Three-dimensional quantification of soft tissue changes and its relationship to skeletal changes after Le Fort III, monobloc, and facial bipartition in syndromic craniosynostosis

To determine the effect of midface surgery on soft tissue changes and their relationship to hard tissue changes in patients with syndromic craniosynostosis. A retrospective analysis of patients who had undergone Le Fort III (LFIII), monobloc (MB), or facial bipartition (FB) was conducted. A 3D soft tissue mesh was generated from the preoperative scan and registered to the postoperative scan, after which the advancement was visualised. A total of 68 patients were included: 28 had undergone LFIII, 27 MB, and 13 FB. The included diagnoses were Apert (n = 23), Crouzon (n = 34), and craniofrontonasal syndrome (n = 11). After LFIII, most soft tissue advancement was seen around subnasale and pronasale (mean 15.1 ± 5.9 mm and 14.7 ± 5.7 mm, at age 7–12 years). After MB, a greater hard tissue than soft tissue advancement was seen for most landmarks, showing a high positive correlation. In patients undergoing FB without distraction (n = 10), mean preoperative inter-canthal distance was 48.9 mm, this reduced by 6.9 mm postoperatively. This study provides a comprehensive overview of the outcomes after midface surgery using 3D quantification for a better understanding of the soft tissue changes and their relationship to hard tissue changes.</p

Numerical models of collisions between core-collapse supernovae and circumstellar shells

Recent observations of luminous Type IIn supernovae (SNe) provide compelling evidence that massive circumstellar shells surround their progenitors. In this paper we investigate how the properties of such shells influence the SN lightcurve by conducting numerical simulations of the interaction between an expanding SN and a circumstellar shell ejected a few years prior to core collapse. Our parameter study explores how the emergent luminosity depends on a range of circumstellar shell masses, velocities, geometries, and wind mass-loss rates, as well as variations in the SN mass and energy. We find that the shell mass is the most important parameter, in the sense that higher shell masses (or higher ratios of M_shell/M_SN) lead to higher peak luminosities and higher efficiencies in converting shock energy into visual light. Lower mass shells can also cause high peak luminosities if the shell is slow or if the SN ejecta are very fast, but only for a short time. Sustaining a high luminosity for durations of more than 100 days requires massive circumstellar shells of order 10 M_sun or more. This reaffirms previous comparisons between pre-SN shells and shells produced by giant eruptions of luminous blue variables (LBVs), although the physical mechanism responsible for these outbursts remains uncertain. The lightcurve shape and observed shell velocity can help diagnose the approximate size and density of the circumstellar shell, and it may be possible to distinguish between spherical and bipolar shells with multi-wavelength lightcurves. These models are merely illustrative. One can, of course, achieve even higher luminosities and longer duration light curves from interaction by increasing the explosion energy and shell mass beyond values adopted here.Comment: Accepted for publication in MNRAS. Tables of numerical results (SN lightcurves and velocities) to be published online. (Updated to fix figures

In Situ EXAFS Study of Sr Adsorption on TiO2(110) under High Ionic Strength Wastewater Conditions

In order to provide important details concerning the adsorption reactions of Sr, batch reactions and a set of both ex situ and in situ Grazing Incidence X-ray Absorption Fine Structure (GIXAFS) adsorption experiments were completed on powdered TiO2 and on rutile(110), both reacted with either SrCl2 or SrCO3 solutions. TiO2 sorption capacity for strontium (Sr) ranges from 550 ppm (SrCl2 solutions, second order kinetics) to 1400 ppm (SrCO3 solutions, first order kinetics), respectively, and is rapid. Sr adsorption decreased as a function of chloride concentration but significantly increased as carbonate concentrations increased. In the presence of carbonate, the ability of TiO2 to remove Sr from the solution increases by a factor of ~4 due to rapid epitaxial surface precipitation of an SrCO3 thin film, which registers itself on the rutile(110) surface as a strontianite-like phase (d-spacing 2.8 &Aring;). Extended X-ray Absorption Fine Structure (EXAFS) results suggest the initial attachment is via tetradental inner-sphere Sr adsorption. Moreover, adsorbates from concentrated SrCl2 solutions contain carbonate and hydroxyl species, which results in both inner- and outer-sphere adsorbates and explains the reduced Sr adsorption in these systems. These results not only provide new insights into Sr kinetics and adsorption on TiO2 but also provide valuable information concerning potential improvements in effluent water treatment models and are pertinent in developing treatment methods for rutile-coated structural materials within nuclear power plants

What is the price of using the Price equation in ecology?

The Dialogue series is intended to promote critical thinking and the expression of contrasting or even opposing viewpoints on important ecological topics. Here, seven researchers debate the use of the Price equation, a framework that has long been used in evolution to analyze temporal changes in the frequency of traits and alleles. This Dialogue describes different philosophical and mathematical perspectives on the application of the Price equation to ecological questions such as the relationship between biodiversity and ecosystem functioning (BEF). The hope is that the broader scientific community will benefit from these contrasting viewpoints

Skeletal changes after midface surgery in patients with craniofacial deformities:a threedimensional quantification method

To determine the skeletal changes after midface surgery in patients with syndromic craniosynostosis who underwent Le Fort III (LFIII), monobloc (MB), or facial bipartition (FB). This was a retrospective study including 75 patients: 33 treated by LFIII, 29 by MB, and 13 by FB. Twenty-five had a diagnosis of Apert, 39 Crouzon, and 11 craniofrontonasal syndrome. A three-dimensional mesh was created from the preoperative scan and registered to the postoperative scan to visualise the advancement. LFIII at age 7–12 years effectuated a higher mean advancement in the maxillary (15.5 mm) and zygomatic (7.6 mm) regions when compared to ≥13 years (10.2 mm and 5.5 mm). After MB, mean advancement of the fronto-orbital region was higher at &lt;7 years (16.4 mm), and similarly lower at ages 7–12 (13.8 mm) and ≥13 (12.5 mm). The mean preoperative inter-dacryon distance (34.4 ± 4.4 mm) was reduced by 8.7 ± 4.2 mm after FB without distraction (n = 10). More advancement was seen when midface surgery was performed at a younger age, due to more severe cases and a desire for overcorrection. The highest mean advancement was observed in the fronto-orbital region. Antero-inferior rotational movement was seen after all three techniques.</p

In and Out of Equilibrium II: Evolution in Repeated Games with Discounting and Complexity Costs

We explore evolutionary dynamics for repeated games with small, but positive complexity costs. To understand the dynamics, we extend a folk theorem result by Cooper (1996) to continuation probabilities, or discount rates, smaller than 1. While this result delineates which payoffs can be supported by neutrally stable strategies, the only strategy that is evolutionarily stable, and has a uniform invasion barrier, is All D. However, with sufficiently small complexity costs, indirect invasions - but now through 'almost neutral' mutants - become an important ingredient of the dynamics. These indirect invasions include stepping stone paths out of full defection

Proteomic analysis identifies FNDC1, A1BG, and antigen processing proteins associated with tumor heterogeneity and malignancy in a canine model of breast cancer

Simple Summary Comparative oncology is centered around the study of naturally occurring tumors in animals as a parallel and complementary model for human cancer research. Canine mammary tumors pose as excellent models since they share similarities in their spontaneous nature, histological subtypes, genetic background, and clinical course, which would be impossible to reproduce in murine models. Our study aimed to investigate cancer heterogeneity in primary tumors and metastasis, by applying bottom-up proteomics and mass spectrometry imaging to identify potential disease-state markers. We have demonstrated that the malignant phenotype may have arisen as a consequence of alterations in the expression of proteins involved in immune evasion facilitating metastatic events. To our knowledge, this is the first study to use mass spectrometry imaging in a dog model of breast cancer, that have demonstrated that poorly described proteins might play important roles in cancer spreading and should be further validated as potential early-stage tumor biomarkers. New insights into the underlying biological processes of breast cancer are needed for the development of improved markers and treatments. The complex nature of mammary cancer in dogs makes it a great model to study cancer biology since they present a high degree of tumor heterogeneity. In search of disease-state biomarkers candidates, we applied proteomic mass spectrometry imaging in order to simultaneously detect histopathological and molecular alterations whilst preserving morphological integrity, comparing peptide expression between intratumor populations in distinct levels of differentiation. Peptides assigned to FNDC1, A1BG, and double-matching keratins 18 and 19 presented a higher intensity in poorly differentiated regions. In contrast, we observed a lower intensity of peptides matching calnexin, PDIA3, and HSPA5 in poorly differentiated cells, which enriched for protein folding in the endoplasmic reticulum and antigen processing, assembly, and loading of class I MHC. Over-representation of collagen metabolism, coagulation cascade, extracellular matrix components, cadherin-binding and cell adhesion pathways also distinguished cell populations. Finally, an independent validation showed FNDC1, A1BG, PDIA3, HSPA5, and calnexin as significant prognostic markers for human breast cancer patients. Thus, through a spatially correlated characterization of spontaneous carcinomas, we described key proteins which can be further validated as potential prognostic biomarkers.Proteomic

Monitoring glycation levels of a bispecific monoclonal antibody at subunit level by ultrahigh resolution MALDI FT-ICR mass spectrometry

Bispecific monoclonal antibodies (BsAbs) are engineered proteins with multiple functionalities and properties. The "bi-specificity" of these complex biopharmaceuticals is a key characteristic for the development of novel and more effective therapeutic strategies. The high structural complexity of BsAbs poses a challenge to the analytical methods needed for their characterization. Modifications of the BsAb structure, resulting from enzymatic and non-enzymatic processes, further complicate the analysis. An important example of the latter type of modification is glycation, which can occur in the manufacturing process, during storage in formulation or in vivo after application of the drug. Glycation affects the structure, function and stability of monoclonal antibodies, and consequently, detailed analysis of glycation levels is required. Mass spectrometry (MS) plays a key role in the structural characterization of monoclonal antibodies and top-down, middle-up and middle-down MS approaches are increasingly used for the analysis of modifications. Here, we apply a novel middle-up strategy, based on IdeS digestion and matrix-assisted laser desorption ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) MS, to analyze all six different BsAb subunits in a single high-resolution mass spectrum, namely two light chains, two half fragment crystallizable regions and two Fd’ regions, thus avoiding upfront chromatography. This method was used to monitor glycation changes during a 168h forced-glycation experiment. In addition, hot spot glycation sites were localized using top-down and middle-down MALDI-in-source decay FT-ICR MS, which provided complementary information compared to standard bottom-up MS

Small-molecule activity-based probe for monitoring ubiquitin C-terminal hydrolase L1 (UCHL1) activity in live cells and zebrafish embryos

Many reagents have emerged to study the function of specific enzymes in vitro. On the other hand, target specific reagents are scarce or need improvement, allowing investigations of the function of individual enzymes in their native cellular context. Here we report the development of a target-selective fluorescent small-molecule activity-based DUB probe that is active in live cells and an in vivo animal model. The probe labels active ubiquitin carboxy-terminal hydrolase L1 (UCHL1), also known as neuron-specific protein PGP9.5 (PGP9.5) and Parkinson disease 5 (PARK5), a DUB active in neurons that constitutes 1 to 2% of the total brain protein. UCHL1 variants have been linked with neurodegenerative disorders Parkinson's and Alzheimer's diseases. In addition, high levels of UCHL1 also correlate often with cancer and especially metastasis. The function of UCHL1 activity or its role in cancer and neurodegenerative disease is poorly understood and few UCHL1-specific activity tools exist. We show that the reagents reported here are specific to UCHL1 over all other DUBs detectable by competitive activity-based protein profiling and by mass spectrometry. Our cell-penetrable probe, which contains a cyanimide reactive moiety, binds to the active-site cysteine residue of UCHL1 in an activity-dependent manner. Its use is demonstrated by the fluorescent labeling of active UCHL1 both in vitro and in live cells. We furthermore show that this probe can selectively and spatiotemporally report UCHL1 activity during the development of zebrafish embryos. Our results indicate that our probe has potential applications as a diagnostic tool for diseases with perturbed UCHL1 activity.Cancer Signaling networks and Molecular Therapeutic

Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis

Background: HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified. Objectives: The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls. Methods: We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls. Results: We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients. Conclusions: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG