Safety and Pharmacokinetics of a Four Monoclonal Antibody Combination Against Botulinum C and D Neurotoxins.

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study

XQCAT: eXtra Quark Combined Analysis Tool

XQCAT (eXtra Quark Combined Analysis Tool) is a tool aimed at determining exclusion confidence levels for scenarios of new physics characterised by the presence of one or multiple heavy extra quarks which interact through Yukawa couplings with any of the Standard Model quarks. The code uses a database of efficiencies for pre-simulated processes of QCD-induced pair production of extra quarks and their subsequent on-shell decays. In the version 1.2 of XQCAT the efficiencies have been computed for a set of seven publicly available search results by the CMS experiment. The input for the code is a text file in which masses, branching ratios and dominant chirality of the couplings of the new quarks are provided. The output of the code is the exclusion confidence levels of the test point for each implemented experimental analysis considered individually and, when possible, in statistical combination.Comment: 18 pages, 2 figures, version accepted for publication in Comp. Phys. Comm., fixed formatting problems caused by the arXiv's autotex syste

Hypervelocity stars from star clusters hosting Intermediate-Mass Black Holes

Hypervelocity stars (HVSs) represent a unique population of stars in the Galaxy reflecting properties of the whole Galactic potential. Determining their origin is of fundamental importance to constrain the shape and mass of the dark halo. The leading scenario for the ejection of HVSs is an encounter with the supermassive black hole in the Galactic Centre. However, new proper motions from the \textit{Gaia} mission indicate that only the fastest HVSs can be traced back to the Galactic centre and the remaining stars originate in the disc or halo. In this paper, we study HVSs generated by encounters of stellar binaries with an intermediate-mass black hole (IMBH) in the core of a star cluster. For the first time, we model the effect of the cluster orbit in the Galactic potential on the observable properties of the ejected population. HVSs generated by this mechanism do not travel on radial orbits consistent with a Galactic centre origin, but rather point back to their parent cluster, thus providing observational evidence for the presence of an IMBH. We also model the ejection of high-velocity stars from the Galactic population of globular clusters, assuming that they all contain an IMBH, including the effects of the cluster's orbit and propagation of the star in the Galactic potential up to detection. We find that high-velocity stars ejected by IMBHs have distinctive distributions in velocity, Galactocentric distance and Galactic latitude, which can be used to distinguish them from runaway stars and stars ejected from the Galactic Centre.Comment: 15 pages, 16 Figures, 1 Tabl

An Approach to Reduce Commissioning and Ramp-up time for Multi-variant Production in Automated Production Facilities

A key requirement for future production facilities is to perform new production processes in a flexible and adaptive way with available and known resources. In this context, a comprehensive description (ontology) of involved components has a high significance. If certain technological aspects are missing during a production process, the production control should respond in a dynamic, versatile and adaptive (agile) manner to the overall value network. The possibility to describe the requirements of products for the necessary processes in the same namespace like the requirements of the necessary processes for the resources is a prerequisite to enable this behavior. Afterwards the different requirements will be placed in relation to the respective requirements. The aim is to define the necessary processes for the production based on the description of the product and the known resources in an agile way. Due to this a framework for a comprehensive description of automated production facilities, products and processes is described in this paper. The idea is that based on this framework a production facility can change the produced products without dedicated commissioning and ramp-up phases

K-Band Spectroscopy of (Pre-)Cataclysmic Variables: Are Some Donor Stars Really Carbon Poor?

We present a new sample of $K$-band spectral observations for CVs: non-magnetic and magnetic as well as present day and pre CVs. The purpose of this diverse sample is to address the recent claim that the secondary stars in dwarf novae are carbon deficient, having become so through a far more evolved evolution than the current paradigm predicts. Our new observations, along with previous literature results, span a wide range of orbital period and CV type. In general, dwarf novae in which the secondary star is seen show weak to no CO absorption while polar and pre-CV donor stars appear to have normal CO absorption for their spectral type. However, this is not universal. The presence of normal looking CO absorption in the dwarf nova SS Aur and the hibernating CV QS Vir and a complete lack of CO absorption in the long period polar V1309 Ori cloud the issue. A summary of the literature pointing to non-solar abundances including enhanced NV/CIV ratios is presented. It appears that some CVs have non-solar abundance material accreting onto the white dwarf suggesting an evolved secondary star while for others CO emission in the accretion disk may play a role. However, the exact mechanism or combination of factors causing the CO absorption anomaly in CVs is not yet clear.Comment: Accepted in A

Applications of Graphene Quantum Dots in Biomedical Sensors

Due to the proliferative cancer rates, cardiovascular diseases, neurodegenerative disorders, autoimmune diseases and a plethora of infections across the globe, it is essential to introduce strategies that can rapidly and specifically detect the ultralow concentrations of relevant biomarkers, pathogens, toxins and pharmaceuticals in biological matrices. Considering these pathophysiologies, various research works have become necessary to fabricate biosensors for their early diagnosis and treatment, using nanomaterials like quantum dots (QDs). These nanomaterials effectively ameliorate the sensor performance with respect to their reproducibility, selectivity as well as sensitivity. In particular, graphene quantum dots (GQDs), which are ideally graphene fragments of nanometer size, constitute discrete features such as acting as attractive fluorophores and excellent electro-catalysts owing to their photo-stability, water-solubility, biocompatibility, non-toxicity and lucrativeness that make them favorable candidates for a wide range of novel biomedical applications. Herein, we reviewed about 300 biomedical studies reported over the last five years which entail the state of art as well as some pioneering ideas with respect to the prominent role of GQDs, especially in the development of optical, electrochemical and photoelectrochemical biosensors. Additionally, we outline the ideal properties of GQDs, their eclectic methods of synthesis, and the general principle behind several biosensing techniques.DFG, 428780268, Biomimetische Rezeptoren auf NanoMIP-Basis zur Virenerkennung und -entfernung mittels integrierter Ansätz

The possible prognostic role of histone deacetylase and transforming growth factor β/Smad signaling in high grade gliomas treated by radio-chemotherapy: a preliminary immunohistochemical study

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-β/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-β/Smad pathway, with high levels of IL-13, Smad2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in Smad 7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-β/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease