Enzymatic, structural, and biophysical characterization of a single-domain antibody (VHH) selectively and tightly inhibiting neutrophil elastase and exhibiting favorable developability properties.

Human neutrophil elastase (hNE), a serine protease released by neutrophils during inflammation, plays a major role in the pathophysiology of several conditions especially in inflammatory lung diseases. Its inhibition constitutes, therefore, a promising therapeutic strategy to combat these diseases. In this work, we characterized the in vitro properties of a VHH (i.

Pharmacovigilance of nephrotoxic drugs in neonates: the Pottel method for acute kidney injury detection in ELBW neonates.

Background: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al.

Nebulization of PEGylated recombinant human deoxyribonuclease I using vibrating membrane nebulizers: A technical feasibility study.

Recombinant human deoxyribonuclease I (rhDNase, Pulmozyme®) is the most frequently used mucolytic agent for the symptomatic treatment of cystic fibrosis (CF) lung disease. Conjugation of rhDNase to polyethylene glycol (PEG) has been shown to greatly prolong its residence time in the lungs and improve its therapeutic efficacy in mice. To present an added value over current rhDNase treatment, PEGylated rhDNase needs to be efficiently and less frequently administrated by aerosolization and possibly at higher concentrations than existing rhDNase.

Development of Nanobodies as Theranostic Agents against CMY-2-Like Class C β-Lactamases.

Three soluble single-domain fragments derived from the unique variable region of camelid heavy-chain antibodies (VHHs) against the CMY-2 β-lactamase behaved as inhibitors. The structure of the complex VHH cAb(254)/CMY-2 showed that the epitope is close to the active site and that the CDR3 of the VHH protrudes into the catalytic site. The β-lactamase inhibition pattern followed a mixed profile with a predominant noncompetitive component.

Clinical and imaging findings, treatment details and outcomes in foals with extensor tendon rupture-A multicentre retrospective study.

Background: Forelimb extensor tendon rupture (ETR) in foals is sparsely documented.

Objectives: To describe clinical and imaging findings, treatment details, and long-term outcome in foals with ETR.

Study Design: Multicentre retrospective case-series.

Impact of the PEG length and PEGylation site on the structural, thermodynamic, thermal, and proteolytic stability of mono-PEGylated alpha-1 antitrypsin.

Conjugation to polyethylene glycol (PEG) is a widely used approach to improve the therapeutic value of proteins essentially by prolonging their body residence time. PEGylation may however induce changes in the structure and/or the stability of proteins and thus on their function(s). The effects of PEGylation on the thermodynamic stability can either be positive (stabilization), negative (destabilization), or neutral (no effect).

Radiotheranostic Agents in Hematological Malignancies.

Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities.

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry.

A non-internalised CD38-binding radiolabelled single-domain antibody fragment to monitor and treat multiple myeloma.

Background: Antibody-based therapies targeting CD38 are currently used as single agents as well as in combination regimens for multiple myeloma, a malignant plasma cell disorder. In this study, we aimed to develop anti-CD38 single-domain antibodies (sdAbs) that can be used to trace CD38 tumour cells and subsequently used for targeted radionuclide therapy. SdAbs are derived from Camelidae heavy-chain antibodies and have emerged as promising theranostic agents due to their favourable pharmacological properties.

Insights on peptide topology in the computational design of protein ligands: the example of lysozyme binding peptides.

Herein, we compared the ability of linear and cyclic peptides generated to target different protein sites: internal pockets and solvent-exposed sites. We selected human lysozyme (HuL) as a model target protein combined with the computational evolution of linear and cyclic peptides. The sequence evolution of these peptides was based on the PARCE algorithm.

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration.

Identifying which among several pharmacological activities is necessary for the proper activity is essential for further drug development against Alzheimer's disease pathophysiological processes. An in-depth structure-activity relationship-based study has been carried out, and two molecules, named MAGS02-14 and PEL24-199, that share a ß-secretase modulatory effect associated or not to a lysosomotropic activity in cellulo have been identified. In terms of chemical formulas, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom.

Transcutaneous auricular VNS applied to experimental pain: A paired behavioral and EEG study using thermonociceptive CO2 laser.

Background: Transcutaneous auricular Vagal Nerve Stimulation (taVNS) is a non-invasive neurostimulation technique with potential analgesic effects. Several studies based on subjective behavioral responses suggest that taVNS modulates nociception differently with either pro-nociceptive or anti-nociceptive effects.

Objective: This study aimed to characterize how taVNS alters pain perception, by investigating its effects on event-related potentials (ERPs) elicited by different types of spinothalamic and lemniscal somatosensory stimuli, combined with quantitative sensory testing (detection threshold and intensity ratings).

The lipopolysaccharide model for the experimental induction of transient lameness and synovitis in Standardbred horses.

An established lipopolysaccharide (LPS) model previously described in Warmbloods, was inconsistent in Standardbred horses, where lameness was not detected despite the presence of synovitis. The present study aimed to determine the dose of LPS from E. coli O55:B5 required to induce mild to moderate lameness following middle carpal joint injection in Standardbred horses and to quantitate the induced lameness over time, with and without anti-inflammatory pre-treatment.

Characterisation of the structural, dynamic and aggregation properties of the W64R amyloidogenic variant of human lysozyme.

The accumulation in vital organs of amyloid fibrils made of mutational variants of lysozyme (HuL) is associated with a human systemic amyloid disease. The detailed comparison of the in vitro properties of the I56T and D67H amyloidogenic variants to those of the T70N non-amyloidogenic variant and the wild-type (WT) protein suggested that the deposition of large amounts of aggregated disease-related lysozyme variants is initiated by the formation of transient intermediate species. The ability to populate such intermediates is essentially due to the destabilisation of the protein and the loss of the global structural cooperativity under physiologically relevant conditions.

Modeling Parkinson's Disease With the Alpha-Synuclein Protein.

Unlabelled: Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of α-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of α-Syn is associated with the dysfunctionality and degeneration of neurons in PD.

Accuracy of transcranial magnetic stimulation and a Bayesian latent class model for diagnosis of spinal cord dysfunction in horses.

Background: Spinal cord dysfunction/compression and ataxia are common in horses. Presumptive diagnosis is most commonly based on neurological examination and cervical radiography, but the interest into the diagnostic value of transcranial magnetic stimulation (TMS) with recording of magnetic motor evoked potentials has increased. The problem for the evaluation of diagnostic tests for spinal cord dysfunction is the absence of a gold standard in the living animal.

Reflections on professor Sir Christopher M. Dobson (1949-2019).

I have been invited to summarize my career with an emphasis on the time I spent in the laboratory of Prof Christopher M. Dobson, who sadly passed away on September 8th 2019, and to describe his role as a mentor. I accepted this slightly unusual request as it constitutes a unique way for me to express my deep gratitude and admiration for Chris.

Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.

Accumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored.

Aprotinin versus tranexamic acid in children undergoing cardiac surgery: an observational study.

Objectives: The upcoming release of aprotinin in paediatric cardiac surgery prompted a re-evaluation of its use in comparison to tranexamic acid (TXA) focusing on their effect on exposure to blood transfusions as well as severe postoperative morbidity or mortality.

Methods: This retrospective study was conducted in a tertiary children hospital from 2002 to 2015. Patients receiving aprotinin (Aprotinin group: 2002-2007) were compared with those receiving TXA group (2008-2015) using propensity score analysis.

Can the hoof be shod without limiting the heel movement? A comparative study between barefoot, shoeing with conventional shoes and a split-toe shoe.

Conventional shoeing restricts heel movement, which may have a negative effect on the orthopaedic health of the horse. A randomised crossover experimental study using noninvasive techniques was performed to compare the mediolateral heel movement in barefoot horses, horses shod with a conventional toe clipped shoe and with a new type of shoe with a split toe. In eight horses, 16 forelimbs were tested barefoot, shod with a conventional shoe and with the split-toe (ST) shoe, in random order.

The use of equine chondrogenic-induced mesenchymal stem cells as a treatment for osteoarthritis: A randomised, double-blinded, placebo-controlled proof-of-concept study.

Background: There is a need to improve therapies for osteoarthritis in horses.

Objectives: To assess the efficacy of equine allogeneic chondrogenic-induced mesenchymal stem cells combined with equine allogeneic plasma as a novel therapy for osteoarthritis in horses.

Study Design: Randomised, double-blinded, placebo-controlled experiment.

Separation and determination of alpha-synuclein monomeric and oligomeric species using two electrophoretic approaches.

Parkinson's disease (PD) is a frequent degenerative disorder that is diagnosed based on clinical symptoms. When the first symptoms appear, more than 70% of the dopaminergic cells are already lost. Therefore, it is of utmost importance to have reliable biomarkers to diagnose much earlier PD.

Mass and charge distributions of amyloid fibers involved in neurodegenerative diseases: mapping heterogeneity and polymorphism.

Heterogeneity and polymorphism are generic features of amyloid fibers with some important effects on the related disease development. We report here the characterization, by charge detection mass spectrometry, of amyloid fibers made of three polypeptides involved in neurodegenerative diseases: Aβ peptide, tau and α-synuclein. Beside the mass of individual fibers, this technique enables to characterize the heterogeneity and the polymorphism of the population.

Combinatorial Design of a Nanobody that Specifically Targets Structured RNAs.

Recent advances in transcriptome sequencing and analysis have revealed the complexity of the human genome. The majority (≈ 98%) of cellular transcripts is not translated into proteins and represents a vast, unchartered world of functional non-coding RNAs. Most of them adopt a well-defined three-dimensional structure to achieve their biological functions.

Equine allogeneic chondrogenic induced mesenchymal stem cells: A GCP target animal safety and biodistribution study.

The safety of the intra-articular use of mesenchymal stem cells (MSCs) is scarcely reported. Therefore, the goal of this study was to investigate the safety of a single intra-articular injection with allogeneic chondrogenic induced MSCs combined with equine plasma (=the investigational product: IVP) compared to a saline (0.9% NaCl) placebo control (=control product: CP).