Deep-learning-based 2.5D flow field estimation for maximum intensity projections of 4D optical coherence tomography

In microsurgery, lasers have emerged as precise tools for bone ablation. A challenge is automatic control of laser bone ablation with 4D optical coherence tomography (OCT). OCT as high resolution imaging modality provides volumetric images of tissue and foresees information of bone position and orientation (pose) as well as thickness. However, existing approaches for OCT based laser ablation control rely on external tracking systems or invasively ablated artificial landmarks for tracking the pose of the OCT probe relative to the tissue. This can be superseded by estimating the scene flow caused by relative movement between OCT-based laser ablation system and patient. Therefore, this paper deals with 2.5D scene flow estimation of volumetric OCT images for application in laser ablation. We present a semi-supervised convolutional neural network based tracking scheme for subsequent 3D OCT volumes and apply it to a realistic semi-synthetic data set of ex vivo human temporal bone specimen. The scene flow is estimated in a two-stage approach. In the first stage, 2D lateral scene flow is computed on census-transformed en-face arguments-of-maximum intensity projections. Subsequent to this, the projections are warped by predicted lateral flow and 1D depth flow is estimated. The neural network is trained semi-supervised by combining error to ground truth and the reconstruction error of warped images with assumptions of spatial flow smoothness. Quantitative evaluation reveals a mean endpoint error of (4.7 ± 3.5) voxel or (27.5 ± 20.5) μm for scene flow estimation caused by simulated relative movement between the OCT probe and bone. The scene flow estimation for 4D OCT enables its use for markerless tracking of mastoid bone structures for image guidance in general, and automated laser ablation control. © 2019 SPIE

Impaired Chromatin Remodelling at STAT1-Regulated Promoters Leads to Global Unresponsiveness of Toxoplasma gondii-Infected Macrophages to IFN-γ

Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites' replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors

NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions

Toxoplasma gondii Clonal Strains All Inhibit STAT1 Transcriptional Activity but Polymorphic Effectors Differentially Modulate IFN gamma Induced Gene Expression and STAT1 Phosphorylation

Host defense against the parasite Toxoplasma gondii requires the cytokine interferon-gamma (IFNγ). However, Toxoplasma inhibits the host cell transcriptional response to IFNγ, which is thought to allow the parasite to establish a chronic infection. It is not known whether all strains of Toxoplasma block IFNγ-responsive transcription equally and whether this inhibition occurs solely through the modulation of STAT1 activity or whether other transcription factors are involved. We find that strains from three North American/European clonal lineages of Toxoplasma, types I, II, and III, can differentially modulate specific aspects of IFNγ signaling through the polymorphic effector proteins ROP16 and GRA15. STAT1 tyrosine phosphorylation is activated in the absence of IFNγ by the Toxoplasma kinase ROP16, but this ROP16-activated STAT1 is not transcriptionally active. Many genes induced by STAT1 can also be controlled by other transcription factors and therefore using these genes as specific readouts to determine Toxoplasma inhibition of STAT1 activity might be inappropriate. Indeed, GRA15 and ROP16 modulate the expression of subsets of IFNγ responsive genes through activation of the NF-κB/IRF1 and STAT3/6 transcription factors, respectively. However, using a stable STAT1-specific reporter cell line we show that strains from the type I, II, and III clonal lineages equally inhibit STAT1 transcriptional activity. Furthermore, all three of the clonal lineages significantly inhibit global IFNγ induced gene expression

Conductive Hybrid Cu-HHTP-TCNQ Metal–Organic Frameworks for Chemiresistive Sensing

Electrically conductive metal–organic frameworks (MOFs) and MOF-like coordination polymers are an emerging class of materials that combine good electrical charge transport with unique properties such as nanoporosity. The combination of different metal nodes and organic linkers allows tailoring MOFs to specific properties and applications in electronics, like selective chemiresistive sensing. The intrinsic crystallinity of MOFs, which usually promotes efficient charge transport, makes them also difficult to integrate into flexible systems, as crystalline MOFs are often brittle. The present study reports on a fast and reliable interfacial synthesis of conductive MOF films composed of two different organic ligands, 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) and 7,7,8,8-tetracyanoquinodimethane (TCNQ), lacking long-range periodic order while preserving good electrical conductivity of 0.033 S cm−1 at room temperature and chemiresistive response toward ambient changes. The hybrid nature of the discontinuous film is investigated multiparametrically by electron and atomic force microscopy as well as by Raman spectroscopy. This study demonstrates that including different types of MOFs is a good compromise between structural order and conductivity, thus making hybrid framework architectures to a promising active material for chemiresistive sensors without the need for high crystallinity

Minimally invasive mastoidectomy approach using a mouldable surgical targeting system: a proof of concept

Hearing restoration using a cochlear implant requires a surgical access to the inner ear. In order to enhance patient safety, reduce trauma, and shorten the patient’s time under anaesthesia current research focusses on minimally invasive cochlear implantation surgery by drilling only a single bore hole. This demands a highly accurate surgical assistance device to guide the drill along a predetermined trajectory planned in patient’s image data. In this study a recently developed surgical targeting system was evaluated for the first time in a human cadaver trial. After screwing a reference frame on a temporal bone specimen and imaging of both, a trajectory through the facial recess was planned in order to reach the middle ear. Based on this plan a patient specific surgical template including a linear guide for the surgical drill was composed utilizing bone cement. After the hardening of the bone cement the surgical template was mounted on top of the reference frame. The drilling could be performed as previously planned without harming facial nerve and chorda tympani. The deviation of the actual drill hole to the planned trajectory was 0.17 mm at the level of the facial recess. The minimal distance of the drill hole to the facial nerve was 0.59 mm. This proof-of-concept study demonstrates the feasibility of performing the access to the middle ear in a minimally invasive manner using the mouldable surgical targeting system. The presented process allows the patient specific individualization of a drill guide under sterile conditions. This might facilitate its integration into clinical routine

Optimal error estimation for H(curl)-conforming p-interpolation in two dimensions

In this paper we prove an optimal error estimate for the H(curl)-conforming projection based p-interpolation operator introduced in [L. Demkowicz and I. Babuska, p interpolation error estimates for edge finite elements of variable order in two dimensions, SIAM J. Numer. Anal., 41 (2003), pp. 1195-1208]. This result is proved on the reference element (either triangle or square) K for regular vector fields in H^r(curl,K) with arbitrary r>0. The formulation of the result in the H(div)-conforming setting, which is relevant for the analysis of high-order boundary element approximations for Maxwell's equations, is provided as well