Intracranial haemorrhage in a dobermann puppy with von Willebrand's disease

Neurological examination of a lethargic, ataxic 12-week-old dobermann revealed decreased conscious proprioception in all its limbs. Haematological examination revealed a low platelet count. Cytological examination of a sample of cerebrospinal fluid revealed evidence of haemorrhage and chronic inflammation. The levels of von Willebrand's factor antigen were extremely low. Skull radiographs were consistent with mild hydrocephalus. Treatment resulted in little clinical improvement and the animal was euthanased. Post mortem examination of the brain revealed an internal hydrocephalus with haemorrhage into the ventricles. It was considered that the animal had suffered severe intracranial haemorrhage as a result of its low level of von Willebrand's factor antigen and that the bleeding may have been potentiated by the low platelet count

Integrating SpyCatcher/SpyTag covalent fusion technology into phage display workflows for rapid antibody discovery.

An early bottleneck in the rapid isolation of new antibody fragment binders using in vitro library approaches is the inertia encountered in acquiring and preparing soluble antigen fragments. In this report, we describe a simple, yet powerful strategy that exploits the properties of the SpyCatcher/SpyTag (SpyC/SpyT) covalent interaction to improve substantially the speed and efficiency in obtaining functional antibody clones of interest. We demonstrate that SpyC has broad utility as a protein-fusion tag partner in a eukaryotic expression/secretion context, retaining its functionality and permitting the direct, selective capture and immobilization of soluble antigen fusions using solid phase media coated with a synthetic modified SpyT peptide reagent. In addition, we show that the expressed SpyC-antigen format is highly compatible with downstream antibody phage display selection and screening procedures, requiring minimal post-expression handling with no sample modifications. To illustrate the potential of the approach, we have isolated several fully human germline scFvs that selectively recognize therapeutically relevant native cell surface tumor antigens in various in vitro cell-based assay contexts

Effects of the bioturbating marine yabby Trypaea australiensis on sediment properties in sandy sediments receiving mangrove leaf litter

Laboratory mesocosm incubations were undertaken to investigate the influence of burrowing shrimp Trypaea australiensis (marine yabby) on sediment reworking, physical and chemical sediment characteristics and nutrients in sandy sediments receiving mangrove (Avicennia marina) leaf litter. Mesocosms of sieved, natural T. australiensis inhabited sands, were continually flushed with fresh seawater and pre-incubated for 17 days prior to triplicates being assigned to one of four treatments; sandy sediment (S), sediment + yabbies (S+Y), sediment + leaf litter (organic matter; S+OM) and sediment + yabbies + leaf litter (S+Y+OM) and maintained for 55 days. Mangrove leaf litter was added daily to treatments S+OM and S+Y+OM. Luminophores were added to mesocosms to quantify sediment reworking. Sediment samples were collected after the pre-incubation period from a set of triplicate mesocosms to establish initial conditions prior to the imposition of the treatments and from the treatment mesocosms at the conclusion of the 55-day incubation period. Yabbies demonstrated a clear effect on sediment topography and leaf litter burial through burrow creation and maintenance, creating mounds on the sediment surface ranging in diameter from 3.4 to 12 cm. Within S+Y+OM sediments leaf litter was consistently removed from the surface to sub-surface layers with only 7.5% ± 3.6% of the total mass of leaf detritus added to the mesocosms remaining at the surface at the end of the 55-day incubation period. Yabbies significantly decreased sediment wet-bulk density and increased porosity. Additionally, T. australiensis significantly reduced sediment bio-available ammonium (NH4+bio) concentrations and altered the shape of the concentration depth profile in comparison to the non-bioturbated mesocosms, indicating influences on nutrient cycling and sediment-water fluxes. No significant changes for mean apparent biodiffusion coefficients (Db) and mean biotransport coefficients (r), were found between the bioturbated S+Y and S+Y+OM mesocosms. The findings of this study provide further evidence that T. australiensis is a key-species in shallow intertidal systems playing an important role as an ‘ecosystem engineer’ in soft-bottom habitats by significantly altering physical and chemical structures and biogeochemical function

Soluble trivalent engagers redirect cytolytic T cell activity toward tumor endothelial marker 1.

Tumor endothelial marker 1 (TEM1) is an emerging cancer target with a unique dual expression profile. First, TEM1 is expressed in the stroma and neo-vasculature of many human carcinomas but is largely absent from healthy adult tissues. Second, TEM1 is expressed by tumor cells of mesenchymal origin, notably sarcoma. Here, we present two fully human anti-TEM1 single-chain variable fragment (scFv) reagents, namely, 1C1m and 7G22, that recognize distinct regions of the extracellular domain and possess substantially different affinities. In contrast to other, well-described anti-TEM1 binders, these fragments confer cytolytic activity when expressed as 2 <sup>nd</sup> generation chimeric antigen receptors (CARs). Moreover, both molecules selectively redirect human T cell effector functions toward TEM1 <sup>+</sup> tumor cells when incorporated into experimental soluble bispecific trivalent engagers that we term TriloBiTEs (tBs). Furthermore, systemic delivery of 1C1m-tB prevents the establishment of Ewing sarcoma tumors in a xenograft model. Our observations confirm TEM1 as a promising target for cancer immunotherapy and illustrate the prospective translational potential of certain scFv-based reagents

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model.

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with <sup>177</sup> Lu. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [ <sup>177</sup> Lu]Lu-1C1m-Fc in patients

Cost-effectiveness analysis of PET-CT guided management for locally advanced head and neck cancer

Background: A recent large UK clinical trial demonstrated that positron-emission tomography–computed tomography (PET-CT)- guided administration of neck dissection in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned neck dissection (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required in order to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT guided management from a UK secondary care perspective. Methods: Initial 6-month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader NHS & personal social services (PSS) costs on the results. Results: PET-CT management produced an average per-person lifetime cost saving of £1,485 and an additional 0.13 QALYs. At a £20,000 willingness-to-pay per additional QALY threshold there was a 75% probability that PET-CT was cost-effective, and the results remained cost-effective over the majority of sensitivity analyses. When adopting a broader NHS & PSS perspective, PET-CT management produced an average saving of £700 and had an 81% probability of being cost-effective. Conclusions: This analysis indicates that PET-CT guided management is cost-effective in the long-term and supports the case for wide scale adoption

A gradient approach to localization of deformation. I. Hyperelastic materials

By utilizing methods recently developed in the theory of fluid interfaces, we provide a new framework for considering the localization of deformation and illustrate it for the case of hyperelastic materials. The approach overcomes one of the major shortcomings in constitutive equations for solids admitting localization of deformation at finite strains, i.e. their inability to provide physically acceptable solutions to boundary value problems in the post-localization range due to loss of ellipticity of the governing equations. Specifically, strain-induced localized deformation patterns are accounted for by adding a second deformation gradient-dependent term to the expression for the strain energy density. The modified strain energy function leads to equilibrium equations which remain always elliptic. Explicit solutions of these equations can be found for certain classes of deformations. They suggest not only the direction but also the width of the deformation bands providing for the first time a predictive unifying method for the study of pre- and post-localization behavior. The results derived here are a three-dimensional extension of certain one-dimensional findings reported earlier by the second author for the problem of simple shear.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42674/1/10659_2004_Article_BF00040814.pd

The Simple View of Reading Made Complex by Morphological Decoding Fluency in Bilingual Fourth-Grade Readers of English

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordThis study examined the complexity of the Simple View of Reading focusing on morphological decoding fluency in fourth-grade readers of English in Singapore. The participants were three groups of students who all learned to become bilingual and biliterate in the English language (EL) and their respective ethnic language in school but differed in the home language they used. The first group was ethnic Chinese students who used English as the dominant home language (Chinese EL1); the other two groups were ethnic Chinese and Malay students whose dominant home language was not English but Chinese (Chinese EL2) and Malay (Malay EL2), respectively. The measures included pseudo word decoding (phonemic decoding), timed decoding of derivational words (morphological decoding fluency), oral vocabulary, and passage comprehension. Path analysis showed that oral vocabulary significantly predicted reading comprehension across all three groups; yet a significant effect of morphological decoding fluency surfaced in the Chinese EL1 and Malay EL2 groups but not the Chinese EL2 group. Multi-group path analysis and commonality analysis further confirmed that morphological decoding played a larger role in the in the Chinese EL1 and Malay EL2 groups. These findings are discussed in light of the joint influence of target language experience and cross-linguistic influence on second language or bilingual reading development.Office of Education Research, National Institute of Education, Nanyang Technological Universit

Small-scale solar magnetic fields

As we resolve ever smaller structures in the solar atmosphere, it has become clear that magnetism is an important component of those small structures. Small-scale magnetism holds the key to many poorly understood facets of solar magnetism on all scales, such as the existence of a local dynamo, chromospheric heating, and flux emergence, to name a few. Here, we review our knowledge of small-scale photospheric fields, with particular emphasis on quiet-sun field, and discuss the implications of several results obtained recently using new instruments, as well as future prospects in this field of research.Comment: 43 pages, 18 figure

Multiwavelength studies of MHD waves in the solar chromosphere: An overview of recent results

The chromosphere is a thin layer of the solar atmosphere that bridges the relatively cool photosphere and the intensely heated transition region and corona. Compressible and incompressible waves propagating through the chromosphere can supply significant amounts of energy to the interface region and corona. In recent years an abundance of high-resolution observations from state-of-the-art facilities have provided new and exciting ways of disentangling the characteristics of oscillatory phenomena propagating through the dynamic chromosphere. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate the role waves play in supplying energy to sustain chromospheric and coronal heating. Here, we review the recent progress made in characterising, categorising and interpreting oscillations manifesting in the solar chromosphere, with an impetus placed on their intrinsic energetics.Comment: 48 pages, 25 figures, accepted into Space Science Review