably represents a pre-lytic effect of the alloreactive CTL, although a CTL-like suppressor cell effect cannot be definitively excluded. These results are discussed with reference to the possible relationships between suppressor and cytolytic T lymphocytes.     

Autophagy regulation and its role in normal and malignant hematopoiesis

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation.     

Storage,fertilization and cost properties highlight the potential of dried microbial biomass as organic fertilizer

The transition to sustainable agriculture and horticulture is a societal challenge of global importance. Fertilization with a minimum impact on the environment can facilitate this. Organic fertilizers can play an important role, given their typical release pattern and production through resource recovery. Microbial fertilizers (MFs) constitute an emerging class of organic fertilizers and consist of dried microbial biomass, for instance produced on effluents from the food and beverage industry. In this study, three groups of organisms were tested as MFs: a high-rate consortium aerobic bacteria (CAB), the microalga Arthrospira platensis (‘Spirulina’) and a purple non-sulfur bacterium (PNSB) Rhodobacter sp. During storage as dry products, the MFs showed light hygroscopic activity, but the mineral and organic fractions remained stable over a storage period of 91 days. For biological tests, a reference organic fertilizer (ROF) was used as positive control, and a commercial organic growing medium (GM) as substrate. The mineralization patterns without and with plants were similar for all MFs and ROF, with more than 70% of the organic nitrogen mineralized in 77 days. In a first fertilization trial with parsley, all MFs showed equal performance compared to ROF, and the plant fresh weight was even higher with CAB fertilization. CAB was subsequently used in a follow-up trial with petunia and resulted in elevated plant height, comparable chlorophyll content and a higher amount of flowers compared to ROF. Finally, a cost estimation for packed GM with supplemented fertilizer indicated that CAB and a blend of CAB/PNSB (85%/15%) were most cost competitive, with an increase of 6% and 7% in cost compared to ROF. In conclusion, as bio-based fertilizers, MFs have the potential to contribute to sustainable plant nutrition, performing as good as a commercially available organic fertilizer, and to a circular economy.     

Eukaryotic translation initiation factor 5A and its posttranslational modifications play an important role in proliferation and potentially in differentiation of the human enteric protozoan parasite Entamoeba histolytica

The eukaryotic translation initiation factor 5A (eIF5A) is a highly conserved protein and is essential in all eukaryotes. However, the specific roles of eIF5A in translation and in other biological processes remain elusive. In the present study, we described the role of eIF5A, its posttranslational modifications (PTM), and the biosynthetic pathway needed for the PTM in Entamoeba histolytica, the protozoan parasite responsible for amoebic dysentery and liver abscess in humans. E. histolytica encodes two isotypes of eIF5A and two isotypes of enzymes, deoxyhypusine synthase (DHS), responsible for their PTM. Both of the two eIF5A isotypes are functional, whereas only one DHS (EhDHS1, but not EhDHS2), is catalytically active. The DHS activity increased ~2000-fold when EhDHS1 was co-expressed with EhDHS2 in Escherichia coli, suggesting that the formation of a heteromeric complex is needed for full enzymatic activity. Both EhDHS1 and 2 genes were required for in vitro growth of E. histolytica trophozoites, indicated by small antisense RNA-mediated gene silencing. In trophozoites, only eIF5A2, but not eIF5A1, gene was actively transcribed. Gene silencing of eIF5A2 caused compensatory induction of expression of eIF5A1 gene, suggesting interchangeable role of the two eIF5A isotypes and also reinforcing the importance of eIF5As for parasite proliferation and survival. Furthermore, using a sibling species, Entamoeba invadens, we found that eIF5A1 gene was upregulated during excystation, while eIF5A2 was downregulated, suggesting that eIF5A1 gene plays an important role during differentiation. Taken together, these results have underscored the essentiality of eIF5A and DHS, for proliferation and potentially in the differentiation of this parasite, and suggest that the hypusination associated pathway represents a novel rational target for drug development against amebiasis.     

Hydromagnetic Flow and Heat Transfer over a Porous Oscillating Stretching Surface in a Viscoelastic Fluid with Porous Medium

An analysis is carried out to study the heat transfer in unsteady two-dimensional boundary layer flow of a magnetohydrodynamics (MHD) second grade fluid over a porous oscillating stretching surface embedded in porous medium. The flow is induced due to infinite elastic sheet which is stretched periodically. With the help of dimensionless variables, the governing flow equations are reduced to a system of non-linear partial differential equations. This system has been solved numerically using the finite difference scheme, in which a coordinate transformation is used to transform the semi-infinite physical space to a bounded computational domain. The influence of the involved parameters on the flow, the temperature distribution, the skin-friction coefficient and the local Nusselt number is shown and discussed in detail. The study reveals that an oscillatory sheet embedded in a fluid-saturated porous medium generates oscillatory motion in the fluid. The amplitude and phase of oscillations depends on the rheology of the fluid as well as on the other parameters coming through imposed boundary conditions, inclusion of body force term and permeability of the porous medium. It is found that amplitude of flow velocity increases with increasing viscoelastic and mass suction/injection parameters. However, it decreases with increasing the strength of the applied magnetic field. Moreover, the temperature of fluid is a decreasing function of viscoelastic parameter, mass suction/injection parameter and Prandtl number.