Harnessing spatial homogeneity of neuroimaging data: patch individual filter layers for CNNs

Neuroimaging data, e.g. obtained from magnetic resonance imaging (MRI), is comparably homogeneous due to (1) the uniform structure of the brain and (2) additional efforts to spatially normalize the data to a standard template using linear and non-linear transformations. Convolutional neural networks (CNNs), in contrast, have been specifically designed for highly heterogeneous data, such as natural images, by sliding convolutional filters over different positions in an image. Here, we suggest a new CNN architecture that combines the idea of hierarchical abstraction in neural networks with a prior on the spatial homogeneity of neuroimaging data: Whereas early layers are trained globally using standard convolutional layers, we introduce for higher, more abstract layers patch individual filters (PIF). By learning filters in individual image regions (patches) without sharing weights, PIF layers can learn abstract features faster and with fewer samples. We thoroughly evaluated PIF layers for three different tasks and data sets, namely sex classification on UK Biobank data, Alzheimer's disease detection on ADNI data and multiple sclerosis detection on private hospital data. We demonstrate that CNNs using PIF layers result in higher accuracies, especially in low sample size settings, and need fewer training epochs for convergence. To the best of our knowledge, this is the first study which introduces a prior on brain MRI for CNN learning

Effects of dimethyl fumarate on neuroprotection and immunomodulation

BACKGROUND: Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects. FINDINGS: We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays. CONCLUSIONS: These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity

3D-визуализация в ультразвуковой дефектоскопии

На сегодняшний день существует множество средств визуализации ультразвуковых данных, но все они, как правило, интегрированы в дефектоскопы. Когда у нас возникает потребность извлечь данные сканирования, произвести собственную обработку, и представить в трехмерном изображении, то мы оказываемся лишенными возможности визуализации. Предложенное программное обеспечение на основе алгоритма SAFT позволяет произвести постобработку данных сканирования (А-сканов) и двумерную и трехмерную визуализацию

Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders

Single‐cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma

Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM‐associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient‐derived GBM stem cell cultures and combined single‐cell RNA sequencing of GAM‐GBM co‐cultures and real‐time in vivo monitoring of GAM‐GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM‐induced GAM polarization and the ability to attract and activate GAMs—features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock‐out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM‐GBM interactions can be studied in a clinically relevant way using co‐cultures and avatar models, while offering new opportunities to identify promising immune‐modulating targets.Deutsche Forschungsgemeinschaft (DFG)Fondation Leducq (Leducq Foundation) http://dx.doi.org/10.13039/501100001674Fonds Wetenschappelijk Onderzoek (FWO) http://dx.doi.org/10.13039/501100003130Helmholtz ImagingHHS ¦ National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002iNAMES (Imaging from NAno to MESo)Kom op tegen Kanker (Fight Cancer) http://dx.doi.org/10.13039/501100011851KU Leuven (Katholieke Universiteit Leuven) http://dx.doi.org/10.13039/501100004040Vlaamse Overheid (Government of Flanders) http://dx.doi.org/10.13039/501100002913VSC (Vlaams Supercomputer Centrum/Flemish Supercomputer Center)Peer Reviewe

Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study

Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy-or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse-free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate

Digitale Schwellen: Freiheit und Privatheit in der digitalisierten Welt

Eine Welt digitaler Techniken im weitesten Sinne verändert die Kommunikationsbeziehungen, die sozialen Beziehungen der Menschen untereinander und damit auch die sozialen Verhältnisse der Menschen in der Gesellschaft in fundamentaler Weise. Wir stehen ganz offensichtlich erst an der Schwelle des Verstehens dieser komplexen und alle Lebensbereiche verändernden Revolution. Die technischen Möglichkeiten, die unser Leben ja auch erleichtern können und schöner und klüger machen, werden in großer Geschwindigkeit erweitert, immer neue Schwellen des Mach- und Denkbaren werden permanent überschritten. Redaktionsschluss: April 201

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Interleukin-6 receptor blockade in treatment-refractory MOG-IgG–associated disease and neuromyelitis optica spectrum disorders

BACKGROUND AND OBJECTIVES: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS: Patients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD