The study of degradation mechanisms of glyco-engineered plant produced anti-rabies monoclonal antibodies E559 and 62-71-3

Rabies is an ancient and neglected zoonotic disease caused by the rabies virus, a neurotropic RNA virus that belongs to the Rhabdoviridae family, genus Lyssavirus. It remains an important public health problem as there are cost and health concerns imposed by the current human post exposure prophylaxis therapy. The use of monoclonal antibodies (mAbs) is therefore an attractive alternative. Rabies mostly affects people that reside in resource-limited areas where there are occasional failures in the cold-chain. These environmental changes may upset the stability of the mAbs. This study focused on mAbs 62-71-3 and E559; their structures, responses to freeze/thaw (F/T) and exposure to reactive oxygen species were therefore studied with the aid of a wide range of biophysical and in silico techniques in order to elucidate their stability and identify aggregation prone regions. E559 was found to be less stable than 62-71-3. The complementarity determining regions (CDR) contributed the most to its instability, more specifically: peptides (EIWD102)-E-99 and (92)ATSPYT(97) found in CDR3, Trp33 found in CDR1 and the oxidised Met34. The constant region "(158)SWNSGALTGHTFPAVL(175)" was also flagged by the special aggregation propensity (SAP) tool and F/T experiments to be highly prone to aggregation. The E559 peptides "(4)LQESGSVL(11) from the heavy chain and (4)LTQSPSSL(11) from the light chain, were also highly affected by F/T. These residues may serve as good candidates for mutation, in the aim to bring forward more stable therapeutic antibodies, thus paving a way to a more safe and efficacious antibody-based cocktail treatment against rabies

Corrosion stability of stainless steel, modified electrochemically with Ce 2 O 3 -CeO 2 films, in 3.5% NaCl media

This work is focused on the study of corrosion-protection ability of the thin ceria film, formed electrochemically on OC404 stainless steel (SS) in non-aqueous electrolytes. The influence of changes in the surface concentration of Ce 2 O 3 -CeO 2 on the corrosion behaviour of OC404 stainless steel in 3.5% NaCl was investigated prior to the thermal treatment as well as after it. A shift of corrosion potential in positive direction was found via polarization curve recording, as well as via decrease in the corrosion current, respectively decrease in the corrosion rate (enhancement of the corrosion protection) in the presence of ceria oxide films. The data, acquired by AFM and XPS, are in a good agreement with these results. On the basis of the obtained results we can conclude that the presence of Ce 2 O 3 -CeO 2 film results in passivation and re-passivation of the steel surface and a slowdown in the pitting corrosion in an aggressive media. These conclusions are explained by the strong polarization influence of the Ce 2 O 3 -CeO 2 layers on the conjugated depolarization cathodic reaction of reduction of the dissolved oxygen

Plasmodium falciparum spermidine synthase inhibition results in unique perturbation-specific effects observed on transcript, protein and metabolite levels

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum</it>, the causative agent of severe human malaria, has evolved to become resistant to previously successful antimalarial chemotherapies, most notably chloroquine and the antifolates. The prevalence of resistant strains has necessitated the discovery and development of new chemical entities with novel modes-of-action. Although much effort has been invested in the creation of analogues based on existing drugs and the screening of chemical and natural compound libraries, a crucial shortcoming in current Plasmodial drug discovery efforts remains the lack of an extensive set of novel, validated drug targets. A requirement of these targets (or the pathways in which they function) is that they prove essential for parasite survival. The polyamine biosynthetic pathway, responsible for the metabolism of highly abundant amines crucial for parasite growth, proliferation and differentiation, is currently under investigation as an antimalarial target. Chemotherapeutic strategies targeting this pathway have been successfully utilized for the treatment of Trypanosomes causing West African sleeping sickness. In order to further evaluate polyamine depletion as possible antimalarial intervention, the consequences of inhibiting <it>P. falciparum </it>spermidine synthase (PfSpdSyn) were examined on a morphological, transcriptomic, proteomic and metabolic level.</p> <p>Results</p> <p>Morphological analysis of <it>P. falciparum </it>3D7 following application of the PfSpdSyn inhibitor cyclohexylamine confirmed that parasite development was completely arrested at the early trophozoite stage. This is in contrast to untreated parasites which progressed to late trophozoites at comparable time points. Global gene expression analyses confirmed a transcriptional arrest in the parasite. Several of the differentially expressed genes mapped to the polyamine biosynthetic and associated metabolic pathways. Differential expression of corresponding parasite proteins involved in polyamine biosynthesis was also observed. Most notably, uridine phosphorylase, adenosine deaminase, lysine decarboxylase (LDC) and S-adenosylmethionine synthetase were differentially expressed at the transcript and/or protein level. Several genes in associated metabolic pathways (purine metabolism and various methyltransferases) were also affected. The specific nature of the perturbation was additionally reflected by changes in polyamine metabolite levels.</p> <p>Conclusions</p> <p>This study details the malaria parasite's response to PfSpdSyn inhibition on the transcriptomic, proteomic and metabolic levels. The results corroborate and significantly expand previous functional genomics studies relating to polyamine depletion in this parasite. Moreover, they confirm the role of transcriptional regulation in <it>P. falciparum</it>, particularly in this pathway. The findings promote this essential pathway as a target for antimalarial chemotherapeutic intervention strategies.</p

Steps towards the hyperfine splitting measurement of the muonic hydrogen ground state: pulsed muon beam and detection system characterization

The high precision measurement of the hyperfine splitting of the muonic-hydrogen atom ground state with pulsed and intense muon beam requires careful technological choices both in the construction of a gas target and of the detectors. In June 2014, the pressurized gas target of the FAMU experiment was exposed to the low energy pulsed muon beam at the RIKEN RAL muon facility. The objectives of the test were the characterization of the target, the hodoscope and the X-ray detectors. The apparatus consisted of a beam hodoscope and X-rays detectors made with high purity Germanium and Lanthanum Bromide crystals. In this paper the experimental setup is described and the results of the detector characterization are presented.Comment: 22 pages, 14 figures, published and open access on JINS

Party system closure and openness: conceptualization, operationalization and validation

The degree of closure of the governmental arena is a central aspect of the stabilization of party systems, and yet little systematic effort has been devoted to its operationalization. The article proposes a new index, examines its reliability and validity, and reports the ranking of 60 party systems. By redefining the units of measurement we suggest new indicators that are uniform and transparent in their logic of construction, can be applied both to specific government-changes and to time periods, and are sensitive to the degree of change. The article finds a hierarchy among the components of party system closure, dominated by coalition formula. While new and established democracies can both produced closed patterns, the analysis of inter-war European party systems shows that closed systems are less prone to authoritarian takeover. The article demonstrates the power of inertia: the completely closed configurations stand out as the most durable ones

Current Applications of Computational Chemistry in JACS

Article discussing molecules, mechanisms, and materials and current applications of computational chemistry in the Journal of the American Chemical Society (JACS)

First measurement of the temperature dependence of muon transfer rate from muonic hydrogen atoms to oxygen

We report the first measurement of the temperature dependence of muon transfer rate from muonic hydrogen atoms to oxygen between 100 and 300 K. Data were obtained from the X-ray spectra of delayed events in a gaseous target, made of a H2/O2 mixture, exposed to a muon beam. This work sets constraints on theoretical models of muon transfer and is of fundamental importance for the measurement of the hyperfine splitting of muonic hydrogen ground state as proposed by the FAMU collaboration

First measurement of the temperature dependence of muon transfer rate from muonic hydrogen atoms to oxygen

We report the first measurement of the temperature dependence of muon transfer rate from muonic hydrogen atoms to oxygen between 100 and 300 K. Data were obtained from the X-ray spectra of delayed events in a gaseous target, made of a H2/O2 mixture, exposed to a muon beam. This work sets constraints on theoretical models of muon transfer and is of fundamental importance for the measurement of the hyperfine splitting of muonic hydrogen ground state as proposed by the FAMU collaboration

Pine cone scale-inspired motile origami

Stimuli-sensitive hydrogels have received attention because of their potential applications in various fields. Stimuli-directed motion offers many practical applications, such as in drug delivery systems and actuators. Directed motion of asymmetric hydrogels has long been designed; however, few studies have investigated the motion control of symmetric hydrogels. We designed a pine cone scale-inspired movable temperature-sensitive symmetric hydrogel that contains Fe3O4. Alignment of Fe3O4 along the magnetic force is key in motion control in which Fe3O4 acts like fibers in a pine cone scale. Although a homogeneous temperature-sensitive hydrogel cannot respond to a temperature gradient, the Fe3O4-containing hydrogel demonstrates considerable bending motion. Varying degrees and directions of motion are easily facilitated by controlling the amount and alignment angle of the Fe3O4. The shape of the hydrogel layer also influences the morphological structure. This study introduced facile and low-cost methods to control various bending motions. These results can be applied to many fields of engineering, including industrial engineering.111Ysciescopu

First FAMU observation of muon transfer from \u3bcp atoms to higher-Z elements

Abstract: The FAMU experiment aims to accurately measure the hyperfine splitting of the ground state of the muonic hydrogen atom. A measurement of the transfer rate of muons from hydrogen to heavier gases is necessary for this purpose. In June 2014, within a preliminary experiment, a pressurized gas-target was exposed to the pulsed low-energy muon beam at the RIKEN RAL muon facility (Rutherford Appleton Laboratory, U.K.). The main goal of the test was the characterization of both the noise induced by the pulsed beam and the X-ray detectors. The apparatus, to some extent rudimental, has served admirably to this task. Technical results have been published that prove the validity of the choices made and pave the way for the next steps. This paper presents the results of physical relevance of measurements of the muon transfer rate to carbon dioxide, oxygen, and argon from non-thermalized excited \u3bcp atoms. The analysis methodology and the approach to the systematics errors are useful for the subsequent study of the transfer rate as function of the kinetic energy of the \u3bcp currently under way